Malaria Control & Elimination

In present day scenario, tetrazole has gained increasing popularity due to its broad-spectrum of biological properties such as antitubercular, anticancer, antimalarial, antidiabetic, antifungal, anti-inflammatory activities etc. Tetrazole, beinga bioisostere of the carboxylic acid group can replace the carboxyl group in drugswhich can be utilized to increase the lipophilicity, bioavailability and to reduce theside effects of drugs. Many tetrazole containing compounds have already been used for the treatment of various diseases primarily due to their better pharmacokineticprofile and metabolic stability. Therefore, this heterocyclic tetrazole moiety having admirable biological, pharmaceutical and clinical applications can be considered as an important pharmacophore in the development of new drugs.The presentsurveyreviews the various approaches available for the synthesis of tetrazole derivatives along with the different biological activity of substituted tetrazole derivatives like antitubercular, anticancer, antimalarial, antidiabetic, and antifungal and anti-inflammatory. This survey will serve as a comprehensive database of the biological, pharmaceutical and clinical applications of tetrazole which will be beneficial in facilitating further research and development on the topic.

Statement of the Problem: Heritable susceptibility to tuberculosis (TB) is complicated and polygenic in the nature. 5-10% of humans that come in exposure with the bacterium Mycobacterium tuberculosis (Mt) will get the disease, provided no acquired- or congenital immunodeficiency were present. We still lack a viable explanation for the observed epidemiologic fact.

Method: Activation of macrophages via proinflammatory cytokines IFN-v and interleukin (IL)-17 can kill intracellular bacteria such as Mt. Instead, macrophages stimulated by the Toll-like receptor (TLR)-10 agonists show an anti-inflammatory effect. The TLR-10 acts by inhibiting the TLR-2 signaling from the cell membrane. The TLR-2 is the Mt-binding protein by which activated macrophages can internalize (and finish) Mt. Inactivation of the TLR-2 protein might create a risk for acquiring the disease. This was supported by our finding that TLR2 gene polymorphisms, which either inactivate the TLR2 gene product or have a dominant negative role in TLR-2-signaling, associated with elevated risk for tuberculosis in the Croatian Caucasian population.

Findings: The genome-wide study found that three single nucleotide polymorphisms (SNPs) within the HLA class II loci were significantly related with TB; suggesting that adaptive immunity is of paramount importance for defense against TB. In our studied population, SNP in the TLR10 gene was associated with risk for Tuberculosis, analyzed by the dominant model of inheritance. However, this was contrasted by the fact that SNPs in the IL17A&F genes were not.

Conclusion & Significance: Studying genetic risk by association studies or genome-wide screening led us to propose that clinical manifestation of TB is a state above certain risk-threshold. Threshold is achieved by deposition of seemingly minor susceptibilities divided between the hallmarks of the disease. The model suggests that every human population has its own criteria’s of genetic risks for TB.

Regarding genetic predisposition to tuberculosis, we advice that the maximal risk for clinical manifestation requires complementation of sub-risks divided among the hallmarks of the disease. Clinical tuberculosis would only be known if at least one from each group of the genes encoding putative 5 (perhaps 7) hallmarks of the disease are mutated or changed epigenetically. These mutations/changes could be either sporadic (usually by the influence of the environment like other infection (HIV), nutrition, smoking, radiation etc.) or inherited. Ignorance of the immune attack is one of the hallmarks for TB that is shared with cancer. Perhaps, a similar immunotherapy as the recent one used in treating immunogenic types of cancer (anti-PD1, or/and anti-CTLA4) could be also successful in therapy of (multi-drug) resistant TB.

Consequently, we believe that it is important to study genetic risk factors for TB in every human subpopulation similarly as it is done for cancer, especially now that novel immunotherapies, have opened new ways to treatment of advanced cases

Active tuberculosis is a multi organ disease caused by primary infection or as a reactivation of hidden tuberculosis. Accordingly, active tuberculosis could be primary tuberculosis or reactivation tuberculosis. Primary tuberculosis occurs when the immune system is unable to protect against the Mycobacterium tuberculosis bacterium (MTB) infection. Reactivation tuberculosis, as the name suggests, is the reactivation of contained mycobacterial infection. Reactivation Tb is the most common form of active tuberculosis,revealing 90% of the cases. The lung is the most commonly known organ, other organ systems commonly affected include the gastrointestinal system, the musculoskeletal system, the lymphoreticular system, skin, liver, and the reproductive system.

The World Health Organization (WHO) estimates that, annually, around 8 million people get active tuberculosis globally, and nearly 2 million people die from this disease. Of every 10 people infected with M. tuberculosis, one may develop an active infection at any point of time in their lifetime. The WHO reported in 2017 that the estimated global incidence rate for tuberculosis has decreased by 1.5% each year since 2000. However, despite these substantial gains and drastic global efforts to eradicate tuberculosis, the disease still accounts for significant morbidity and mortality worldwide. Developing countries like India, Pakistan, the Philippines, China, South Africa, Indonesia, and Nigeria experience the highest morbidity and mortality rates. When combined, these countries accounted for 64% of all tuberculosis-related deaths in 2016, according to the WHO.

According to the facts of physics, if temperature progresses, thermal expansion of an object is positive it will expand and with the decline in temperature, it will shrink. Pressure will increase due to an increase in temperature. On the contrary, during fever we can observe blood vessels and skin are shrunk, pressure decreases, body shivers, sleep increases, motion decreases, inflammation increases, body pain increases, blood circulation decreases, dislike cold things etc. In fever, the firing rate of Warm sensitive neurons declines, and the firing rate of cold-sensitive neuron increases. At the same time if we apply hotness from outside by thermal bag or if we drink hot water, our body responds according to the facts of physics: increase of temperature pressure will also increase, expands blood vessels and skin, body sweats, motion will increase, inflammation will decrease, body pain will decrease, blood circulation will increase, like cold substances etc. During fever, why do our body acts against facts of physics? When disease progresses, pressure and temperature will decline. Blood circulation will decrease due to a decrease of pressure. If the essential temperature of the body is going out, essential temperature and pressure will further decline. This will further endanger the life or action of the organ. When disease increases, it is the sensible and discreet action of the brain that tends to respond against facts of physics to sustain life or prevent organ. There is no way other than this for a sensible and discreet brain to prevent the life or organ. We will get a clear answer if we find out the purpose of fever, sensible and discreet action of the brain. No medical books clarify this. During fever, if the temperature of fever is not a surplus temperature or if it is not supposed to be eliminated from the body, the shrinking of skin and blood vessels, shivering of body, dislike towards cold substances etc., are a protective covering of the body to increase blood circulation to important organs of the body it is against the facts of physics.

According to the facts of physics, if temperature increases, thermal expansion of an object if positive it will expand and with decrease of temperature it will shrink. Pressure will increase due to increase of temperature. On the contrary, during fever we can see the following situations - blood vessels and skin are shrunk, pressure decreases, body shivers, sleep increases, motion decreases, inflammation increases, body pain increases, blood circulation decreases, dislike to have cold substances etc. The temperature increasing and decreasing controlled by brain. Disease or cause of diseases signals the brain to create fever and shivering. In temperature increasing hyperthermia, the firing rate of warm sensitive neurons increases, and inhibit cold sensitive neurons. Contrary to this during fever the firing rate of warm sensitive neurons decreases and the firing rate of cold sensitive neurons increases. In temperature decreasing hypothermia, as in fever the firing rate of warm sensitive neurons decreases and the firing rate of cold sensitive neurons increases. If the aim of cold sensitive neurons increasing their firing rates in hypothermia is to increase blood circulation, then the aim of cold sensitive neurons increasing their firing rates during fever is also to increase blood circulation. If the aim of shivering in hypothermia is to increase blood circulation, then the aim of shivering during fever is also to increase blood circulation. If set point is below there is no necessary of shivering to increase temperature. At the same time, if we apply heat from outside by thermal bag or if we drink hot water, our body acts according to the Facts of Physics -which means, if temperature increases pressure will also increase, expands blood vessels and skin, body sweats, motion will increase, inflammation will decrease, body pain will decrease, blood circulation will increase, like to have cold substances etc. We will get a clear answer if we discover the purpose of fever, sensible and discreet action of brain. No medical books have ever clarified this till date. When disease progresses, pressure and temperature will decline. Blood circulation will decrease due to decrease of pressure. If the essential temperature of the body is going out, essential temperature and pressure will further decrease. This will further endanger the life or action of organs. When disease increases, it is the sensible and discreet action of brain that tends to act against facts of physics to sustain life or protect organs. There is no way other than this for a sensible and discreet brain to preserve the life or organ. During fever, if the temperature of fever is not a surplus temperature or if it is not supposed to be eliminated from the body, the contraction of skin and blood vessels, shivering of body, an aversion towards cold substances etc. are a protective covering of the body to increase essential blood circulation to important organs of the body and this action is against the facts of physics. In all diseases, which decreases essential blood circulation, our body will acts against the facts of physics to increase essential blood circulation.

Foodborne illness afflicts people throughout the world. The CDC defines a foodborne disease outbreak as the occurrence of two or more similar illnesses resulting from intake of a common food. Each year, in USA, one in 10 people experiences a foodborne illness, 128,000 are hospitalized, 3,000 die, and 33 million healthy life-years are lost. While few patients with foodborne illness are alive with life-threatening symptoms, there are a number of foodborne infectious diseases and toxins that the emergency physician or other health care provider must consider in the reports of these patients. Given the frequency of international travel, as well as the risk relation with recurrent outbreaks of foodborne illness from commercial food sources, it is important to recognize various syndromes of foodborne illness, including those which may require specific analysis and management steps. Foodborne illness shows a significant public health threat to the United States. The disease is defined as any ailment associated with the ingestion of contaminated food and is most oft en associated with gastrointestinal symptoms, including diarrhea, nausea, and/or vomiting. Individuals who are aged less than 5 years or more than 60 years or who are immune compromised are at greatest risk for acquiring a foodborne illness. The most common cause of gastroenteritis is Salmonella infection. Annually, nontyphoidal Salmonella causes 1.2 million cases of foodborne illness and 450 deaths. Most Salmonella presence was attributed to seeded vegetables (6.9%), pork (4%), or vegetable row crops (1.7%).

Adults older than 65 years, people with weakened immune systems, and nonbreastfed infants are more likely to have severe infections. Approximately 8% of patients with nontyphoidal salmonellosis will develop bacteremia and require treatment with antibiotics, including ceftriaxone or azithromycin in children and a fluoroquinolone (commonly levofloxacin) or azithromycin in adults. The summer months (peaking in July or August) had the highest percentage of cases. The use of certain medications to reduce stomach acidity can increase the risk of Salmonella infection. The food safety systems in some countries does better consumer protection than others. This situation, combined with differing climates and ecologies, results in the association of different types of foodborne illness with different regions of the world. In a global economy, both people and food travel the world. Clinicians must consider foreign travel as well as the consumption of food from other parts of the world when determining the cause of foodborne disease. The point to decline the incidence of foodborne illness is prevention. Proper food storage, refrigeration, handling, and cooking are vital. Patients should be aware enough to avoid high-risk items such as unpasteurized milk and milk products, as well as raw or undercooked items like oysters, meat, poultry, and eggs. The use of more meals in the home may also decrease the risk of foodborne illness.

CDC defines a foodborne disease outbreak as the occurrence of two or more similar illnesses resulting from ingestion of a common food. The disease is defined as any filament associated with the ingestion of contaminated food and is most often associated with gastrointestinal symptoms, including diarrhea, nausea, and/or vomiting. It is important to identify various syndromes of foodborne illness, including those, which may require specific evaluation and management strategies. The food safety systems in some countries afford better consumer protection than others. This situation, combined with differing climates and ecologies, results in the association of different types of foodborne illness with different regions of the world. In a global economy, both people and food travel the world and can offer foodborne morbidity everywhere.

From eating contaminated food, anyone can get food-borninfection, which as case definition, includes specific criteria for person, place, time, and clinical aspects.

• Every country around the world, get medical social and economic sufferings from foodborne illnesses, which became a possible active today medical emergency everywhere.

• The population must be educated for good Hygiene uses, to avoid the illnesses.

• For protecting people from the disease, there is needed tosurvive correct each chain of food production: processing, transportation, handling, and all correct food preparation steps.

• To prevent a Food-born infection, there is necessary to washregular hands and surfaces, as more often possible.

• A useful prevent and control activity in Food born disease, is to put together: epidemiologists, environmental health specialists, laboratory specialists, clinicians, as all other specialists with possible enteric disease outbreak connections and therapy responsibilities.

Universal influenza vaccine is proposed and under development. Universal vaccine seems not to be payable for many people in developing countries, (dangerous pandemics usually start at developing countries from bird influenza). Artificial pandemics by infectious attenuated live vaccine are proposed. Ferret nasal mucosa is carcinized using carcinogen for easiness of incubation. Bird influenza virus is attenuated by reverse genetics. The virus is marked by green fluorescent protein. This attenuated virus is sprayed to many cultured cancer cell specimen incubated. In some specimen attenuated virus will mutate to increase in cancer cells, checked by green fluorescence. Then the virus is tested to infect ferret and then human volunteers without serious syndrome. Virus with strongest virus titer to infect ferret is selected as seed virus of infectious attenuated live vaccine. The seed virus will be increased in incubated cancer cells by bioreactors all over the world and sprayed to vulnerable people, e.g. soldiers, students, people in slams, medical staffs and people engaged in lifeline. Artificial pandemics of dangerous virus as H7N9, H5N1 etc. are to be created serially with few years interval. Artificial pandemic should be initiated before wild type pandemic starts. One reason is to avoid reassortment (mixture) of virus RNA and another is to avoid clinical confusion. It should not overlap with influenza season. All inclusive flu immunization is proposed and being worked on. All inclusive antibody appears not to be payable for some individuals in creating nations, (risky pandemics typically start at creating nations from winged animal flu). Fake pandemics by irresistible constricted live immunization are proposed. Ferret nasal mucosa is carcinized utilizing cancer-causing agent for ease of hatching. Winged creature flu infection is weakened by invert hereditary qualities. The infection is set apart by green fluorescent protein. This constricted infection is splashed to many refined malignancy cell example brooded.

In some example weakened infection will transform to increment in malignancy cells, checked by green fluorescence. At that point the infection is tried to taint ferret and afterward human volunteers without genuine condition. Infection with most grounded infection titer to taint ferret is chosen as seed infection of irresistible lessened live antibody. The seed infection will be expanded in hatched malignant growth cells by bioreactors everywhere throughout the world and showered to weak individuals, for example officers, understudies, individuals in pummels, clinical staffs and individuals occupied with help. Fake pandemics of perilous infection as H7N9, H5N1 and so on are to be made sequentially with not many years stretch. Counterfeit pandemic ought to be started before wild sort pandemic beginnings. One explanation is to maintain a strategic distance from reassortment (blend) of infection RNA and another is to keep away from clinical disarray. It ought not to cover with flu season.

Infectious attenuated live influenza vaccine of candidate virus of new influenza pandemic is to be distributed to many people. Artificial pandemic happens as people have no immunity against it. Resultantly, they will obtain basic immunity to the virus. So wild type outbreak of pandemic does not occur. Even if wild type human to human transfer occurs, the scale is of seasonal influenza and number of victims are much less. It should be started as it is ready. If artificial pandemic overlaps with wild type pandemic, reassortation (mixture) of RNA may happen in patients’ cell infected to both of them simultaneously. It should avoid influenza season of winter as well by the same reason. If infection is done intensively, artificial pandemic will be finished within 2 month all over the world (initiate on April or September). It will not increase virulence as 1918 Spanish influenza did during long period of transmission. Especially vulnerable people, e.g., soldiers, students, people in slums, medical staffs, and people engaged in lifelines, policemen, firemen, and officials of politics are to be eagerly infected by spray of live vaccine virus on the nose. As infectious live attenuated vaccine is incubated in nasal mucosal cancer, airborne transmission seems to be dominant and strongly infectious between people. Method to increase infectious attenuated vaccine and to distribute all over the world. Quality of Infectious attenuated live influenza vaccine should be kept assured concerning its infectivity, effectiveness against wild bird influenza, and minimal virulence. If once low quality infectious vaccine were infected to men, it will result pandemic with miserable result.