Mohamad Miqdady
Mohamad Miqdady
Dr. Natalia Spierings
Dr. Natalia Spierings
Conference Series organizes the 25th International Conference on Dermatology & Skin Care on April 27-28, 2020 on Amsterdam, Netherlands. The milestone of the conference is to build strong networking with individuals from different countries and exchange the knowledge they have gained in the field of Dermatology and Skin Care After all, Dermatology is a field that is growing steadily and has the potential value for the products in the world market. The organization provides a great chance for the experts who seek future in the field of Dermatology and shows various applications and possibilities
from different minds.
INTRODUCTION: In 2015 just about 6,000,000 kids passed on all around before the age of five. Over half passed on from preventable irresistible ailments. In spite of the fact that immunizations decrease horribleness and mortality, a few guardians don't inoculate their kids. While in creating nations absence of access to immunization and family attributes, for example, low training, education and financial status make up most of reasons why youngsters are not inoculated, in created nations guardians settle on cognizant choices not to utilize promptly accessible immunizations. Seeing how to energize take-up is an significant general wellbeing point.
Numerous investigations around there are guided by an unequivocal hypothesis of conduct change (for example, which recognize factors which may foresee immunization conduct. Antibody refusal has been related with: saw expenses of inoculation, for example, accepting that immunizations cause short-or long haul symptoms or are inadequate; attitudinal factors, for example, accepting that youngsters get an excessive number of inoculations and that immunizations over-burden the invulnerable framework; struggle with strict convictions ; doubt of social insurance frameworks and governments; and enthusiastic factors, for example, liking to endure the negative outcomes of inaction rather than those brought about by immunizing. Different elements incorporate overlooking and not realizing that the youngster needs an immunization promoter. Past writing surveys have concentrated on immunizations, for example, MMR and HPV. Be that as it may, it is hard to sum up these discoveries to every single routine immunization. We utilized a methodical survey to recognize mental, social and relevant variables influencing the take-up of routine youth inoculation for solid kids matured 5 and under in high-pay nations.
Method: We did an audit as per PRISMA measures. We looked Embase, Medline, PsycINFO, Maternity and Baby Care, Health Management Information Consortium and Social Policy and Practice through OvidSP, and Scopus. Databases were looked from beginning to the 22nd November 2016. We utilized the accompanying hunt terms: ((vaccine⁄ OR innocul⁄ OR immunis⁄ ) AND (child⁄ OR infant OR newborn child OR infant) AND (take-up OR adherence OR consistence OR decision⁄ OR hesitanc⁄ OR concern Or then again question)). Where conceivable, we restricted the pursuit to human examinations. A MeSH expressions search yielded 52,429 references. Checking an irregular example of 100 of these yielded no applicable papers. The MeSH search was in this way surrendered as unfeasible.
Consideration standards
Consideration standards were:
Members: Studies were incorporated if kids were matured five or under. Studies were barred if kids were enlisted due to previous sick wellbeing.
Indicators/Exposures: Studies were incorporated on the off chance that they introduced information on the relationship between conceivable mental indicators furthermore, youth immunization, or gave a quantitative record of guardians' self-detailed purposes behind or against inoculation. Studies introducing just segment indicators or indicators identified with the method of conveyance of data, nearness of a mediation (such as sending an update for the arrangement) or recurrence of inoculation arrangement updates were rejected.
Results: Studies were incorporated in the event that they introduced information on take-up of a named antibody and if the immunization was business as usual inoculation plan for that locale.
Study announcing: Studies utilizing quantitative system and led in high-pay nations (as characterized by the World Bank) were incorporated. For down to earth reasons, we included just investigations distributed in English.
Information extraction
For each examination, we extricated insights about nation, study structure, immunization, mental indicators of take-up and reasons for and against immunization.
Danger of inclination
Danger of inclination was evaluated utilizing an adjustment of the Downs and Dark agenda, which is reasonable for use in precise surveys and has been approved. Things identifying with mediations were dropped as they were not pertinent to any included investigation.
Results:
Study qualities
Following screening, sixty-eight references were incorporated in the audit, depicting sixty-four investigations. Studies were directed in twelve nations and explored thirteen immunizations. Thirty-seven examinations utilized cross-sectional structures, fifteen utilized case-control plans and twelve utilized accomplice structures.
Danger of predisposition
Scores on the corrected Downs and Black agenda ran somewhere in the range of two and eighteen out of a potential nineteen, with a middle score of thirteen. Just ten investigations announced a force estimation. Forty-nine examinations scored inadequately for outside legitimacy; twenty-eight scored inadequately for revealing; eight scored inadequately for inward legitimacy (predisposition); and six scored inadequately for frustrating (choice predisposition). Scores for singular examinations are appeared in the advantageous materials.
Mental, social and relevant indicators of take-up
Indicators and purposes behind or against immunizing are summed up. Just balanced examinations are accounted for, where pertinent.
Impression of antagonistic impacts from inoculation
There is solid proof for a relationship between recognition of antagonistic impacts and inoculation. Self-detailed explanations behind not inoculating included: accepting the antibody to cause reactions or to be dangerous; trusting one's kid to be oversensitive to the immunization; past experience of the youngster or another person encountering reactions; accepting that antibodies are perilous or cause injury; being worried about the kid getting sick because of inoculation. In spite of the fact that proposals express that youngsters can be inoculated in the event that they are somewhat sick, guardians in nine examinations announced not immunizing their kid on the grounds that they were unwell. Explanations behind inoculation incorporated that guardians themselves had been immunized without inconvenience and that inoculation would not hurt the kid regardless of whether it didn't profit them.
Twelve of fifteen investigations saw a relationship between seeing immunization as dangerous and antibody refusal. Four investigations were acceptable quality; every one of those not finding an affiliation were moderate quality. Eleven of fourteen investigations found an affiliation between seeing an antibody to cause reactions and immunization refusal. Every one of the fourteen were moderate or acceptable quality. An affiliation was found between immunization refusal and the kid being sick at the hour of immunization also, the conviction that the youngster is frequently too sick to even think about receiving immunizations. One examination found that accepting a youngster can't be inoculated in the event that they are sick without a fever was related with immunization status, though another didn't. These were of moderate also, great quality separately. Another investigation found an affiliation among refusal and accepting that inoculation is increasingly perilous than the sickness.
Discussion: This is the primary complete audit portraying mental, social and logical elements related with inoculation in youthful kids. In accordance with discoveries from past audits of kid inoculation and more extensive surveys of medicine adherence, seeing inoculation to cause unfriendly impacts was reliably related with immunization refusal. Numerous top notch papers discovered this affiliation and it was likewise the most ordinarily self-announced explanation against inoculation. While there was solid proof of a relationship between low apparent weakness to a sickness and immunization refusal, proof for a job of apparent ailment seriousness was frail. This might be on the grounds that guardians will initially consider whether their kid is vulnerable to a disease before thinking about how serious the sickness might be. Future interchanges should concentrate on youngsters' helplessness to a disease instead of seriousness of the ailment
This is the principal precise audit recognizing mental indicators of take-up of routine youngster immunizations. Our outcomes show that to improve take-up, correspondences to guardians should address worries over immunizations making unfriendly impacts and spotlight on kids' weakness the sickness just as advancing the conviction that the immunization is viable. Expanding guardians' information on the immunization plan and guaranteeing all medicinal services suppliers suggest inoculation may likewise build take-up. More examination on the impact of various wellsprings of data is expected to decide the most ideal approach to disperse data to guardians.
NOTE: This work is partly presented at 36th Euro Global Summit and Expo on Vaccines & Vaccination, June 03-04, 2019 held at London, UK
Background: The CSANZ Heart Failure (HF) guidelines state that sodium-glucose co-transporter-2 inhibitors (SGLT2i) are the preferred second line agent in patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease to reduce CV events and HF hospitalisation.
Aim: To review glucose lowering therapies in patients with T2DM who had been hospitalised with HF at Austin Health, and the percentage of patients who may be eligible for SGLT2i therapy.
Methods: A retrospective analysis of glucose lowering therapies in patients with a discharge diagnosis of HF and T2DM from 1/1/2016 to 31/12/2018. Eligibility for SGLT2i therapy was based on insufficient glycaemic control (HbA1c ³7%), eGFR ³30 mL/min/1.73m2 and age £84 years.
Results: We identified 1182 patients with T2DM who had a discharge diagnosis of HF. After exclusion of patients aged >84 years, eGFR <30 mL/min/1.73m2 and/or HbA1c <7%, 318 (27%) patients were potentially eligible for SGLT2i therapy. Of these, 36 were already on SGLT2i therapy leaving 282 (24%) patients eligible for SGLT2i therapy. They had a mean (±SD) age of 70±10 years and HbA1c of 8.6±1.8%. Medication for heart failure included diuretics (94%), ACEi/ARB (58%), beta blockers (72%). Patients were on a median of 2 glucose lowering agernts including metformin (61%), sulfonylureas (35%), gliptins (23%), GLP-1 analogues (4%), insulin (71%).
Fasting blood glucose, postprandial blood glucose and glycated haemoglobin are considered three important indicators for diabetes treatment. There is increasing evidence that glucose variability has more detrimental effects on the coronary arteries than does chronic sustained hyperglycaemia. This overview summarises recent findings in the field of glucose variability and its possible relationship with coronary artery disease. Glucose variability may be a marker of increased progression of coronary disease and plaque vulnerability. It might be a potential new therapeutic target for secondary prevention of coronary artery disease. Future studies will focus on the early detection and control of glucose variability to improve the clinical outcomes in patients with coronary artery disease. This is a retrospective observational study utilising data collected after patients had left the hospital. This study was performed on 137 non-diabetic patients undergoing coronary artery bypass grafting from January 2011 to June 2013. Blood glucose at 72 hours post operation was obtained and glucose variability was measured by mean postoperative blood glucose and mean of daily difference (MODD). Short-term outcomes included duration of intensive care unit (ICU) stay, mechanical ventilation time, length of hospital stay, and occurrence of arrhythmia. Patients with mean postoperative blood glucose ≥7.00 mmol/L were defined as hyperglycaemic, and patients with MODD ≥1.40 mmol/L were considered to be abnormal. Outcome variables were compared between patients in euglycaemic and hyperglycaemic groups, and between patients in normal and abnormal groups.
The diabetic heart is a complex entity with multiple contributing mechanisms. One of these mechanisms is the increased flux through the hexosamine biosynthesis pathway leading to O-GlcNAc post–translational modification, which has emerged as a potential therapeutic target. Two enzymes regulate this post–translational modification: O-GlcNAc transferase (OGT) facilitates the addition of the O-GlcNAc substrate to Ser/Thr residues, and O-GlcNAcase (OGA) facilitates its removal. The aim of the current study was to investigate the role of cardiac O-GlcNAc signalling in the diabetic heart. Streptozotocin-induced diabetic mice were administered a single intravenous injection of recombinant-adeno-associated-virus-6 (rAAV6)-O-GlcNAc transferase (OGT), rAAV6-O-GlcNAc-ase (OGA), or empty null-vector (2 × 10 11 vg each). Mice were then maintained for a further 8 weeks before further in vivo/ex vivo analyses. Administration of rAAV6-OGT to non–diabetic mice impaired left ventricular (LV) diastolic function (↓E/A 20 ±Ã¢Â€Â…10%), increased cardiac collagen content (↑177 ±Ã¢Â€Â…5%), and gene ANP expression (↑155 ±Ã¢Â€Â…73%), resembling the characteristics of diabetic cardiomyopathy (all p<0.05 vs sham-null). In contrast, administration of rAAV6-OGA to diabetic mice limited LV diastolic dysfunction (↑E/A 29 ±Ã¢Â€Â…15%; p = 0.05) and cardiac fibrosis (↓collagen content 73 ±Ã¢Â€Â…13%; p < 0.001). A more marked improvement was evident with the higher dose of rAAV6-OGA (1 × 10 12 vg) diabetic mice (↑E/A 39 ±Ã¢Â€Â…15%, ↓LV collagen 57 ±Ã¢Â€Â…10% and ↓ANP 34 ±Ã¢Â€Â…16%; p < 0.05, p < 0.001, and p = 0.06, respectively, vs diabetic-null). This marked improvement seen in high-dose rAAV6-OGA treated diabetic mice was accompanied by restoration of cardiac PI3Ka and its downstream target Akt signalling. In conclusion, we demonstrate that cardiac O-GlcNAc modification play a vital role in modulating characteristics of diabetic cardiomyopathy, and may represent a novel therapeutic approach for diabetes-induced heart failure.
Conclusion: As many as 24% of patients with T2D and HF seen in in real world clinical practice are eligible for SGLT2i therapy. We suggest that increasing familiarity and utilisation of SGLT2i may improve cardiovascular outcomes in this high-risk population. In our study, patients with hyperglycaemia spent more time staying in ICU ( p< 0.01), and patients with large glucose variability (abnormal MODD) had higher incidences of arrhythmia (23% vs 4.2%, p< 0.05). Regression analysis showed that MODD can affect occurrence of arrhythmia ( p = 0.004) and that mean postoperative blood glucose levels can affect duration of ICU stay ( p< 0.001).
This work is partly presented at 25th World Cardiology Conference July 01-02, 2019 held at Osaka, Japan
Introduction: Among the methods of surgery for reshaping and redrawing the contour of our ageing face, currently one may go for suture thread materials or other energy-based devices or formal face-lifting surgery. There has been a trending and constant upsurge in the application of thread suspension surgery all over the world. The evolution of barbed suture technologies and their application in the field of plastic surgery has been already here for about three decades. According to surveys Face-lifting comes in the 4th position for most common surgical procedures worldwide. Barb suspension thread can be an alternative option to formal surgery as thread surgery is minimal invasive, office-based procedure, bearing lower risks and less down time. Successful thread usage has been started since 1950s and is widespread later with the introduction of permanent thread system by Sulamanidze in late 90s. Designs that were primarily developed and later enhanced for use in aesthetic facial procedures include free-floating, bidirectional barbed sutures; unidirectional barbed sutures; anchored, bidirectional double- threaded sutures. To summarize, the major thread system in the market currently are barb and smooth suture materials. Further in the barb suture there are two methods, it can be either unidirectional and bidirectional barb system. Theoretically, bidirectional barb thread system is more advantageous at it provides better mechanical advantage by positioning more barb in the suspension and the antagonistic traction between the barbs in two opposite directions. However, the long-term results after the resolution of the physical thread materials is done also rely on the effective bio-stimulation.
Barb suspension surgery is getting popular as a supplementary choice for facial contouring and reshaping. Compared with formal face lifting, barb suspension provides a safer, minimally invasive and office-based surgical procedure. However, barb suspension surgery does have certain risks due to the invasive nature.
Objective: We would like to evaluate the incidence of adverse events after thread suspension surgery. Through this retrospective analysis, we would like to standardize the possible adverse events to facilitate future reporting and prevention strategies.
Methods:
To evaluate the bard methodology we have used Happy LiftTM (Revitalizing) Double Needle threads (or in Europe and some other countries known as DefinisseTM threads). The one used is a range of absorbable, monofilament, suspension-barbed threads of synthetic origin (poly-L-lactic acid and caprolactone, p(LA-CL). The thread ends have two straight sharp needles 100 mm long with a diameter of 0.462-0.488 mm for the thread with the 12 cm barbed section. The thread with the 23 cm barbed section has two 150 mm long needle with the same diameter. The barbs distribution is bidirectional and convergent. The sutures interact with the tissues with a double action.
Procedure:
The field of procedure includes midface, lower face and neck areas. This procedure should be performed under local anaesthesia with adrenaline using standard aseptic technique in all cases. Depending on the vector for reshaping, the surgical procedures are standardized into five categories for different approaches of facial reshaping as follows:
Techniques with lateral vectors
• Jawline Reshaping (JR) (18%);
• Malar Reshaping (MR) (37%);
• Lateral Reshaping (LR) (13%);
Techniques with vertical vectors:
• Oval Reshaping - Vertical Reshaping (ORV) (18%);
• Oval Vertical Reshaping-H (OR H) (14%)
Post-operative care:
Patients were discharged with standard dressing materials including chlorhexidine, fusidic acid or equivalent ointment and paracetomol after the procedure. The patients were followed up one week, two weeks and four weeks after surgery.
Results:
The incidence of adverse event rate in the first week is 13.5%. It drops in the first 4 weeks, 9.6% at week 2, and 5.5% at week 4. The reported adverse events which persist after 4 weeks(number in brackets) include headache(0), redness(0), swelling and bruising(0), persistent surgical site pain(0), surgical site infection(1), asymmetry(0), palpability of threads(0), early recurrence(0), protrusion and extrusion(5), injury of the local anatomical parts like parotid gland(1), post-inflammatory hyper pigmentation(0),bunching, pleating and dimpling(5).
Both patient factor, operator factor, material and surgical field can contribute to the incidence. Barb suspension thread surgery is a relatively safe procedure. With careful selection of candidates, well-planned surgery, and respect to the sterility of surgical field and individual anatomical structures, majority of the incidents are avoidable. Clear post-operative care instruction and prompt intervention should issues arise are essential.
This is a single centre retrospective cohort study on the surgical outcomes. A collection of 200 pairs of thread were used in the period of 2017-2019 (two years). The patients were followed up one week, two weeks and four weeks after surgery. The adverse events are stratified according to defined categories. Photos were taken for documentation after patients’ consent.
The incidence of adverse events is sub sectored into 1. Mild (either improves with time, or manageable by simple, conservative and non-surgical intervention) and 2. Significant (needs active, aggressive or surgical intervention, one case of surgical site infection and one case of parotid gland injury). At Week 4, the incidence rate of adverse events is 5.5% (5.0% mild, 0.5% significant).
Discussion:
Office-based procedures have risen substantially every year. According to the American Society for Aesthetic Plastic Surgery (ASAPS), there was over approximately 5% increment each year. The art of aesthetic procedures, as well as from the expectations of the clienteles in this category require not only good aesthetic outcome, but also a tidy, swift and uneventful recovery. Overall, across all facilities, 1.9% of patients developed one major complications (2016). A 6-year retrospective review by Byrd et al demonstrated a complication rate of 0.73% [14], compared with 1.9% in another study by Gupta et al. [9]. Among these vascular complication like hematoma and infections were the major complication risks.The surgeon places the thread using 5 standard approaches (see procedure). In this way the aesthetic outcomes are more predictable. Surgeons can have better surgical handling in the field by improvising the surgery of each individual based on the standard techniques. Apart from home care counseling, routine structured follow-ups are helpful as well (one week, two weeks and four weeks after the surgery). We believe this will facilitate reporting of any issues related to the recovery and early intervention if necessary.
Conclusion
Barb suspension thread surgery is a generally safe procedure compared with most other aesthetic procedures. Patient factor, operator factor, material and surgical field can contribute to the incidence of adverse outcomes. With careful selection of candidates, well-planned procedure and respect to the sterility of surgical field and individual anatomical structures, majority of the incidents are avoidable. Clear post-operative care instruction and prompt intervention should issues arise are essential.
Note: This work is partly presented at 15th World Conference on Cosmetic Dermatology & Skin Diseases September 25-26, 2019 in Lisbon, Portugal
Introduction & Objectives: Platelet-rich Plasma (PRP) can be defined as an analogous concentration of human platelets in small volume of plasma. This concentration contains the tropic growth factors that are released once the platelets there in are activated either by calcium chloride, thrombin, or fibrinogen. PRP has long been known as an effective treatment in various surgical and medical fields. Platelet-rich Plasma (PRP) has been shown to improve skin function parameters like skin elasticity and angiogenesis by release and degranulation of growth factors and cytokines. Platelet rich plasma can also enhance fibroblast generated elastine production and my fibroblast stimulation. PRP promotes tissue remodeling in aged skin and may used as adjuvant treatment to lasers for skin rejuvenation. Facial rejuvenation utilizing antilogous platelet growth factors, such as platelet derived growth factors, vascular endothelial growth factor, insulin like growth factor, and epidermal growth factor is natural approach to restore dermal degeneration. Quantifiable improvement of skin complexion was observed with visible changes noticeable in 3-4weeks, especially forehead, cheeks, neck, and back of hands. It is not a volumetric filler but a biological cell therapy with patients own cells and a popular relatively painless inject able treatment for the aging face in cosmetic practice. The present study uses bioengineering methods to evaluate skin specific functional parameters and collagen reestablishment and neo-synthesis by Confocal Laser Scanning Microscopy (LSCM) in a group of patients with photo aging submitted to PRP treatments during 3 months. It is great treatment for improving overall skin texture and tone. It is particularly good for people who suffer from acne. It also induces reduction in the manifestations of skin aging by increasing number of fibroblasts and blood vessels and collagen density in the skin.
Materials & Methods: 12 patients were submitted to a PRP treatment, due to photo aging on the face. (PRP) is obtained from sample of patients (phlebotomy) .A 30cc venous blood draw will yield 3-5cc of PRP depending on the baseline platelet count of an individual and the device used. The blood draw occurs with the addition of anticoagulant such as (citrate dextrose A) to prevent platelets activation prior to its use. Do not chill the blood at any time before or during platelet separation and then centrifuge the blood using a soft spin and transfer the supernatant plasma containing platelets in to another sterile tube. Centrifuge tube at higher speed to obtain a platelet concentrate. The lower 1/3 is (PRP) and upper 2/3 is platelet poor plasma. There are many ways to prepare PRP. And by BUFFY COAT METHOD also we prepare (PRP). By this method white blood cells should be stored at 20 to 24 degree centigrade before centrifugation and centrifuge at high speed and three layers formed because of its density. Bottom layer consists of RBC, middle
layer consists of platelets and white blood cells and the top most one is the PPP layer. One should remove plasma from top layer and transfer to another sterile tube and centrifuge at low speed to separate WBC. After the completion of this finally PRP preparation will be obtained to which a local anesthetic has to apply and then SC injection should be administrated on the affected area, all of this should be performed at D0, D30 and D60. All the patients were evaluated for wrinkle 3D parameters, collagen quantification, and Photo aging parameters through Primos 3D, LSCM and VISIA-CR systems before and after each treatment. The study was photographically documented for the results evaluation, using a digital camera (lumix DMC-FX07). The photographs were taken at every treatment session (T0,T30,T60) and at one month after the last session(T90).The results were evaluated 1 month after the last session by a photograph score, a patients satisfaction score(Phss). Finally a definitive graduated score (DGS) was calculated for each patient.
Results & Discussion: The results which were obtained using this method show a 36.6 % wrinkle reduction on both crow’s feet and nasolabial fold areas. We could see results within a week after one or two months depending upon individuals, you should see rejuvenated skin that appear younger and feel softer and suppler. Results may remain from one to two years following treatment. Regarding collagen formation and reorganization, there was a 9.3 % increase in both parameters after the end of the study. The PRR and PPP smears were stained with WRIGHT-GIEMSA-SOLUTION subsequent micro examination indicated that PRP has a higher platelet concentration then PPP. The concentration of platelets in PRP was approximately 9.4-fold greater than in whole blood. Finally, results suggest a decrease in the Brown and UV spots evaluated by VISIA-CR system. These findings suggest a neo-synthesis of collagen and other matrix components, probably due to activation and proliferation of fibroblasts that improves the skin appearance and reverts in a significant way some effects of photo aging. PRP is an analogous modification of fibrin glue which has been described and used in various applications with apparent clinical success. PRP obtained from antilogous blood is used to deliver growth factors in high concentration to a region requiring augmentation. In this study, there are significant improvements in WSRS score for nasolabial folds and for facial wrinkle after PRP injection. Although PRP is one of the best procedures, it has its limitations. Most patients adapt to PRP quite well however there are few contradictions onto which we should not use this treatment. PRP may not be the best option for
1. Pregnant women
2. People who have recently used Accutane for acne
3. People who still have the problem of active acne which may result in scarring
4. People who have pertaining skin conditions like facial eczema or rosacea
5. For people whose skin scar easily
6. For those who’s wound healing history is not impressive
7. And for those who have undergone skin radiation in last 12 months.
Conclusions: Skin improvement was observed in during the treatments. PRP is a natural approach of facial rejuvenation; it is safe and tolerable procedure. The results, particularly the collagen formation and reorganization, suggest an effect on dermis functionality that improves skin condition in photo aging patients. And the patient’s satisfaction achieved will be much greater.
Note: This work is partly presented at 15th World Conference on Cosmetic Dermatology & Skin Diseases September 25-26, 2019 in Lisbon, Portugal.
INTRODUCTION: Myocardial energetic has a central role in patho-physiology of heart failure. The heart is an example of specialized type 1 (red) striated muscle in that is continuously active and reliant principally on aerobic metabolism for its energy supply. However, failing of heart is by insufficient ATP supply is currently lacking. Over the last couple of years, an increasingly complex picture of mechanisms evolved that suggest that potentially metabolic intermediate and redox states could play the dominant role for signaling that eventually results in left ventricular remodeling and contractile dysfunction. In the patho physiology of heart failure, mitochondria emerge in the cross fire defective excitation, contraction coupling and energetic demand which may provoke oxidation stress as an important upstream mediator of cardiac re-modeling and cell death.
Thus further therapies may be guided towards restoring defective ion homeostatic and mitochondrial redox shifts rather than aiming solely at improving the generation of ATP. Our hypothesis was that cardiac metabolic therapeutic approach must be integrative improving both substrate utilization and complete substrate oxidation i.e., supporting normal mechanism of energy production without increased generation of reactive oxygen species. Since the energy metabolism is linked to cardiac function, we accessed the effect of the integrative metabolic approach on the functional ability and quality of patients with heart failure and reduced ejection fraction
AIM: The aim was to study the effects of integrative metabolic and therapeutic approach of symptomatic patients with left ventricular dilation and reduced ejection fraction.
METHODS &RESULTS: Heart failure with reduced ejection fraction (HFrEF) happens when the left side of your hear does not pump blood out to the body as well as normal. The types of heart failure are based on measurement called ejection fraction. The ejection fraction measures how much the blood inside the ventricle is pumped out with each contraction. The left ventricle squeezes and pumps some (but not all) of the blood in the ventricle out to your body. A normal ejection is more than 55%.this means that 55% of total blood in the left ventricle is pumped out with each heart beat.
HEART FAILURE WITH EJECTION FRACTION happens when the muscle of left ventricle is not pumping as well as normal. The ejection is 40% or less.
The amount of blood is being pumped out of the heart is less than the body needs. A reduced ejection fraction can happen because the left ventricle is enlarged and cannot pump normally. Three main heart types describe heart failure according to the left ventricular ejection fraction (EF) and the differentiation between these types is important due to different demographics, co-morbidities and response to therapies:
All patients with HFrEF have concomitant diastolic dysfunction; in contrast, diastolic dysfunction may occur in the absence of systolic function. More than two-thirds of heart failures are attributable to ischemic heart disease, COPD, hypertensive heart disease & rheumatic heart disease. Other possible heart failure include congenital heart disease, myocarditis, infiltrative disease, pepartum, cardiomyopathy, human immune virus, amyloyidosis, substance abuse, long standing alcohol use, obesity, diabetes mellitus, hyperthyroidism, pulmonary hypertension, constrictive pericarditis( can cause HFpEF), pulmonary embolism (can cause HF) and chemotherapies (like doxorubicin)
We investigated 33 patients with left ventricular dilation>60 mm/and reduced ejection fraction <40% in 76% supportive complementary therapy/CST. Prior to each CST period, therapy was optimized for one month.CST is consisted of a 10 day session. In addition to optimization the patients were treated with carnitine, L-arginine, Magnesium, vitamin-b, coenzyme Q-10, vitamin –c, vitamin-e, and selenium while lying for 30 minutes inside a pulsed electromagnetic field with intensity up to 30 micro teslas and inhaling negatively ionized oxygen. Before and after each CST period, patients were asked to evaluate the equality of life using the MINNESOTA LIVING with heart failure questionnaire and the visual analogue scale VAS, EF, LVIDd, NYHA classes were determined. Statistical analysis was based on t-test, spearman’s rank correlation coefficient WILCOXONS signed ranks test. The longest period observation was 122 months.
After administrating metabolic supportive therapy, a statistically significant improvement was noticed in particular items of MLHFQ in emotional and physical dimensions. The values of VAS and EF are increased where as the values of NYHA and LYID decreased significantly.
CONCLUSION: HFpEF is not a true cardiac disease, but rather a systemic disease with morphological and functional heterogeneity. Clinical manifestations HFpEF appear to be the consequences of other underlying pathologies not are insufficiently treated. HFpEF emerges as a model with pro inflammatory cardiovascular and non-cardiovascular co-existing co morbidities, frequently present in the elderly, constituting a potential geriatric syndrome. Integrative metabolic therapeutic approach significantly improved the functional capacity and quality of life in the patients of HFpEF
Note: This work is partly presented at 8th World Heart Congress May 11-12, 2020 webinar
The role of the three dimEvaluation of left ventricular (LV) size and function are by far the most common reasons for performing echocardiography in the adult patient. The most important diagnostic, prognostic, and treatment decisions are measured based upon LV morphology analysis; the widespread availability of the bedside, occuring cost, and non invasive nature of echocardiography has made this technique the best method of choice in most situations for performing this analysis. Most of the echocardiographic departments perform an analysis called “eyeball” which gives an analysis of global and regional LV function and provide visual estimates of ejection fraction because existing quantification methods (from M mode and 2D Echo), however they are both time consuming and immensely difficult to perform. At a period of time where so many important and often costly decisions are being made upon with the help of this data it is incumbent upon departments that shows highly accurate data and are reproducible echo quantification methods are utilised—especially since the technique called “gold standard” of cardiac magnetic resonance (CMR) is not so widely available, is more costly, cannot be used on those with implanted pacemakers or defibrillators, and is disliked by many patients.
As mentioned previously, early 3D echocardiographic techniques depended upon the acquisition of multiple cross sectional (2D) images using freehand transthoracic or transoesophageal imaging. The spatial and temporal relationships of each image had to be registered and gating to the cardiac and respiratory cycle also performed before a time consuming reconstruction of a 3D dataset could be undertaken.
Acquiring the 3D datasets in real time ECG and respiratory cycle gating can largely be avoided and all of this can be achieved by using a matrix array probe. To test these the probe should contain complex electronics and 3–4000 individual elements which permits multidirectional beam steering and it has to allow a 3D dataset of approximately 30°Ã¢Â€Â…× 60° to be acquired. Using which facilitates 3D visualisation of valve structures or part of the LV in real time. However, in order to capture a dataset large enough to cover the entire LV, the transducer has to positioned over the apex and several (usually four or five) smaller real time datasets have to be acquired whilst briefly holding the respiration and electronically “stitched” together over four or five sequential cardiac cycles. A pyramidal 3D dataset of 90°Ã¢Â€Â…× 90° is obtained at a frame rate of 20–25 Hz can be acheived using this way. The dataset acquired using this tchnique is usually large enough and also fast enough to allow comprehensive analysis of the LV.
Despite the improved accuracy compared with 2DE, the majority of previous studies reported that 3DE measurements underestimate LV and right ventricular (RV) volumes when compared with cardiac magnetic resonance reference. This systematic error has been shown to be mostly a result of manual tracing of the endocardial boundaries on 3DE images too far into the ventricular cavity, where the eye has been perceived as the blood-tissue interface to be located on ultrasound images . This is because 3DE images do not always have sufficient spatial resolution to differentiate endocardial trabeculae from the compacted myocardium, especially in the right ventricle, and particularly during systole, when the trabeculae are compressed together as a result of increasing blood pressure. This finding underscores the need for further technological developments that would bring 3DE up to par with 2DE imaging in terms of spatial and temporal resolution and also for standardization of the measurement methodology with 3DE.
Conclusion
A 3-dimensional echocardiography is a non-invasive technique which can be performed in many clinical scenarios. Hence we conclude that it can be ideal for knowing daily performance and for serial follow-up examinations of left ventricular volume and function.
Inspite of the many improved techniques coming forth in the concept of three-dimensional echocardiography, the amount of time consumption has been the major limitation hampering its everyday use for daily diagnostic echocardiography and for volume and function assessment. Faster data acquisition by reducing the number of cross-sections for reconstruction of the cavity, using a high-speed rotation transducer or a volumetric real-time three-dimensional echocardiographic transducer is being investigated. Data processing and three-dimensional image reconstruction has been accelerated and on-line processing and reconstruction is under investigation. Development of various automatic border detection algorithms along with the improvement of ultrasound spatial resolution and advances in other novel modalities such as harmonic, power-mode Doppler tissue imaging and development of stable intravenous ultrasound contrast agents that enhance the delineation of endocardium, should be able to avoid the need of manual border tracing and provide automatic, even on-line, volume measurement segment of inferior wall, basal segment of lateral wall and apex) than other segments.
The 3-D echocardiography provides objective and assessment of regional wall motion abnormalities in patients with ACS. However, it does not show superiority over the routine assessment of RWMA by 2D echocardiography.
Keywords: 3-D Echocardiography, ACS, wall-motion abnormality.
The mortality can be better predicted with GLS than EF by both 3DE and 2DE analysis, whereas 3D EF is a better predictor than 2D EF. Also, LV shape indices provide additional risk assessment. Left ventricular (LV) ejection fraction (EF) is the most commonly used echocardiographic parameter of LV function, known to be an independent predictor of mortality, and is routinely used to guide patient management. However, assessment of LVEF in 2-dimensional (2D) echocardiographic, both in case of qualitative and quantitative measurement is dependent on reader experience and imaging plane, and the value of its accuracy changes with image quality. The recent and newer techniques used in the quantitative evaluation of LV function consists of speckle tracking echocardiography (STE), which helps in the exact measurements of myocardial deformation parameters, such as global longitudinal strain (GLS). The strengths of GLS include better reproducibility and ability to detect subtle changes in myocardial function that precede changes in EF, as reported in a variety of disease states (). Studies have shown that GLS can also predict mortality, potentially more accurately than EF (). Most outcomes studies focusing on LV function were performed using 2D echocardiography (2DE).
Three-dimensional echocardiography (3DE) offers better reproducibility and higher accuracy than 2DE for the assessment of LV size and function () because it avoids apical foreshortening and is based on direct volumetric measurements without geometrical assumptions. Furthermore, because 3DE can track myocardial motion independently of the imaging plane, 3DE-derived GLS may also be more accurate and reproducible. Recently, LV shape has been gaining interest with the availability of 3DE analysis tools, and there is growing evidence that it may carry additional diagnostic and prognostic information. Accordingly, we can state from the hypothesis that:
1) 3DE parameters can be the better predictors of cardiovascular (CV) mortality than that of 2DE; 2) Similarly, 3D GLS can predict better CV mortality than 3D EF; and
3) 3DE-derived shape indices can also be used inorder to predict CV mortality. This study was designed to investigate the relationship between these indices and long-term survival.
Although 3DE analysis of left atrial (LA) volume has been a topic of investigation, the development of software tools specifically designed for LA quantification is still lacking. Nevertheless, similar to LV volume quantification, 3DE measurements of LA volume were shown to be more accurate and more reproducible than the traditional 2DE measurements . Importantly, the 3DE approach has significantly reduced the underestimation of LA volume compared with the magnetic resonance reference, thus underscoring the need for reevaluation of the cutoff values defining atrial enlargement . This could potentially result in reclassification of the presence and/or severity of diastolic dysfunction in a large proportion of patients, a clinically relevant issue that needs to be addressed, as recognized by the latest ASE/EACVI guidelines (). To settle this issue, normal values of LA volume need to be derived from 3DE images in a large number of normal subjects over a wide range of ages. Because only few published studies have to date focused on normative values of LA volume , the recent guidelines have not provided such values (). One of the important recent developments in the 3DE evaluation of LA size is that it can now be accurately measured automatically using new machine learning techniques, without the need for manual tracing of LA boundaries.
Note: This work is partly presented at 8th World Heart Congress May 11-12, 2020 webinar
Introduction: Heart failure (HF), previously called congestive heart failure, is a serious condition most commonly caused by weak pumping of the heart muscle. Arrhythmia is a common finding in heart failure (HF) patients. It has a greater impact on prognosis in those patients, especially atrial fibrillation arrhythmia type.
The most common cardiovascular conditions that are encountered in clinical practice and frequently coexist are Heart failure (HF) and atrial fibrillation (AF). Heart failure can be considered as a measure to predict the development of AF and conversely the presence of AF in an individual can also predict the development of HF at later stage. The prevalence of Heart failure in the society has reached the proportions of a global epidemic with an estimated prevalence of 3-20 cases in a 1000 whereas population raising to above 100 cases per 1000 population in elderly people those aged over 65 years. Also the annual incidence rate of heart failure in middle aged men and women which was 0.1-0.2 % has been rising steadily to 2-3 % in those aged above 85 years.
The most common sustained arrhythmia seen in clinical practice recorded is atrial fibrillation. The studies done by Framingham as well as the Rotterdam have estimated around 25% lifetime risk of developing AF. The studies show that only in the United States the prevalence of AF is estimated between 2.7 to 6.1 million, which is expected to rise to between 5.6 and 12 million. The prevalence in the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) according to a study predicted that it will rise 2.5 times by 2050. The incidence is expected to rise steeply with the age, rising to an estimated of value 17.4% surge in those above 85 years of age. Similar to Heart Failure, AF also carries an enormous burden of morbidity, mortality and healthcare costs.
Objective: The study aimed to evaluate the effect of arrhythmia on the mortality & morbidity among heart failure patients.
Methods: Methods were conducted to analyse the effect of atrial / Ventricular Fibrillation on patients with Heart Failure: A prospective observational study at a tertiary care center, study data was collected from period of November to January 2018. This study was divided primarily into two groups, first group consists patients diagnosed with heart failure & the second group is the controlled group (HF + arrhythmia). Studies showed that AF was associated with an increased risk for all-cause mortality in comparison to those in sinus rhythm (34% vs. 23%), this was done using retrospective analysis of the studies of Left Ventricular Dysfunction (SOLVD) by Dries et al. (involving 6517 patients with LVEF of less than 35%). The studies on the subjects were also applicable to asymptomatic as well as symptomatic patients and mainly attributable to an increased risk of pump failure deaths. Similarly the investigators of Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) explained and showed an increased and independent effect of AF on cardiovascular outcomes in patients with either reduced or preserved LV systolic function. However both the above traditional analyses are limited by the fact that data for these studies were derived from the analysis of subgroup. The Potential and prospective data from Stevenson et al. looked and analysed the influence of Atrial Fibrillation on all-cause mortality in 390 patients with advanced systolic heart failure. After many observations and discussions the conclusion was that AF is an independent predictor of all-cause mortality (actuarial survival at 1 yr with AF 52% vs. 71% with sinus rhythm). However interestingly, atrial fibrillation was associated with increased 1-year mortality only in patients with a pulmonary capillary wedge pressure lower than 16mmHg rather than the ones with higher filling pressures suggesting that the relative risk of sudden death is highest in patients with relatively better ventricular function as compared to patients with more advanced ventricular dysfunction.
A number of modalities related to non-pharmacological methods are in clinical use for the management of AF in daily basis. Anti-arrhythmic drug therapy for the management of AF may in itself increase adverse cardiac events. The trial patients with AF-CHF who were monitored in the rhythm control arm were more frequently hospitalized for dosage readjustment and cardio version especially in the first year. Furthermore, many patients are unable to achieve rhythm or rate control targets due to inadequacy of the drugs or side effects. Consequently, use of electrophysiological interventions to achieve this aim is increasing. AV nodal (AVN) ablation accompanied by a permanent pacemaker is often a last resort option for definitive AF rate control when medical therapy to achieve this has failed. This treatment strategy may only be of symptomatic benefit since AF is not eliminated and deleterious effects of A-V dysynchrony and loss of atrial transport still persist. While atrial lead placement and chronic atrial pacing has not shown any benefit in reducing AF recurrences, chronic RV pacing leads to progressive LV dysfunction due to inter-ventricular desynchronisation. As a result, upgrade to biventricular pacing has been suggested as a promising option provided it can be ensured that the device is pacing nearly 100% of the time for maximum benefit.
Results: A total 200 participants, most of the respondents were males 153 (76.5), more participants were have 2 risk factors & highest one is HTN (Hypertensive)149(74.5%), interventionist procedure used among our patients were PCI for both patients have one or more interventions 99(49.3%) ,most of patients with ICD(Implantable Cardioverter Defibrillator) 90(44.8%), most type of arrhythmia atrial fibrillation 71 (35.5), a majority of NHYIA class(New York Heart Association) is class I 137 (68.16), the most symptom palpitation 176(87.56%) , ejection fraction in were patients 30% with total 52(25.87%) & highest medication used is beta-blocker185(92.04%).
Conclusions: Arrhythmias one of most factors cause of heart failure disease. AF(atrial fibrillation) is the most common arrhythmia in HF, AF prevalence and its associated complications have been well studied in established HF. Clinical management of HF needs to take into account the high risk of arrhythmias among these patients. Also to be noted that HF and AF frequently co-exist and the presence of Atrial Fibrillation in patients with HF has been reported to be independently associated with an increase in mortality in many studies and the studies show that this increased risk is observed in patients with both preserved and impaired LV systolic function. Despite the fact that many studies have shown that the presence of AF in HF patients is associated with an adverse prognosis, most studies that have targeted AF in patients with HF with a view to maintaining SR have shown no noteworthy improvements in outcomes compared to those patients in which a rate control strategy has been adopted.
Note: This work is partly presented at 8th World Heart Congress May 11-12, 2020 webinar
Cor triatriatum is one of the rarest cardiac disease or condition that involves the left atrium. It happens and represents only 0.1-0.4% of all congenital heart diseases. It can be illustrated or denoted as one of the atrium gets divided into two chambers by a fibromuscular membrane and in general appear on the left atrium. Cor triatriatum is considered as a result because of embryologic failure of the common pulmonary vein to become subsume into the left atrium during the fifth week of embryonic development.1 The insuffucient incorporation of the common pulmonary vein results into a obstructive membrane at junction of the common pulmonary vein and the left atrium. As a result it creates two separate chambers within the left atrium; the proximal chamber consists of pulmonary veins and their convergence, whereas the distal chamber includes the left atrium and left atrial appendage . Cor triatriatum is an unusual membrane, or split, present in the left atrium above mitral valve, resulting in varying degrees of obstruction to flow into the left ventricle. It is a rare lesion, accounting for only 0.1% of CHD defects87 . The pathophysiology is essentially identical to that of mitral stenosis, and only echocardiography often differentiates the two conditions. Surgical repair is undertaken when the diagnosis is made. Mild forms of cor triatriatum might be undetected for months and might also take years in patients whose only real symptoms are recurrent respiratory infections and wheezing. CTS was first found and noted in the 1800s by Andral and Church and named “cor triatriatum” by Borst in 1905; it occurs in 0.1% of clinically diagnosed cases of congenital heart disease (CHD) and 0.4% of CHD autopsy cases. This discrepancy reflects the fact that most cases involve a nonobstructive membrane with questionable clinical relevance. The prevalence in the general population is likely to be less than 0.004%.1-3 Fewer than 350 cases have been reported since 1968. There may be a slight male predominance.Cor triatrium sinistrum is more common. In this defect there is a proximal chamber which receives the pulmonic veins and a distal chamber located more anteriorly where it empties into mitral valve. The membrane which separates the atrium into parts varies significantly in size and shape. It may appear similar to a diaphragm or be funnel-shaped, bandlike, entirely intact (imperforate) or contain one or more openings (fenestrations) ranging from small, restrictive-type to large and widely open.
In the pediatric population, this anomaly may be associated with major congenital cardiac lesions such as tetralogy of Fallot, double outlet right ventricle, coarctation of the aorta, partial anomalous pulmonary venous connection, tenacious left superior vena cava with unroofed coronary sinus, ventricular septal defect, atrioventricular septal defect, and common atrioventricular canal. Rarely, asplenia or polysplenia will be reported in these patients. In an adult, cor triatriatum is frequently an isolated finding. Cor triatriatum dextrum is very rare and results from the complete persistence of a right sinus valve of the embryonic heart. The membrane divides the right atrium into a proximal (upper) and a distal (lower) chamber. The upper chamber receives the venous blood from both vena cavae and the lower chamber is in contact with the tricuspid valve and the right atrial appendageThe natural history of this defect depends on the size of the communicating orifice between the upper and lower atrial chambers. If the communicating orifice is small, the patient is critically ill and may succumb at a young age (usually during infancy) to congestive heart failure and pulmonary edema. If the connection is big, patients may present in childhood or young adulthood with a clinical picture similar to that of mitral stenosis. Cor triatriatum may also be an peripheral finding when it is non obstructive. Diagnosis by ECHO, possibly followed by MRI.
The ductus arteriosus is a usual fetal artery connecting the main body artery and the main lung artery (pulmonary artery). The ductus allows blood to deflect away from the lungs before birth.
Every baby is born with ductus arteriosus. After birth, the opening is not needed and it usually narrows and closes within the first few days.
Sometimes, the ductus doesn't close after birth. Failure of ductus to close is common in premature infants but not common in full-term babies. In most children, the cause of PDA is unknown. Some babies can have other heart defects along with the PDA. Normally the heart's left side pumps blood only to the body, and the right side pumps blood only to the lungs. In a baby with PDA, excess blood gets pumped from the body artery into the lung (pulmonary) arteries. If the PDA is large, the excess blood being pumped into the lung arteries makes the heart and lungs work hard and the lungs becomes congested.
If PDA is small, it will not cause any symptoms because the heart and lungs don't have to work hard. The only unusual finding may be distinctive type of murmur. Whereas if the PDA is large, the child may breathe faster and harder than normal. As a result high blood pressure may occur. Over time this may cause permanent damage to the lung blood vessels.If the PDA (ductus) is small, it doesn't make the heart and lungs work harder. Surgery and other treatments may not be needed. One good thing about Small PDAs is they often close on their own within the first few months of life.
Normally the heart's left side only pumps blood to the body, and the right side only pumps blood to the lungs. Extra blood gets pumped from the body artery (aorta) into the lung (pulmonary) arteries in a person who is suffering with PDA. If the PDA is larger than usual, the extra amount of blood which is being pumped abundously into the lung arteries makes the heart and lungs work harder and there is a chance that lungs can become congested.
Surgery may be the best treatment option for patients suffering with PDA. The surgeon doesn't have the need to open the heart to fix or cure the PDA. An incision is made in the left side of the chest, between the ribs. The best option to perform repair on PDA is to closing it by tying it with suture (thread-like material) or by permanently placing a small metal clip around the PDA to squeeze it closed. Occasionally in the adult, a surgical patch is used. If there's no other heart defect, this restores the circulation to normal.
We report the case of a 23-year old Filipino female with orofacial cleft, presenting with symptoms of decompensated heart failure. Clinical examination revealed the presence of diastolic murmur, 5/6, with accentuated pulmonary component of the second heart sound. Cardiomegaly was seen on chest x-ray and right ventricular hypertrophy on electrocardiogram. On performing Transthoracic echocardiogram (TTE), it shows Cor triatrium sinistrum; dilated left atrium divided by a membrane into a proximal and distal chamber; dilated right atrium; dilated right ventricle with right ventricular hypertrophy; dilated main pulmonary artery; and severe pulmonic regurgitation with severe pulmonary hypertension.
The TTE perfomed should be able to provide accurate and sufficient characterization of cardiac anatomy for optimal diagnosis but because of the rarity of the disease, it can be missed. A transesophageal echocardiography (TEE) provides excellent resolution and offers invaluable assistance to surgical intervention. TEE was done upon follow up to rule out associated congenital abnormalities which only showed patent ductus arteriosus.
Surgery provides a satisfactory early and long term survival. Therefore the key is the accurate evaluation of cor triatriatum. Our report highlights early diagnosis and the utility of transesophageal echocardiography in the diagnosis of such congenital cardiac abnormalities and associated lesions.
Note: This work is partly presented at 8th World Heart Congress May 11-12, 2020 webina
Introduction: One of the rarest but highly serious congenital cardiac anomalies can be distinguished as Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). Anomalous left coronary artery from the pulmonary artery (ALCAPA) is also a kind of heart defect. The artery that carries the blood to the heart muscles i.e., left coronary artery (LCA), actually begins from the pulmonary artery instead of the aorta.
History: The term ALCAPA was first described in 1866. Bland and colleagues in the year 1933 described the first clinical description in conjunction with the autopsy findings, and hence this particular anomaly is named as Bland-White-Garland syndrome. In the year 1962, a series of 58 postmortem specimens that demonstrated that most patients had died at a young age was reported by cardiologists Fontana and Edwards.
The Description of the abnormality is given as follows: Both coronary arteries should arise (branch) from the aorta in case of a normal heart, However in the case of an anomalous left coronary artery from the pulmonary artery (ALCAPA), while the heart of an infant is forming in the mother’s womb something goes wrong, and the left coronary artery arises from the right pulmonary artery instead of arising from the aorta. And the medical personalities have named this type of heart defect as “anomalous origin of the left coronary artery from the pulmonary artery.” The word Anomalous means irregular. 1 in every 300 000 live births has been recorded with this heart defect of Anomalous origins of the left coronary artery arising from the pulmonary artery (ALCAPA).
The most common origin of the abnormal LCA is from the pulmonary truncal sinuses. In the most common form of ALCAPA, the abnormal coronary artery arises from the adjacent pulmonary valvar sinus, rather than the pulmonary trunk. In this case, the Anomalous Left Coronary Artery originated the Right Pulmonary Artery. Such case has an incident of 1 in 2,000,000 live births. This is the first reported case in a tertiary cardiovascular referral center. In fetal life, this has no detrimental effect since pressures and saturations are similar in the aorta and pulmonary artery. After birth, however, the pulmonary artery contains de-saturated blood at pressures that rapidly fall below systemic pressures. The left ventricle is perfused with de-saturated blood at low pressures leading to infarction with ventricular dysfunction. Coronary translocation and Lecompton maneuver was done which provided relief for the patient’s condition. In children suffering from with ALCAPA heart defect, the left coronary artery arises from the pulmonary artery and it carries blood without oxygen to the left side of the heart. In this situation, the heart muscles can weaken or die which is similar to having a heart attack because the heart doesn’t get enough oxygen. Hence the damaged heart muscle cannot pump effectively, which becomes the route cause for cardiomyopathy and heart failure. In infants, ALCAPA is a very rare and dangerous health condition that may cause dangerously poor cardiac function. Performing Surgery is a must in order to correct the defect. Without intervention, most babies don’t survive their first year, but with timely surgery, most babies do well and live a normal life.
The rarest form of ALCAPA presents with anomalous left coronary artery arising from the right pulmonary artery. This is a case of 1 month old female presenting with Dyspnea, 2D echocardiography revealed ALCAPA. Intraoperativley, the Left Coronary Artery was found to be originating from the Right Pulmonary Artery. The patient underwent coronary implantation and LeCompte procedure.
Causes:
ALCAPA is a heart defect or a problem that is most likely to occur early in the pregnancy when the baby’s heart is still developing. This issue arises when the developing blood vessel does not attach to the heart muscle correctly.
The LCA originates from the pulmonary artery in children suffering with the rarest disease of ALCAPA. The pulmonary artery which acts as the major blood vessel that pumps oxygen and poor blood from the heart to the lungs to pick up oxygen.
Hence the blood that is lacking or insufficient in oxygen is carried to the heart muscle on the left side of the heart when this defect occurs. And hence the heart muscle does not get enough of oxygen. As a result of which, the tissue begins to die due to lack of oxygen. This can become the root cause a heart attack in the baby.
Another deadliest condition which is known as "coronary steal" evokes the further damages the heart in babies with ALCAPA. The blood from the abnormally connected LCA is flowed back toward the pulmonary artery instead of toward the heart muscle because of the low blood pressure in the pulmonary artery. This backward flow causes and results in less blood and oxygen transferred to the heart muscle. This problem can also lead to a heart attack in a baby. If the condition is not treated as early as possible in babies with ALCAPA, Coronary steal develops over time.
Treatment: Surgery is needed to treat anomalous left coronary artery from the pulmonary artery (ALCAPA). There are mainly two options for repair which are performed commonly, they are 1. Detaching the anomalous left coronary artery from the pulmonary artery and moving it over to the aorta directly (translocation) 2. With the help of a Takeuchi repair method that includes creating a natural tunnel from its abnormal location to the aorta. If the mitral valve is leaking, it can be repaired at the same time. However in some extreme cases where the heart is severely damaged the support of mechanical circulatory/ventricular assist device may be required and a heart transplant may be needed.
Though ALCAPA is a serious issue with the help of a timely therapy, most children do very well once after the surgery is performed and can be expected to live a normal and healthy life. However, there should be routine checkup and life-long follow-up with a heart-failure specialist will be necessary to ensure recovery of the heart muscle and good function of the mitral valve. An increased risk for heart-rhythm problems later in life time can be seen in children born with ALCAPA. However, adults have been reported to survive better owing to the development of collateral perfusion from right coronary artery. In these cases, however, revascularization is necessary to prevent sudden cardiac death.
The Takeuchi procedure for treating ALCAPA refers to performing a direct anastomosis of the anomalous left coronary artery from the pulmonary artery directly to the aorta was described in the 1970s and currently remains the best procedure of choice.
An intrapulmonary aorta-coronary tunnel or baffle was performed by Takeuchi prior to the above procedure. If the above procedure is not feasible due to coronary anatomy or due to lack of surgical experience this surgery is performed even today.
Medication:
In order to build up the strength necessary for the procedure, some children may need medications prior to surgery. These medications for building up the strength may include:
Note: This work is partly presented at 8th World Heart Congress May 11-12, 2020 webinar
Research in the Visual Development Unit on ‘‘dorsal stream vulnerability’ (DSV) arose from research in two somewhat different areas. In the first, using cortical milestones for local and global processing from our neurobiological model, we identified cerebral visual impairment in infants in the first year of life. In the second, using photo/video refraction in population refractive screening programs, we showed that infant spectacle wear could reduce the incidence of strabismus and amblyopia, but many preschool children, who had been significantly hyperopic earlier, showed visuo-motor and attention deficits. This led us to compare developing dorsal and ventral streams, using sensitivity to global motion and form as signatures, finding deficits in motion sensitivity relative to form in children with Williams syndrome, or perinatal brain injury in hemiplegia or preterm birth. In current research, we find that individual differences in motion coherence sensitivity in typically developing children are correlated with MRI measures of area variations in parietal lobe, fractional anisotropy (from TBSS) of the superior longitudinal fasciculus, and performance on tasks of mathematics and visuo-motor integration. These findings suggest that individual differences in motion sensitivity reflect decision making, attentional control.
Introduction
Emerging cortical function and infant cortical impairment
The work will discussed at the beginning of the review arose out of the first twenty years of my research with Oliver Braddick and our team in the Visual Development Unit in the Cambridge, particularly John Wattam Bell and Shirley Anker. We began by devising new methods, both behavioral and electrophysiological to measure the normal visual capacities of infants such as acuity and contrast sensitivity, over the first years of life. We then looked at the time scale of development with basic visual cortical function’s: binocularity, orientation and direction selectivity, symmetry of monocular optokinetic nystagmus and control of visual attention. This research led to be neurobiological model of the course of visual cortical brain development, in which an initially subcortical system came under the control of progressively emerging cortical functions. The milestones of this sequence provided the basis for identifying the cortical visual impairment in infant’s with early brain injury. This is the starting point for extended the collaboration’s with paediatric neurologist’s including the extensive studies of visuo-cognitive consequences of perinatal brain injury in infant’s were identified with hypoxic ischemic encephalopathy and in infant’s with very preterm birth.
Overview
I have been ranged widely through the evidence for particular vulnerability of the dorsal cortical stream in development, and the value of relative sensitivity to global motion and form as a measure of this vulnerability and of variations even in the typical development. However, given the very different cognitive and social-behavioural profile’s in the phenotypes of different developmental disorder’s and the commonality of deficits in the global motion processing, there must be much debate as to whether the deficit originates across all disorder’s at the same neural level of visual processing, within the complex dynamic cascade from retina to cortex and within the cortex itself—whether we talking about top-down constraint’s or bottom up, or both. There is an added problem of identifying whether a deficit in early life at a relatively low level of processing has a knock-on effect at later ages at ‘‘higher’’ levels in the visual and visuo-cognitive system’s. Lack of space prevents these issues from being fully explored here. However, from our own work with typically and atypically developing the infants and children, we would argue that there is unlikely to be a single limiting constraint at one level in processing global motion across all disorders, unless it is a very early developing visual attentional deficit, such as infant ‘‘dis-engagement’’ in selective attention task’s. When added to the different perceptual biases across different disorders, this leads to an apparently common deficit in global motion sensitivity and to other ‘‘higher level’’ deficits in spatial, mathematical, and attentional cognition.
So we are left with many unanswered questions including the following:
These questions, and many more, are need to be answered by inter-disciplinary team’s in developmental vision from psychology, cognitive neuro-science, genetics, paediatric ophthalmology and optometry, paediatric neurology, developmental computational science, and education, especially if we are go on to find child friendly, reliable intervention’s to reduce and overcome these visually related problems, which may affect many aspects of everyday life. The exploration of global motion sensitivity is a signature of some of these wider cognitive processes, and their vulnerability in atypical development, provides the goal’s for future research.
Note: This work is partly presented at 3rd Global Pediatric Ophthalmology Congress during March 22-23, 2018 at London, UK
Autosomal dominant cone dystrophy is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer membrane-associated protein in 2 Swedish families. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of non-receptor protein tyrosine kinases, PYK2.
Introduction
Progressive cone or cone-rod dystrophies are characterized by a defective cone function and demonstrated by the abnormalities in cone-mediated electro-retinogram components. The presenting symptoms are defective colour vision, impaired central visual acuity and sensitivity to light. A variant of autosomal-dominant cone dystrophy has been mapped to 17p12–p13 in the Swedish family. Two other reports, one from United Kingdom and one from the United States and also showed linkage of dominant cone dystrophy to chromosome 17p. The disorder in the British family, designated as the CORD6 was found to be caused by the mutations in GUCY2D gene. Mutations with in GUCY2D gene also cause Leber congenital amaurosis and autosomal recessive retinitis pimentos. In the USA family, the disease mapped to 17p12–p13 was later reported to be caused by same mutation in British CORD6 family, and therefore it was concluded by the CORD5 and CORD6 having the same disease.
Materials and methods
Patients and clinical examination
To identify the gene causing CORD5, we analysed two multi-generation in a Swedish families originating from the same geographical area in Northern Sweden. Family 151, reported previously, is five-generation family with total of 48 individuals of which 18 will be affected. Family 152 is a seven-generation family of 32 individuals with 15 affected and two individual’s with unknown disease status. Informed the consent was obtained from all individual’s participating in the study and the research following to the tenets of Declaration of Helsinki was approved by the Ethics Committee of University of Umea˚. All individuals were classified as unaffected were symptom less, and had normal visual acuity and normal colour vision. In family 152 the corresponding clinical examinations in progress, however have not yet been completed. A full ophthalmologic examination included assessment of visual acuity and evaluation of the anterior segment and the fundus. Visual fields were tested in a Goldmann perimeter by using standard objects. In selected cases, a more detailed investigation was performed. The course of dark adaptation was determined by using a Goldmann-Weekers adaptometer. Colour vision was tested with the pseudoisochromatic plates. Electrooculography, and full-field, single flash and flicker ERGs were recorded by using the UTAS-E 2000 and UTAS-E 3000-mf LKC technologies Inc.,
Genotyping, linkage analysis, and mutational screening
DNA from 80 individuals was extracted from peripheral blood lymphocytes according to standard protocol’s reported by Balciuniene et al. Twelve microsatellite markers included in the Rutgers Combined Linkage-Physical Map were used for genotyping. The markers mapped to the 17p13 in proximity to D17S938 were situated approximately 2 cM apart. The GDB Human Genome Database was used for the information about microsatellite markers and primer sequences. PCR mixes were prepared in 7.5 ml reactions using 0.3U of AmpliTaq Gold, 0.75 ml of GeneAmpPCRbuffer II, 0.075 mM of dNTP, 0.75 mM of MgCl2, and 0.1 mM of primers. Polymerase chain reaction was performed with a temperature profile of 951C for 10 min, 941C for 15 s, 551C for 15 s, 721C for 30 s for 10 cycles, 891C for 15s, 551C for 15s and 721C for 30s for 20 cycles, and the final extension at 721C for 10 min. Fragment analysis of the samples was performed on a 3730xl DNA analyser, and the collected raw data were analysed with ABI Prism GeneMapper Software v3.0.
For bidirectional sequencing of phosphatidylinositol transfer membrane-associated protein, coding exons and adjacent intrinsic sequences were amplified from genomic DNA of two affected patients from each family and one unaffected individual. Primer pairs designed with Primer software is listed. PCR amplification of the 19 exons was performed in 25 ml reactions with 0.5 U of AmpliTaq Gold, 2.5 ml of PCR buffer II 10, 1.5 mM of MgCl2, 0.1 mM of dNTP, 0.4 mM of primers, and 50 ng of genomic DNA. PCR cycling consisted of an initial denaturing step at 941C for 5 min; then 30 cycles of denaturing at 941C for 1 min, annealing at temperature dependent on primer sequence for 1 min, and extension at 721C for 1 min; and final elongation step at 721C for 7 min. PCR products were purified using MicroSpin columns. The sequencing reactions were performed using Big Dyes Terminator v3.1. The products of sequencing reactions were run on 3730xl DNA analyzer.
Results and discussion
Two Swedish families, are originating from same geographical area in the Northern Sweden were included in the study. The majority of the patients in family 151 had subnormal visual acuity and light sensitivity from childhood. Signs of macular degeneration were observed to early as well. There was a progressive decrease of VA leading to legal blindness in the early adulthood. Electro-physiological tests showed a progressive loss of photoreceptor function restricted to the cones. The macular regions were presented a normal appearance at early stages of the disease. In the young patient a bull’s-eye maculopathy could be seen. In more advanced cases, finding’s varied from pigment mottling to pronounced central choroidal atrophy. There was no peripheral restriction of the visual field and patients did not have any history of nyctalopia. Photopic ERGs representing cone function were greatly diminished or absent, whereas scotopic ERGs showed normal amplitudes. The EOG was normal. Dark adaptation curves showed absence of a normal cone segment, but the final rod dark adaptation threshold was not elevated.
In summary, this study adds one more gene on 17p, which causes the retinal degeneration. We can provide the evidence of CORD5 in Swedish patients was distinct clinical entity and describe the first disease causing mutation within the PYK2–binding domain in the PITP family.
Note: This work is partly presented at 17th International Conference on Clinical and Experimental Ophthalmology October 01-03, 2018 Moscow, Russia.
Purpose: To study peripapillary choroidal thickness (PPCT) in healthy subjects using swept-source optical coherence tomography (SS-OCT), and to evaluate PPCT differences between Parkinson´s disease (PD) patients, and age- and sex-matched healthy controls.
Introduction
Parkinsons disease (PD) is a neurodegenerative process that leads to the selective loss of dopaminergic neurons, mainly in the basal ganglia of the brain. Clinical manifestations were include movement alterations as well as non-motor symptoms, such as dementia, depression, and autonomic dysfunction. Neurons and neural circuits are outside the basal ganglia can be affected simultaneously or upstream of the substantia nigra.
Vision is one of the non-motor systems which was altered in PD, especially the visual field was corresponding to fovea. Recent studies were demonstrated the retinal thinning in different macular sectors and retinal nerve fibre layers in PD patients compared with healthy subjects, and alterations in multifocal electroretino-grams.
Several mechanisms have been proposed to be axonal loss in PD disease, leading to the tissue degeneration and ultrastructural changes of the retinal ganglion cells, but the changes of the choroidal layer have not been thoroughly evaluated. Mechanobiologic response of tissues and cells depends on the mode of deformation, and the magnitude and temporal profile of the stimulus, as well as the type of tissue or cell and its biologic state. Understanding the particular deformations observed in each tissue and ocular layer in patients with PD might facilitate diagnosis and treatment.
The main advantage of the present study was PPCT evaluated in a wide area of the parapapillary choroid using an automatic and the accurate new method.
Material and Methods
Study population and design
This is a prospective, observational, cross-sectional case-control study. The study included the patients with definite PD, and age- and sex-matched healthy control’s. Based on our preliminary studies, we calculated the necessary sample size to detect differences in choroidal thickness of atleast 20 μm as measured by the OCT, applying a two-tailed test with an alpha of 5% and a beta of 10%, and a risk ratio of 0.5. Based on this calculation, at least 70 eyes were needed. A total of 40 eyes of 40 PD patients and 80 eyes of 80 healthy controls were evaluated. PD diagnosis was based on the UK Brain Bank Criteria, which included, in the first stage, bradykinesia and one additional symptom, i.e., rigidity, 4–6 Hz resting tremor, or postural instability. Patients with a visual acuity less than 0.1, intraocular pressure (IOP) >20 mmHg, optic neuritis antecedent, no transparent ocular media and systemic disease that could affect the eye were excluded from the study. Subject’s with refractive errors greater than 5 dioptres (D) of spherical equivalent refraction or 3D of astigmatism were also excluded from the study.
Standard protocol approvals, registrations, and patient consent
The study procedures were performed in accordance with the tenets of the Declaration of Helsinki, and the study protocol was reviewed and approved by the Aragon Ethics Committee For Clinical Research before the study began. Written informed consent to participate in the study was obtained from all the subjects.
Main outcome measures
All the subjects underwent a complete neuro-ophthalmic examination, including assessment of best-corrected visual acuity using the Snellen chart, pupillary reflexes, and ocular motility; examination of the anterior segment, IOP with the Goldmann applanation tonometer, and papillary morphology by funduscopic exam; as well as the OCT. In the PD group, disease severity was assessed using the Unified Parkinson Disease Rating (UPDRS) and the Hoehn and Yahr scales, and disease duration, since the PD diagnosis were recorded. The Hoehn and Yahr scale is a commonly used diagnostic tool for quantifying the progression of PD symptoms. Stages range from 0 (no signs of disease) to 5 (requiring a wheelchair, or bedridden unless assisted). Clinician’s and researchers most commonly use the UPDRS, and the motor section in particular, to follow the longitudinal course of PD in clinical studies.
OCT
An optic disc 6.0×6.0 mm three-dimensional scan was obtained using the DRI OCT. This scan will combine’s morphometric optic disc parameters and various parapapillary parameters, including RNFL and choroidal thickness. The subjects were seated and properly positioned. All DRI-OCT images were obtained by a single well-trained technician blinded to the presence or absence of PD. The DRI-OCT Triton includes the new SMART Track tool that enhances the tracking, corrects for motion, and guides the operator to reduce potential errors while acquiring image’s. Only eyes with good quality scans were included in this analysis. Good-quality SS-OCT images were defined with those with a signal strength, and without motion artifact, involuntary saccade, or overt misalignment of decentration. A total of three eyes were excluded due to poor DRI-OCT image quality. These eyes were substituted with two new patients in the PD group and one new healthy subject in the control group. The same investigator performed all of the OCT scan’s and checked the accuracy of segmentation in each scan and the lack of artifacts. A total of 15 scan’s in the PD group and 10 in the control group were excluded and repeated again. A 26×26 cube-grid will centred on the optic disc was generated automatically measure choroidal thickness. This grid was comprised 676 cubes around the optic nerve head with the 88 central cubes and corresponding to the optic nerve head area not analyzed; therefore the DRI-OCT Triton displays choroidal thickness for a total of 588 parapapillary cubes.
Results
PPCT was significantly thicker in PD patients compared with controls in all four concentric zones evaluated (p0.0001). PPCT was followed a similar pattern in the control’s and PD; it was thicker in temporal superior region, followed by superior, temporal, nasal, and inferior regions.
Conclusion
PD Patients were presented with an increased PPCT in all the zones surrounding the optic disc compared with healthy subjects. The peripapillary choroidal tissue showed an concentric pattern, with the thickness increasing with increasing the distance from the optic nerve. SS-OCT could be useful for evaluating the choroidal thinning in clinical practice.
Note: This work is partly presented at 17th International Conference on Clinical and Experimental Ophthalmology October 01-03, 2018 Moscow, Russia.
A total of 319 consecutive patients were included in the study. The majority of those latter surgeries involved volume displacement methods. Demographic data was collected. Statistical analysis was performed using SPSS software. Our results demonstrated that OPS excised significantly larger tumors (p (p<0.05) of greater weights(p<0.05) with little cosmetic penalty. There was no significant difference in margin clearance (p = 0.10) or the number of patients requiring further surgery in both groups (p=0.254).OPS provides a better cosmetic and oncological result compared to standard wide local excisionsbased on the weight and size of the tumor. Margin clearance is comparable in both groups.
Keywords:
Breast conserving surgery; Oncoplastic breast surgery; Wide local excision; Breast cancer; Cosmesis
Introduction:
In women with early stage unifocal carcinoma, breast conserving surgery followed by radiotherapy is the recommended choice. However, in some women, lesions are difficult to excise without the danger of cosmetic deformity or inadequate margin clearance. These women often present with large tumors in relatively small breasts requiring an excision of roughly 15% to twenty% of the breast volume or over 30% in large breasts. Another factor affecting poor cosmesis after breast conserving surgery is tumors located in aesthetically sensitive areas such as the central, medial, and inferior quadrants.. OPS combines the principles of oncologic and cosmetic surgery techniques to gain oncologically and aesthetically pleasing results . As these techniques become more accepted there is a demand for surgeons to become familiar with the indications and skills required to make oncoplastic surgery safe and effective . The choice between different oncoplastic techniques are determined mainly by the location of the tumor in the breast, tumor characteristics, extent of resection, breast characteristics (size, shape and glandular density), previous surgery, and the expectations and wishes of the patient.
Patients and Method:
Patients were not matched for age. Those who underwent a standard WLE included a total of 265 consecutive patients whilst 54 in number underwent OPS. The symptomatic and screening populations with a diagnosis of invasive cancer or DCIS were included. All patients were operated on by a team of breast surgeons. Appropriate axillary surgery was carried out at the time of the initial procedure. Intraoperative sentinel lymph node analysis was carried out with PCR analysis. If it it absolutely was reported as macrometastases, axillary lymphatic tissue clearance was performed. Intra-operative radiography of the excised specimens confirmed the presence of the lesion and determined that the lesion was clear of the margins. Final pathology results were discussed at the multi-disciplinary meeting. Patients who underwent a standard WLE were assessed for their suitability for a satisfactory cosmetic outcome. Therefore, in this procedure, no glandular mobilization was performed. According to the NICE guidelines, our criteria for margin clearance was 1mm for an invasive cancer and two mm for DCIS.
Results:
The procedures employed were the tennis racquet technique for upper outer quadrant tumors (n= 19); vertical scar techniques (n=15), Z-plasty techniques (n=13), Grisotti flaps (n=3), intramammary flaps (n=2), B-plasty (n=1) and reduction mammoplasty (n=1). There was a significant difference in the age of the patients (p=0.0003). Our results showed that OPS favored younger patients. Both groups showed a majority of ductal carcinomas, with lobular following second in the OPS group and DCIS in the WLE group. There was no significant difference between both groups in terms of the type (p value=0.2) and grade of the tumor . OPS excised a significantly larger tumor size compared to the WLE procedure (p<0.05). Significantly heavier specimens were removed from patients undergoing OPS relative to WLE (P<0.05) which is illustrated. The mean margin clearance for the OPS group was 4.7 mm. As for the WLE group, it was 3.5 mm. There was no statistical difference between the margin clearances of both of the groups (p value=0.10). Of the specimens with involved margins, 14 re-excisions and 5 completion mastectomies were performed in the WLE group. A further two completion mastectomies were due to one patient being identified as later having the BRCA1 mutation and another developing complications related to radiotherapy. In the OPS group there was two wider excisions and six completion mastectomies. Out of the six completion mastectomies in the latter group, three of these patients opted for a reconstruction. Two underwent implant based reconstructions, and one underwent a deep inferior epi gastric flap reconstruction. Margin involvement in the OPS group primarily affected those patients with lobular tumors or DCIS extending over 40 mm in size (n=6), while patients with involved margins in the WLE
group had ductal carcinoma or in situ disease.
Discussion:
We found that OPS was being performed on significantly larger tumors than those treated with a WLE (32.1 mm vs. 18.8 mm; p<0.05). This was similarly the case where the weight of the tumor was concerned (177 grams vs. 73.1 grams; p<0.05). Hence, some patients underwent a quadrantectomy which is not a routine practice in the UK. These procedures resulted in a decrease in the number of mastectomies we would have performed in these circumstances. The findings from our study are in agreement with the existing literature on operative outcomes in OPS surgery. Clough [15] and Down et al. have previously reported a preference for OPS in managing larger tumors. An average tumor size of 32 mm in a series of 101 therapeutic mammoplasties was reported by the former study, while the latter reported an average size of 23.9 mm in 37 OPS patients. Similarly, previous studies have reported specimen weights for therapeutic mammoplasty ranging from 222-236
Conclusion :
OPS was performed in patients with larger tumors suggesting it should be considered. Our study has demonstrated acceptable cosmetic outcomes and low recurrence rates.
Bottom line: This work is partly presented at 3rd World Conference on Breast and Cervical Cancer September 24-25, 2018 Abu Dhabi, UAE
The number of bariatric procedures performed each year has increased exponentially worldwide. Obesity is increasing at an alarming rate in the developed world, reaching epidemic proportions. In Europe one fifth of the population is obese [1]. Several studies have shown a significant weight loss in patients treated surgically, with a long-term maintenance of the weight loss and improvement in many of the obesity-related medical illnesses [2]. Peritoneal encapsulation is a very rare developmental malformation, characterized by the presence of an accessory peritoneal sheath covering part or the entire small bowel. Clinically, most of the cases are diagnosed as incidental findings during unrelated surgery, and only few presented as bowel obstruction [3-6]. The incidence of colon malrotation in adults has been estimated to be 0.2-0.5 % in older reports .the majority are asymptomatic; found incidentally at the time of another operation or radiologic examination, and very few will become clinically evident .
Case Report:
A 38 years old man with a long-standing history of morbid obesity and body mass index of 35.5 kg/m2 was schedule for laparoscopic Roux-en-Y gastric bypass and met the International Federation for the Surgery of Obesity, IFSO, consensus criteria for bariatric surgery [11]. Preoperative assessment was performed and the patient underwent surgeon, dietitian, nurse and anesthesiologist consults, and routine blood tests were run. The patient did not have other associated comorbidities or previous medical history, and no other preoperative radiological examinations were performed. He denied any abdominal complaints of pain, nausea, vomiting or constipation, and had no past surgical history. The patient underwent schedule LRYGB. The surgery was started routinely in French position, with the surgeon standing between the patient’s legs with the patient in reverse Trendelenburg position. The procedure was performed using four 12 mm trocars and a Nathan’s retractor to lift up the liver. the remainder trocars were placed over the right upper quadrant, midline, subxiphoid and left flank regions under direct laparoscopic.To identify the Treitz ligament, the proximal small intestine was not found in its usual location at the base of the transverse mesocolon. Instead, a peritoneal membrane was found at the place of the duodenaljejunal flexure. Despite extensive exploration, the anatomy could not be clearly defined, and an extra 12-mm trocar was placed in the left lower quadrant. The accessory peritoneal membrane lied posterior to the greater omentum, separating it from the small intestine. The colon and ileo-cecal valve were found at the normal position.
Discussion:
With the increasingly number of gastric bypass procedures for treatment of morbid obesity, unexpected challenges might encounter. This case highlights the need for bariatric surgeons to have full understanding of congenital anomalies and their management. Understanding the embryology and development of the midgut is essential in understanding and treating rotational defects of the intestines. The primitive digestive tube in the early embryo is a straight tube that consists of the foregut supplied by the celiac artery, the midgut supplied by the superior mesenteric artery (SMA), and the hindgut, supplied by the inferior mesenteric artery. a process divided in three stages: the first stage starts in the fifth g.w., when the midgut’s cranial limb will rise to the distal portion of the duodenum, jejunum and major portion of the ileum. the orientation of the limbs in the creation of the entero-enterostomy: laying the bilio-pancreatic limb towards the patient’s right side instead of the left, and the alimentary limb towards the left side instead of the right side like in the standard procedure, is the best orientation to prevent internal hernia, kinking and rotation. Moreover, a clear understanding and visualization of the anatomy are mandatory, and extra trocars should be widely used. In our case, the colon and caecum where placed in their normal position in the abdomen, no Ladd´s bands were found, but the Treiz’s ligament was rudimentary and the duodenal-jejunal junction was placed in the right upper quadrant. Both malformations take place in the same time frame of embryologic development, at 12th g.w.
Bottom line: This work is partly presented at Joint Conference on 6th International Conference on Clinical & Medical Case Reports & 11th Global Healthcare & Fitness Summit October 16-18, 2017 San Francisco, USA
We present evidence that reestablishing of P53 expression by transient transfection of P53 cDNA in these cells enhances the expression level of MDM2 p90 isoform. Chronic neutrophilic leukemia (CNL) could be a rare myeloproliferative neoplasm characterized primarily by leukocytosis, but often lacking distinct clinical, laboratory, and molecular features. Assessing the patient with an atypical myeloproliferative picture and correctly making the diagnosis of CNL can be challenging for pathologists and clinicians alike. The aims of this report are to detail the clinical case of a 59-year-old male veteran with initial presentation of hyperleukocytosis so as to demonstrate the laboratory and clinical criteria utilized to establish a diagnosis of CNL. We also briefly review the current literature on the diagnosis and treatment of CNL.
Keywords: MDM2, isoforms, p53, p90, progesterone, MCF-7, breast cancer
INTRODUCTION:
The mdm2 gene was originally cloned as an amplified gene on a murine double-minute chromosome in the tumorigenic 3T3DM murine cell line (Fakharzadeh et al, 1991). MDM2 expression is controlled at the transcriptional level from P53-independent (P1) and P53-responsive (P2) promoters (Zauberman et al, 1995), both encoding a 90 kDa full length MDM2 (p90) protein (Brown et al, 1999). In addition, MDM2 proteins of smaller sizes have been identified (Olson et al, 1993; Perry et al, 2000; Bartel et al, 2002). These differently sized proteins arise through either proteolytic cleavage (Pochampally et al, 1998), internal translational initiation (Saucedo et al, 1999) or alternative splicing (Sigalas et al, 1996; Matsumoto, 1998). Although the biochemical functions of these small proteins have not yet been determined, the MDM2-p90 isoform binds to and inactivates P53 tumor suppressor protein suggesting that MDM2 can function as a negative feedback regulator of P53 (Momand et al, 1992; Barak et al, 1993). Lukas et al (2001) suggested that MDM2 expression is altered in invasive breast cancer and is associated with more aggressive disease. We have recently demonstrated that the progesterone-induced growth inhibition of the MCF-7 human breast cancer cell line was associated with down-regulation of P53 endogenous levels (Alkhalaf and El-Mowafy, 2003). Because the regulation of MDM2 expression by P53 has been proposed by several authors to be the mechanism by which P53 balances its own activity (Juven et al, 1993; Midgley and Lane, 1997; Prives, 1998), we hypothesized that the decrease in P53 levels seen in MCF-7 cells treated with progesterone would affect MDM2 expression. We report here that in MCF-7 human breast cancer cells treated with progesterone, MDM2 p90 but not MDM2 p57 is down-regulated.Overexpression of P53 in MCF-7 cells stimulated the MDM2 expression and abrogated the effect of progesterone.
MATERIALS AND METHODS:
Cell lines and culture conditions:
The breast cancer cell lines MCF7, T47D, and MDA-MB231 were kindly provided by Bohdan Wasylyk (IGBMC Core Facility, Strasbourg, France). The MCF-7 cells contain functional P53 protein localized at the nucleus (Wasylyk et al, 1999) and classified as progesterone and estrogen receptor positive. The T47D cells have a mutated type of P53 which is localized in the cytoplasm (Schafer et al, 2000) and contain both estrogen and progesterone receptors. The cells were grown in RPMI1640 medium (Gibco BRL) supplemented with 5% fetal bovine serum, glutamine and gentamicin and maintained in a 5% CO2 humidified atmosphere in a 37 °C incubator.
Western Blot Analysis:
Cells were washed twice with PBS buffer then the preheated (95°C) lysis buffer [20 mM Tris-HCl pH 7.4, 20 mM dithiothreitol (DTT), 2 mM EDTA (sodium salt), 1% (v/v) Triton X-100, 1% (v/v) NP40, 1% (w/v) sodium deoxycholate, 1 mM sodium pyrophosphate, 1 mM sodium orthovandate (prepared in Tris buffer) and 1 mM phenylmethylsulphonyl-fluoride] was added directly to the cell monolayer. The cells were scraped and mixed with a rubber policeman, transferred to Eppendorf tubes and centrifuged at 13000 x g for 5 min. The resulting supernatant was saved and the protein was determined by the Bradford method. Extracts were boiled for 3 min in 2 x SDS buffer. Equal amounts of protein were loaded on 10% (w/v) polyacrylamide gels according to the method of Laemmli and then electrotransferred onto nitro-cellulose membranes. The blots were incubated first with anti-MDM2 (Ab-1, clone IF2) monoclonal antibody (Oncogene Research Product, Calbiochem). The antibody is directed against the N-terminal fragment between amino acid residues 26-169 of human MDM2 (Fakharzadeh et al, 1991) then incubated with peroxidase-conjugated anti-mouse IgG (Jackson Laboratory, USA) at 1/2000 dilution. Immunoreactive bands were visualized by incubation with luminol (according to manufacturer's instructions; ECL Western blotting detection system from Amersham). The blots were stripped and hybridized with P53 (DO1) monoclonal antibodies (Oncogene Research, Cambridge, MA, USA) and processed as for the MDM2 antibodies. The TATA- Binding Protein (TBP) monoclonal antibody was used as a loading control (kindly provided by IGBMC Core Facility, Illkirch, France). Another MDM2 antibody was used, MDM2 (C-18) purchased from Santa Cruz Biotechnology (California, USA). It is an affinity purified rabbit polyclonal antibody raised against a peptide mapping within the carboxyl terminal domain of MDM2 of human origin. A prestained SDS-PAGE molecular weight protein standards (low range) is used to estimate the molecular weights of proteins ((Bio-Rad, UK).
RESULTS:
The expression of MDM2 proteins in MCF7, T47D, and MDA-MB231 human breast cancer cell lines was analyzed by Western blotting with anti-MDM2 (Ab-1) monoclonal antibody. shows that, with this antibody, four MDM2 isoforms were detected, the p57, p76, p80, and p90 kDa in all three cell lines. A prominent expression of MDM2 p57 protein as compared to the p90, p80 or p76 was observed in the three cell lines used in this study. In MCF-7 cells that contained functional P53 protein, the endogenous MDM2 p90 protein level was higher than these in T47D and MDA-MB 230 cell lines (both have mutated P53 proteins). In contrast, MDM2 p57 appeared to be lower in MCF-7 as compared to its levels in the cells which have mutated P53. The high level of MDM2 p57 was observed in other breast cancer cells, a normal breast cell line and in other types of cancer cell lines .
Bottom line: This work is partly presented at 8th International Conference on Human Genetics and Genetic Diseases November 25-26, 2019 Madrid, Spain, USA
Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously obsessed on cocaine are reviewed.
Keywords: Drug abuse, Stimulants, Tolerance, Pharmacotherapies, Prodrug
Introduction:
Cocaine increases central catecholamines that are linked to its positive subjective and reinforcing effects . Drugs with similar pharmacological action to it of cocaine like d-amphetamine (AMPH) and medically formulated methamphetamine (METH) administered chronically produce tolerance to its reinforcing effects and should be useful in treating cocaine dependence.Accordingly, recent clinical studies show that AMPH attenuates cocaine’s positive subjective effects and that treatment with sustained-release METH reduces rates of cocaine positive urine and decreases craving for cocaine in cocaine-dependent individuals. Consistent with these studies, we review three unique case histories of METH-dependent participants previously obsessed on cocaine who abruptly stopped once they started using METH. In essence, they stated that METH “cured” them of their drug addiction.
Materials and Methods:
A detailed demographic and drug use history was obtained during a basic screening interview for admission into one of our clinical laboratory trials. Participants tested positive for METH on initial screening yet none demonstrated overt clinical signs of METH intoxication. Participant primary and secondary screens were reviewed. Inquiry was aimed at why they thought METH may have helped them and what new adverse consequences they may have experienced by abusing another highly addictive substance.
Results:
Participant 1 (P1):
P1 was a 40 year-old male Caucasian of Philippine descent who used cocaine and alcohol heavily before 2005. By his own estimation he was “severely” obsessed to cocaine and alcohol. Addiction to these substances directly contributed to numerous adverse interactions with law enforcement and irreparable harm in relations with his family and friends.. He described cocaine because the “ultimate evil” that brought out the “hater” in him. Depression, suicidal ideation, financial stress and threats of violence from cocaine dealers forced him to leave his home. Soon after he moved to Houston, he was given METH at a party and felt it had “benefitted his being”.. He stated emphatically that he had not used, nor had any searching for cocaine or alcohol, since first starting METH even when given the chance to use these substances. During screening, he reported that he used METH 25 days out of the 30 before to the interview and no cocaine or alcohol for 4 years. Similar to consequences he suffered when abusing cocaine, he continued to own financial and legal problems associated with his heavy METH intake. In contrast to his past cocaine and drug abuse, METH had no effects on his daily nicotine (1 pack per day) and cannabis (2 joints per day) use. In fact, P1 indicated that cannabis, but not nicotine, increased both the ‘high’ and ‘desire’ associated with using METH.
Participant 2 (P2):
P2 was a 40 year old, Caucasian male musician who had some success touring and recording with various popular bands in the 1980s and 1990s. According to P2, METH allowed him to be more productive even though he felt he rarely finished any projects he initiated. His last gainful employment was in 2009 teaching guitar lessons which he left likely due to paranoia secondary to METH. Similarly, P2 stated that the reason he left his last band was because the leader: “kept giving me that evil eye, ya know, when they look at you like that, it’s a bad sign. P2’s responses on multiple drug, use questionnaire indicated that cannabis reduced the ‘high’ associated with METH and decreased ‘desire’ for the drug whereas nicotine had not effect.
Participant 3 (P3):
P3 was a 30 year old Hispanic male, who had been using METH for 7 years. Similar to the participants reviewed above, P3 enjoyed METH’s cognitive effects and felt he was more productive yet he always needed money to support his large METH intake (approximately 1 gram per day). He was inconsistently employed and held numerous jobs often circumventing resources from them clandestinely. He also stated that METH enhanced his sexual performance, which was important to him since he worked in pornography.
Discussion:
These cases appear to support preclinical and clinical studies suggesting that chronic treatment with AMPH-like stimulants—such as METH—may be efficacious for cocaine dependence. Interestingly, each participant’s searching forcocaine was abolished once they began using METH. This could suggest that they are likely replacing one addictive substance for another similar to methadone maintenance therapy for opioid dependence. Still, once they started using METH, their searching for cocaine was abolished. This anecdote is according to recent controlled clinical studies showing that chronic treatment with AMPH blocks cocaine’s positive subjective effects and sustained-release formulations of METH decrease cocaine use in humans ..AMPH and METH are not viable treatments for cocaine dependence due to high abuse liability and obvious adverse social, financial and psychiatric consequences associated with use of these stimulants as demonstrated by the cases described above. Medications used to treat attention deficit hyperactivity disorder in children and adolescents in sustained – release formulations may be a better option. Also, stimulant pro-drugs like lisdexamfetaminedimesylate that’s activated only after its metabolized may offer a viable option since their inherent slow onset of action and entry into the CNS reduces abuse liability . Our research group is currently planning laboratory studies assessing stimulant pro-drugs as potential medications for cocaine dependence.
Bottom line: This work is partly presented at 8th International Conference on Addictive Disorders and Alcoholism May 17-18, 2018 Singapore
Ordered and self-organized nano-array structures have been developed by Mn2+ doping in TiO2 thin fi lms deposition on conducting substrates by dip coating technique. Mn doped TiO2 thin fi lms exhibits better bioactivity for enzyme immobilization and cyclic voltammetry measurement has been used for qualitative characterization of electrochemical induction of oxidation-reduction process in TiO2 and Mn doped TiO2 fi lms. Due to presence of Mn2+ ions at fi lm surface, current voltage characteristic of Mn doped TiO2 matrix was enhanced by a factor of ten and it had also reduced the crystallite size and promoted transformation of anatase to rutile phase of TiO2 . Urea concentration in the electrolyte was determined by observing chronoamperometry response on urease immobilized working electrodes. The urea detection sensitivity of the Mn doped TiO2 thin fi lms base platform was 2.3 μA mM−1 cm−2 which is about 15 times higher from only TiO2 base platforms. Such kind of enzyme–TiO2 /Mn nano-array electrode could contribute a potential prospect in low cost biomedical diagnosis..
Keywords: Nano-array structures; Mn doped TiO2 ; Chronoamperometry; Cyclic voltammetry
Introduction:
Application of nanoscale materials for electrochemical biosensors has been grown exponentially due to high sensitivity and fast response time . These factors eventually controlled by the interaction effectiveness and determine selectivity and sensitivity of materials for potential application in the area of biomedical diagnosis . Extensively TiO2 and TiO2 with different polymer matrixes have been used for different applications such as DNA biosensor, enzyme immobilized platforms, detection of Pseudomonas aeruginosa and detection of toxic compounds . Stability and usefulness of structural modification for efficient immobilization of biomolecules in TiO2 nanotube arrays based biosensor has been also discussed . It has been demonstrated that the large surface area, good chemical stability and nontoxicity of the TiO2 have been achieved with different nanocomposite and 3D macroporous structures . Electrochemical synthesis of titanium oxide nanotubes (TiO2 ) in different types of electrolytes and applications for biosensors applications has showed great interest . The length and pore diameter of the TiO2 layers have been tailored by varying electrolyte composition, applied potential, pH, and anodizing time . We report a new strategy for Mn2+ induced nano-arrayed structures in sol-gel derived TiO2 platforms for biosensing applications. Previously, anatase–rutile phase transformation of TiO2 in sol–gel method synthesized has been achieved by various amount of manganese (Mn) ions and has been reported to be among the most efficient transition-metal oxide catalysts for catalytic disposal of pollutants . However, using Mn doping with TiO2 for biosensor applications has not been explored.
Experimental:
0.25 mole of HNO3 was added to alcoholic solution of 0.5 M Ti(OBu)4 in 1:2 molar ratio of HNO3 : Ti(OBu)4 . After that 0.5 mole water was added to this solution drop wise using dropping funnel in 1:1 molar ratio of H2 O: Ti(OBu)4 . A clear yellowish, transparent and stable TiO2 colloidal sol was obtained. A stock solution of 0.5M Manganese (II) acetylacetonate (Mn(acac)2) was prepared in isopropanol. To prepare 5 mole % Mn2+ ion doped TiO2 sols of stock solution was added respectively to TiO2 sol. After 24 hours, the above solution used to coat the thin films by dip-coating technique at constant pulling speed 25cm/min on 2x4cm2 ultrasonically cleaned glass substrates under controlled relative humidity (30-40%) condition and room temperature. These samples were further dried at 100°C in electric oven for 60 minutes followed by annealing at 550°C for five hours in programmable furnace. All chemicals were analytical grade and purchased from Sigma Aldrich otherwise were specified. The TiO2 and TiO2 /Mn electrodes were immersed in 50 g L−1 urease prepared in 0.1M phosphate buffer solution for 12 h at 4°C. The enzyme immobilized electrodes were washed with phosphate buffer solution to remove unbounded sites.
Result and Discussion:
0. 2θ values of diffraction peaks observed in XRD spectra of undoped TiO2 were at 25.28, 37.78, 48.02, 53.92, 55.06, 62.72, 68.80, 70.36, and 75.12. These peaks were assigned to reflections from (101), (004), (200), (105), (211), (204), (116), (220), and (215) crystal planes, which mainly corresponds to anatase phase of TiO2 . Prominent diffraction peaks of 5 mole % Mn2+ doped TiO2 films 2θ values were at 25.41, 27.60, 36.13, 37.80, 39.24, 41.29, 44.13, 48.13, 54.46, 56.79, 62.59, 64.14, 68.79, and 75.12. These peaks were assigned to reflections from (101A), (110R), (101R) (004A), (200R), (111R), (210R), (200A), (211R), (220R), (204A), (310R), (116A), (215A) crystal planes, which corresponds to both anatase and rutile phase of TiO2 and notation ‘A’ and ‘R’ were associated with anatase and rutile. After Mn2+ doping in TiO2 the mix phase of anatase and rutile was obtained and a small shift in 2θ value was also observed. For analysis of particle size from XRD peak broadening, the strongest peak i.e. 101 was chosen and Debye-Scherrer’s equation was used for calculation. The calculated value of average crystallite size in pure & 5 mole % Mn doped TiO2 samples is 28±2 nm & 20±2 nm respectively. XRD studies showed decrease in crystallite size induced by the dopant ion, therefore more surface free energy in case of doped samples. Secondly, the incorporation of foreign atoms in a lattice of TiO2 can create defects during formation of original crystal lattice. These results agree with other reported work in literature on effects of manganese to accelerate anatase-to-rutile transformation [19]. The most common effect of incorporation of foreign atoms in a lattice is the defect formation in the original crystal lattice which could develops regular patterns of nano-structures.
Conclusion:
Mn induced nano-arrayed structured TiO2 platform has been developed by simple sol-gel process and dip coating techniques. Such types of platforms has demonstrated usefulness for biosensor which could provide more effective interaction areas and more feasible electron transfer interfaces to support amperometric response of electrode. On the base of enzyme catalysis and electrochemical reduction reaction under a potentiostatic condition, the biosensing application was achieved by applying the uresae–TiO2 /Mn electrode. This biosensor exhibited a very high sensitivity and low detection limit for urea detection. Such kind of enzyme–TiO2 /Mn nanotube array electrode could contribute a potential prospect in low cost biomedical diagnosis.
Bottom line: This work is partly presented at 9th Euro Biosensors & Bioelectronics Congress November 29-30, 2018 Dublin, Ireland
Chronic neutrophilic leukemia (CNL) is very rare myeloproliferative disorder that presents diagnostic challenges for both pathologists and treating clinicians. Because this disease entity is extremely rare, and because it’s typically a diagnosis of exclusion, its important for pathologists and hematologists to be accustomed to CNL when approaching the patient with a myeloproliferative clinical picture. Thus, the objectives of this report are: 1) to detail the clinical case of a 59 year old male veteran with initial presentation of hyperleukocytosis, 2) to review the differential diagnosis of a granulocytic myeloproliferative presentation and demonstrate the laboratory and clinical criteria utilized to establish a diagnosis of CNL during this case, and 3) to briefly review the current literature on the diagnosis and treatment of CNL
Keywords: Chronic neutrophilic leukemia; A typical chronic myelogenous leukemia; Myeloproliferative diseases
Introduction:
Chronic neutrophilic leukemia (CNL) could be a rare myeloproliferative neoplasm characterized primarily by leukocytosis, but often lacking distinct clinical, laboratory, and molecular features. Assessing the patient with an atypical myeloproliferative picture and correctly making the diagnosis of CNL can be challenging for pathologists and clinicians alike. The aims of this report are to detail the clinical case of a 59-year-old male veteran with initial presentation of hyperleukocytosis so as to demonstrate the laboratory and clinical criteria utilized to establish a diagnosis of CNL. We also briefly review the current literature on the diagnosis and treatment of CNL.
Case Report:
A 59-year-old male veteran presented to our facility (VA Connecticut Healthcare System, West Haven, CT, USA) with chief complaints of shortness of breath (SOB) and fatigue of approximately two weeks duration. The patient had been diagnosed with hypertension in the past and was taking amlodipine, labetalol, and aspirin. He had no relevant case history and was a non-smoker. On review of systems the patient denied wheezing, cough, orthopnea, syncope, chest pain, fever or any particular exacerbating or remitting factors for his current condition. Pertinent physical exam findings included a lethargic appearance, mild splenomegaly, and a 2x2x1cm fixed painless, hard mass on the right anterior mandible.
Imaging studies were also performed to investigate for the possibility of other malignant or reactive causes for the patient’s leukocytosis. Chest x-rays, performed on admission and on several days during the course of the patient’s hospital stay, showed some evidence of pulmonary congestion consistent with mild congestive heart failure, but without evidence of an infectious infiltrate or malignant process. A CT scan of the thorax performed on day 4 of admission showed mild, “non-specific” mediastinal adenopathy, without other significant findings. Retroperitoneal ultrasound demonstrated echogenic kidneys and a 4 cm hepatic cyst cluster, but no other significant abnormal findings. In the absence of any evidence for a reactive cause of the leukocytosis, a bone marrow aspirate and biopsy were performed. The bone marrow core biopsy was markedly hypercellular for age with a cellularity estimated at 90% (Figure 1a). Myeloid maturation was sequential with a predominance of mature granulocytes, mainly localized in interstitial areas (Figure 1b and 1c). proliferation but otherwise appeared normal and megakaryocytes were mildly increased with normal morphology .There was no relative increase in myeloblasts, eosinophils, basophils, or mast cells. Moderate focal reticulin fibrosis was noted in paratrabecular regions, but didnt reach to cortical areas. The bone marrow aspirate reiterated the core biopsy findings. There was toxic granulation noted on neutrophils and a few hypersegmentation noted on peripheral smear.
Discussion:
Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders characterized by proliferation of one or more elements of the neoplasms associated with abnormalities of PDGFRα and PDGFRβ were also essentially ruled out by negative molecular testing. Second, neutrophil precursors make up less than 10% of circulating leukocytes. Finally, the patient’s chronic, relatively indolent clinical course is consistent with most reports of CNL as opposed to atypical CML which often follows a rapid and aggressive downward course. In summary, this is a case of a 59-year-old man presenting with SOB and hyperleukocytosis ultimately diagnosed as CNL. This case demonstrates the issue in firmly establishing a diagnosis of CNL and the way clinical and laboratory criteria may be utilized to discriminate between similar, but distinct, disease entities. In this case, a diagnosis of CNL not only influenced the initial treatment choice, but also provided important prognostic implications. A lack of reproducible molecular abnormalities remains a major hurdle in clearly identifying CNL cases. Future work in characterizing the molecular profiles of this and other rare myeloproliferative neoplasms would aid not only in their classification and diagnosis, but could also yield novel treatment options.
Acknowledgments :
The authors wish to acknowledge the assistance of Dr. Nelofar Shafi for this case. This material is the result of work supported with resources and the use of facilities at the VA Connecticut Healthcare System.
Bottom line: This work is partly presented at 16th World Hematology Congress March 18-19, 2019 Rome, Italy
Background/Aims: (-)-Nutlin-3 (nutlin) may be a cis-imidazoline analog, which activates p53 by antagonizing murine double minute (Mdm2) protein. We therefore conducted a study in hairless mice to analyze the effect of topical nutlin on murine epidermis after UVB-radiation.
Methods: Animals were euthanized 24 hours after irradiation, the dorsal, treated skin was biopsied and fixed in 4% formalin. Sections were incubated with the antibodies against p53, thymine dimers and terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling (TUNEL).
Results: We showed here that nutlin was active after topical application in hairless mice and potentiated the p53 nuclear translocation in epidermal keratinocytes after ultraviolet B irradiation. Moreover, topical treatment with nutlin resulted in a decrease in the number of keratinocytes exhibiting positive nuclear staining for thymine dimers (P<0.05compared with the vehicle control) and decreased the frequency of apoptotic, TUNEL-positive cells (P=0.02).
Conclusion: We hypothesize that nutlin stimulates DNA photodamage repair in the epidermis and may prove useful for the chemoprevention of skin cancer.
Keywords: Nutlin-3; p53; Apoptosis; Thymine dimer; Hairless mice
Experimental Design:
Animals: Female C3.Cg/TifBomTac immunocompetent mice (age 15 weeks) were purchased from Taconic (Ry, Denmark). The mice were kept in an animal facility on a 12 h light/dark cycle at 23 - 24°C. Animal care and treatment followed Danish national guidelines.
Drug treatment, ultraviolet source and experimental design :
Mice were sedated with 0.05 ml HypDorm (fentanyl citrate 0.158 mg/ml, fluanisone 5mg/ml, midasolam 2.5mg/ml) and treated on one of the lateral halves of the back skin with 100 µl isopropanol solution of 43 mM nutlin [(-) 4-(4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4- methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2- one] (Cayman Chemical) 30 min before irradiation. The other half was treated with the same volume of isopropanol. The mice were then irradiated with 3 SED (100 mJ/cm2 ) UVB from a light source comprising an array of 6 TL12 tubes (Philips, Eindhoven, The Netherlands) and re-treated with nutlin or isopropanol, as above. Control mice were not irradiated. Animals were euthanized 24 hours after irradiation because studies in vitro in human skin and in vivo in mice skin suggest that after 24 hours about half of the CPD are repaired [5,6]. The treated dorsal skin was biopsied and fixed in 4% formalin.
Immunohistochemistry :
4 µm sections were cut from the paraffin embedded skin biopsies, deparaffinised with xylene, re-hydrated and incubated with the antibodies against p53 (rabbit, polyclonal, Novocastra Newcastle upon Tyne, UK) or peroxidase-conjugated monoclonal anti-thymine dimer antibody (Kamiya Biomedical, Seattle, WA). The antibodies were visualised using the LSAB+ System-HRP (Dako, Glostrup, Denmark). Terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling (TUNEL) was performed using the DeadEnd Colorimetric TUNEL system (Promega, Madison, WI). Apoptotic, TUNEL-positive cells were counted in a 3 mm long section of epidermis. The extent of thymine-dimer positivity was assessed on an ordered categorical interval scale: 1) 0% stained nuclei, 2) 1-25%, 3) 26-50%, 4) 51-75% positive nuclei. In no samples the frequency of positive nuclei exceeded 75%.
Results :
As shown in Figure 1, the p53 staining of unexposed epidermis revealed moderate immunoreactivity in the cytoplasm but not in the nuclei of epidermal keratinocytes. After UVB irradiation the cytoplasmic staining was more intense and single cell nuclei were stained positive for p53. In non-irradiated skin nutlin did not induce p53. Since it is known that p53 is induced by DNA photoproducts and p53 is involved in the repair of CPD [7] we stained skin biopsies with the antibody against thymine dimers. Topical treatment with nutlin resulted in an overall decrease in the number of keratinocytes exhibiting positive nuclear staining for thymine dimers.Nutlin treatment significantly inhibited the UVB-induced apoptosis (Figure 2C-D). TUNEL staining revealed 9.0 ±2.6 (mean ±standard deviation) TUNEL-positive cells / mm epidermal length in UVB-irradiated, vehicle-treated skin versus 1.7 ±0.5 TUNEL-positive cells /mm in the nutlin-treated skin (P=0.02, paired t-test).
Conclusions :
This study shows that the Mdm2 inhibitor, nutlin, activates p53 in the epidermis in UVB-irradiated mice. This was accompanied by a significant decrease in the frequency of the cells harbouring thymine dimers and diminished keratinocyte apoptosis. We suggest that the decreased apoptosis is caused by enhanced CPD repair due to p53 activation by topically applied nutlin. It is conceivable that nutlin may be used for chemoprevention of squamous cell carcinoma in humans.
Conflicts of Interest :
This study was financed solely by the Bispebjerg University Hospital and has not been supported by any pharmaceutical company.
Bottom line: This work is partly presented at 17th European Dermatology Congress March 01-03, 2018 | Paris, France.
Milton Guyer
Research and Reports in Medical Sciences received 13 citations as per Google Scholar report
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