Vitamin D deficiency: concern for rheumatoid arthritis and COVID-19?

Vitamin D is an immunomodulatory hormone with an established role in calcium and phosphate metabolism and skeletal mineralization. Evidence showing its immunological benefits by regulating essential components of the innate and adaptive immune system is prevalent. Vitamin D deficiency is reported worldwide and is thereby found to be associated with various immune-related diseases. Rheumatoid Arthritis and COVID-19 are two such diseases, sharing a similar hyperinflammatory response. Various studies have found an association of lower Vitamin D levels to be associated with both these diseases. However, contrasting data is also reported. We review here the available scientific data on risk factor association and supplementation benefits of Vitamin D in Rheumatoid Arthritis and COVID-19, intending to critically evaluate the literature.

Typhoid fever: Control & challenges in India.

Enteric fever is a common but serious disease that affects mostly children and adolescents in the developing countries. Salmonella enterica serovar Typhi remains responsible for most of the disease episodes; however, S. Paratyphi A has also been reported as an emerging infectious agent of concern. The control measures for the disease must encompass early diagnosis, surveillance and vaccine to protect against the disease. Sanitation and hygiene play a major role in reducing the burden of enteric diseases as well. The current status of diagnostics, the surveillance practices in the recent past and the vaccine development efforts have been taken into account for suggesting effective prevention and control measures. However, the challenges in all these aspects persist and cause hindrance in the implementation of the available tools. Hence, an integrative approach and a comprehensive policy framework are required to be in place for the prevention, control and elimination of typhoid fevers.

Malaria control in India: A national perspective in a regional and global fight to eliminate malaria.

Since the declaration of the vision of malaria eradication in 2007, the overall burden of malaria has been reduced substantially in many countries in the endemic world. This progress has, however, recently slowed worldwide and even an increase of morbidity and mortality has been observed in some regions. That reality has led to reflection on the strategy for malaria elimination, noting that focusing only on low transmission sites has competed with the efforts in countries that still have foci with high malaria burdens. This opinion piece outlines the collaboration of the ICMR-National Institute of Malaria Research (ICMR-NIMR) and other partner Institutions in India with the WorldWide Antimalarial Resistance Network (WWARN), one part of a global effort to manage the spread of Plasmodium falciparum parasites associated with antimalarial resistance.

Probiotic foods: can their increasing use in India ameliorate the burden of chronic lifestyle disorders?

Probiotics are defined as live microorganisms which, when ingested in adequate amounts, confer health benefits on the host. Chronic diseases such as diabetes, non-alcoholic fatty liver disease, coronary artery disease, a variety of chronic inflammatory disorders with an immune basis, and some forms of cancer are increasing in incidence around the world and in India, and may be attributable in part to rapid changes in our lifestyle. There is considerable public interest in India in the consumption of probiotic foods. This brief review summarizes the background of the gut microbiota, the immunological reactions induced by these, the evidence linking the microbiota to health outcomes, and the evidence linking the use of probiotics for amelioration of chronic lifestyle diseases.

Tackling the malaria problem in the South-East Asia Region: need for a change in policy?

Malaria is largely neglected in the South-East Asia Region (SEAR), although it has the highest number of people susceptible to the disease. Malaria in the SEAR exhibits special epidemiological characteristics such as "forest malaria" and malaria due to migration across international borders. The Greater Mekong Subregion (GMS) has been a focal-point for the emergence of drug resistant malaria. With the recent emergence of artemisinin resistance, coupled with the limited availability of insecticides, malaria control efforts in the SEAR face a steep challenge. Indirect man-made factors such as climate change, as well as direct man-made factors such as the circulation of counterfeit drugs have added to the problem. Increased monitoring, surveillance, pharmacovigilance as well as cross-border collaboration are required to address these problems. Regional networking and data-sharing will keep all stakeholders updated about the status of various malaria control programmes in the SEAR. Cutting-edge technologies such as GIS/GPS (geographical information system/global positioning system) systems and mobile phones can provide information in "real-time". A holistic and sustained approach to malaria control by integrated vector management (IVM) is suggested, in which all the stakeholder countries work collaboratively as a consortium. This approach will address the malaria problem in a collective manner so that malaria control can be sustained over time.

Multi-center surveillance for pneumonia & meningitis among children (<2 yr) for Hib vaccine probe trial preparation in India.

BACKGROUND & OBJECTIVES: Severe clinical pneumonia and meningitis caused by Haemophilus influenzae type b in children less than 5 yr old is preventable by use of Hib vaccine. However, data on Hib burden in India are limited. To support an evidence-based decision for Hib vaccine introduction in India, a vaccine probe study was planned. This paper presents the results of the preparatory phase for such a study, which aimed to determine the feasibility of conducting a randomized vaccine probe study and to estimate the incidence of all causes of pneumonia and meningitis. The preparatory study included population- based, hospital-based and carriage surveillance. METHODS: Children aged 18-24 months and were enrolled at PGIMER, Chandigarh, CMC, Vellore and NICED, Kolkata, from July 2005 to December 2006. At the time of enrollment, parents were informed about the signs and symptoms of pneumonia and meningitis, and were encouraged to take the child to study hospitals for treatment. Hospitalized children less than two years of age suspected of having pneumonia and/or meningitis were enrolled in study hospitals, whether or not they were from the cohort population. Patients were examined clinically and received chest radiograph for suspected cases of pneumonia or lumbar puncture for suspected cases of meningitis. Blood culture was done for both pneumonia and meningitis patients. Cerebrospinal fluid (CSF) was tested for biochemistry, culture, latex agglutination test and polymerase chain reaction. Nasopharyngeal swabs were collected from healthy children less than 2 yr of age at immunization clinics to estimate Hib carriage. RESULTS: A cohort of 17,951 children were recruited for the population-based arm. The incidence of severe clinical pneumonia ranged from 2717 to 7890 per 100,000 child-years of observation; suspected meningitis ranged from 1971 to 2433 per 100,000 child-years of observation. In the hospital-based study 7/90 (7.8%), 29/98 (29.6%) and 38/181 (21.0%) of CSF samples with cell count > or =100 WBCs/mm(3); were purulent at Chandigarh, Kolkata and Vellore respectively. Of these purulent CSF samples, Hib was detected in 2, 6 and 11 cases, respectively. The Hib nasopharyngeal carriage prevalence ranged from 6.0 - 7.6 per cent. INTERPRETATION & CONCLUSIONS: Incidence of severe clinical pneumonia is comparable with other studies from India but that of suspected meningitis is higher. Although rates of Hib meningitis cannot be calculated from a hospital-based study, there is evidence of Hib meningitis in these study settings. Hib carriage prevalence indicates that Hib is present and circulating in these study areas. There is a significant burden of pneumonia and meningitis among children in India. Continued strengthening of laboratory capacity and bacterial surveillance systems are necessary.

Natural prevalence of antibody titers to glucosyltransferase of Streptococcus mutans in serum in high and low caries active children.

In this investigation, serum immunoglobulin G (IgG) and immunoglobulin A (IgA) titers, as well as total immunoglobulin concentration (IgG + IgA + IgM), were found to be raised with the increase in the number of dental caries. Only the total serum antibody titer in high dental caries (HDC) group was found to be significantly raised as compared to no dental carries (NDC) group. Although the IgG and IgA titers were raised in blood with the increased number of caries, the results were not statistically significant. However, we could not find any correlation between serum antibodies and dental caries except that there was an increased trend of serum antibodies to GTF with the increased number of carious lesions.

Intestinal microbiota and vaccine efficacy in children from resource poor settings - potential impact for the usefulness of probiotics?

Developing countries continue to contribute significantly to the global burden of childhood mortality due to infectious diseases. Infections leading to diseases like diarrhoea, pneumonia and meningitis account for millions of deaths annually. Most of these diseases are preventable by vaccination and therefore global vaccination rates have risen substantially with clear benefits. But paradoxically, the vaccines have demonstrated lower immunogenicity in developing countries as compared to their industrialised counterparts. Malnutrition in resource poor settings along with repeated polymicrobial infections at early age are some of the reasons for the differences in vaccine efficacy in different settings. Recent studies indicate that the gastrointestinal microbiota possibly influences maturation of immune system as well as vaccine efficacy. In this review we discuss evidences from in vitro, animal and human studies showing that probiotics can positively modulate gut microbiota composition and exert immunomodulatory effects on the host. We also discuss how they should be evaluated for their ability to improve vaccine performance especially in low resource settings.

Trials of the killed oral cholera vaccine (Shanchol) in India and Bangladesh: Lessons learned and way forward.

Cholera has been endemic in India and Bangladesh for the greater part of recorded history, giving this region the reputation of being the 'homeland of cholera'. The causative organism Vibrio cholerae O1 has been responsible for large epidemics and pandemics. Bangladesh and India have conducted several sequential studies of Oral Cholera Vaccine (OCV) to ascertain its safety, efficacy, effectiveness, field feasibility and acceptance in high-risk urban populations. The objective of this article is to illustrate the experience of OCV use in these endemic settings, its major challenges, and how policymakers can grant vaccine licenses as well as implement its use in the national immunization programme. The relevant aspects of the OCV studies, such as boosting the effect of vaccine, single-dose versus double-dose trials and thermal stability of the vaccine during delivery have generated strong evidence for recommendation of vaccine use in these settings. Studies have shown that a single dose is effective for children of five years of age and older age groups. The locally manufactured vaccine in India is thermostable and can be delivered in field settings without use of cold chain. The vaccine delivery is feasible and the protective efficacy (PE) of this vaccine above five years of age against cholera was 53-65%. Administration of an OCV boosting regimen elicits an immune response similar to those who received a two-dose vaccine five years back. OCV can be used as a preemptive measure in endemic settings, in natural calamities and during political instability when there is total disruption as well as collapse of safe water supply, sanitation and hygiene (WASH) facilities and other control measures. Clear identification of areas and target population (who will gain benefit from the OCVs) is required to be developed in endemic settings.

Epidemiology of group A streptococcal pharyngitis & impetigo: a cross-sectional & follow up study in a rural community of northern India.

BACKGROUND & OBJECTIVE: Group A streptococcus (GAS) causes a wide array of human diseases. Epidemiological picture of streptococcal infection in India is not complete. Hence, disease burden due to GAS in 5-15 yr old school children in northern India was studied and emm typing of GAS isolates was carried out to help in designing prevention strategies. METHODS: A cross-sectional survey was carried out among 4249 school children (5-15 yr) from Raipur Rani Block of Panchkula district in Haryana during 2000-2002; 334 children were followed up fortnightly for one year. Standard clinical and microbiological procedures were used for collection of swabs from throat and skin and confirmation of GAS and its emm types. RESULTS: Of the 4249 children studied, 658 (15.5%) had pharyngitis; 579 of them could be swabbed, of which 2.8 per cent had GAS. From 3591 children without pharyngitis, 3385 who could be swabbed, GAS was found in 1.3 per cent of them. Impetigo was rare (0.7%), but 7.1 per cent (2/28) children had GAS. In the followup study, 17.4 per cent (776/4447 child-contacts) had pharyngitis, 761 could be swabbed and 2.4 per cent had GAS; among those without pharyngitis, 2016 swabs could be taken and GAS was found in 1.3 per cent; whereas only 2.6 per cent (2/75) of skin sores had GAS. Three children had GAS pharyngitis twice during follow up. Fourteen different GAS emm types were found. emm 71, 77 and 81 constituted 69 per cent of the pharyngeal isolates. GAS pharyngitis and impetigo were more common in winters and summers respectively. INTERPRETATION & CONCLUSION: In north India, pharyngitis was more common than impetigo. Most prevalent emm types of GAS in this region differ from those included in M protein-based vaccines.

Natural prevalence of antibody titres to GTF of S. mutans in saliva in high and low caries active children.

The present study was conducted to find out the role of natural immunity against dental caries. Whole stimulated saliva of various caries from active children was collected. Antigen glucosyltransferase (GTF) was prepared from Streptococcus mutans serotype C and the antibody titre was estimated using ELISA. Salivary IgG, s-IgA and total immunoglobulins (IgG + s-IgA+ IgM) concentration were assayed. The result showed an increased level of salivary IgG concentration with the increased number of dental caries, which was not statistically significant. But there were significant decrease of s-IgA titre as well as total immunoglobulin concentration in saliva with the increased number of dental caries. This study showed that because of lack of local immunity the children are more prone to dental caries.

Preparedness for AIDS vaccine trials in India.

India bears a heavy disease burden of HIV/AIDS infected and affected people. A safe, effective and accessible preventive AIDS vaccine, used along with other preventive interventions, is urgently needed to stem the epidemic. This review highlights the extensive preparedness activities undertaken from 2002 by the International AIDS Vaccine Initiative (IAVI), its Indian government and non government partners with the Indian scientific, political, media and community stakeholders and the capacity building process, before the conduct of the first ever AIDS vaccine trials in India in early 2005. Issues addressed included mistrust of clinical research due to past history of some unethical trials, transparency, community involvement, stigma and discrimination, provision for care and treatment of participants, informed consent, gender considerations, approval process, and operational aspects. The strong political support along with preparedness activities led to the successful conduct of AIDS vaccine trials enrolling equitably healthy women and men from all sections of society. This has paved the way for future vaccine trials in the country.

Cholera prevention and control in Asian countries.

Cholera remains a major public health problem in many countries. Poor sanitation and inappropriate clean water supply, insufficient health literacy and community mobilization, absence of national plans and cross-border collaborations are major factors impeding optimal control of cholera in endemic countries. In March 2017, a group of experts from 10 Asian cholera-prone countries that belong to the Initiative against Diarrheal and Enteric Diseases in Africa and Asia (IDEA), together with representatives from the World Health Organization, the US National Institutes of Health, International Vaccine Institute, Agence de médecine préventive, NGOs (Save the Children) and UNICEF, met in Hanoi (Vietnam) to share progress in terms of prevention and control interventions on water, sanitation and hygiene (WASH), surveillance and oral cholera vaccine use. This paper reports on the country situation, gaps identified in terms of cholera prevention and control and strategic interventions to bridge these gaps.

Nipah/Hendra virus outbreak in Siliguri, West Bengal, India in 2001.

BACKGROUND & OBJECTIVE: The viral encephalitides caused by animal or human viruses are characterized by sudden outbreaks of neurological disease in both tropical and temperate regions. An outbreak of acute encephalitis occurred in Siliguri (West Bengal) town of India between January 31 and February 23, 2001. This outbreak was investigated by a team of scientists from four major institutions, and the findings are presented here. METHODS: Detailed information about the outbreak was collected with the help of local health authorities. Limited entomological investigations were also done. Samples collected from cases and contacts were sent for analysis. RESULTS: A total of 66 probable cases and 45 deaths were reported. Epidemiological linkages between cases point towards person-to-person transmission and incubation period of around 10 days. There was neither any concurrent illness in animals nor was there any exposure of cases to animals. Centres for Disease Control and Prevention, Atlanta, USA concluded on the basis of tests carried out on serum specimen from four cases and two contacts that the causative pathogen appears to be Nipah/ Hendra or closely related virus. INTERPRETATION & CONCLUSION: This outbreak highlights the importance and urgency of establishing a strong surveillance system supported by a network of state-of-the-art laboratories equipped to handle and diagnose new pathogens and including patient isolation techniques, use of personal protective equipment, barrier nursing and safe disposal of potentially infected material in the prevention and control measures for Nipah/Hendra virus infection.

Role of intracellular second messengers and reactive oxygen species in the pathophysiology of V. cholera O139 treated rabbit ileum.

Vibrio cholerae O139 has pandemic potential and it produces copious amounts of fluid secretion. The levels of various second messengers (intracellular Ca2+, cAMP, IP3, PKC) were measured to determine the cause of fluid secretion produced by this strain of V. cholerae. There was a significant increase in the levels of these second messengers in V. cholerae O139 treated ileum as compared to control ileum (enterocytes). Levels of these second messengers were also assessed in V. cholerae 569B induced fluid secretion in rabbit ileum and it was found that the levels were raised more in V. cholerae O139 treated ileum than in V. cholerae 569B treated rabbit ileum. The intestinal damage was assessed by measuring changes in the extent of lipid peroxidation of the enterocytes. Intracellular second messengers are known to raise the extent of lipid peroxidation. In V. cholerae O139 treated loops calcium ionophore A23187 enhanced the extent of lipid peroxidation whereas l-verapamil could only marginally decrease the lipid peroxidation. Dantrolene and H7 significantly decreased the extent of lipid peroxidation of enterocytes in V. cholerae O139 treated rabbit ileum. However, PMA could not enhance further the extent of lipid peroxidation in V. cholerae O139 treated rabbit ileum. So intracellular calcium and protein kinase C appear to be involved in intestinal damage caused by V. cholerae O139. Reactive oxygen species are responsible for causing tissue damage and the extent of oxidative damage depends on the balance between the pro-oxidants and the anti-oxidants. So the changes in the enterocytes' antioxidant level during V. cholerae O139 mediated intestinal infection was estimated. There was a significant decrease in the enterocyte level of the antioxidant enzymes SOD, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase and glucose-6-phosphate dehydrogenase in V. cholerae O139 mediated intestinal infection. So a significant decrease in the levels of antioxidant defenses and a significant increase in the levels of second messengers appear to be important in mediating V. cholerae O139 induced lipid peroxidation which contributes to the changes in membrane permeability and thus to fluid secretion.

Studies on the mechanism of Salmonella typhimurium enterotoxin-induced diarrhoea.

The unidirectional fluxes of Na+ and Cl- were studied in Salmonella typhimurium enterotoxin-treated rats. There was net secretion of Na+ and Cl- in toxin-treated animals, while in control animals there was net absorption of these ions. In the presence of the Ca(2+)-ionophore, there was net secretion of Na+ and Cl- in the control group, while the ionophore enhanced the secretion of these ions in experimental animals. The calcium channel blocker, verapamil, decreased the secretion induced by salmonella toxin, but could not reverse the secretion to absorption. There was no difference in the net absorption of Ca2+ in both the control and experimental animals. There was a significant increase in the intracellular free calcium concentrations in enterocytes isolated from toxin-treated rat intestines as compared to that in enterocytes isolated from control animals. In the presence of PMA (phorbol-12-myristated-13-acetate) there was net secretion of Na+ and Cl- in the control group, while in the experimental group there was no change in the fluxes of these ions. The selective, potent inhibitor of protein kinase C, H-7 (1-(5-isoquinolinylsulphonyl)-2-methylpiperazine) reversed the secretion of Na+ and Cl- in the toxin-treated group to absorption. The addition of indomethacin also inhibited the secretion induced by salmonella toxin, but failed to reverse it to absorption. However, the addition both H-7 and indomethacin to the experimental group had a partial additive effect. These studies demonstrate that the Salmonella enterotoxin-mediated fluid secretion involves protein kinase C and the arachidonic acid metabolites and perhaps does not involve the extracellular calcium pools.

Study on the mechanism of Giardia lamblia induced diarrhoea in mice.

The transmucosal fluxes of Na+ and Cl- were studied in Giardia lamblia infected mice in the presence or absence of phorbol-12-myristate-13-acetate (PMA), the activator of protein kinase C (PKC) or 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H-7), the inhibitor of PKC or Ca(2+)-calmodulin. There was net secretion of Na+ and Cl- in infected animals, while in control animals there was net absorption of these ions. The addition of ionophore or PMA resulted in net secretion of Na+ and Cl- in the control group while in the infected group there was no change in the fluxes of these ions. The selective potent inhibitor of protein kinase C, H-7, reversed the secretion of Na+ and Cl- in infected group to absorption. The addition of PMA and Ca(2+)-ionophore together in the infected group had a partial additive effect. This study suggests that G. lamblia induced fluid secretion involves protein kinase C and further protein kinase C acts in synergism with calcium.

Calcium and protein kinase C play a significant role in response to Shigella toxin in rabbit ileum both in vivo and in vitro.

The role of second messengers in Shigella toxin (STx) induced fluid secretion in rabbit ileum was evaluated. In vivo and in vitro studies were carried out in presence or absence of following modulators: Ca2+ ionophore A23187 (15 microM), l-verapamil (200 microM), phorbol-12-myristate-13-acetate (PMA, 200 ng), 1-(5-isoquinolinyl-sulphonyl)-2-methyl-piperazine (H-7, 15 microg) and indomethacin (20 microM). In in vivo studies, the fluid accumulation into rabbit ileal loops in response to STx was measured in presence or absence of these modulators. In in vitro studies, unidirectional fluxes of Na+ and Cl- were carried out in presence or absence of these modulators. The addition of Ca2+ ionophore A23187 along with STx further increases the amount of fluid already induced by STx. Whereas the presence of l-verapamil along with STx did not decrease the amount of fluid induced by STx. In vitro findings were in consonance with the in vivo studies. A significant increase in inositol triphosphate (IP3) levels was observed in enterocytes isolated from STx treated rabbit ileum. The addition of PMA into rabbit ileal loops in presence of STx mimicked the effect of STx while the presence of H-7 reversed the secretion caused by STx to absorption. Similar results were obtained while determining unidirectional fluxes of Na+ and Cl- in presence of PMA and also with H-7. A significant increase in PKC levels was observed in the membrane fraction of enterocytes isolated from STx treated rabbit ileum as compared to control. Further a marked decrease in PKC levels was observed in the presence of H-7 in membrane fraction of enterocytes isolated from STx treated rabbit ileum. The addition of indomethacin into rabbit ileal loops reversed the secretion (caused by STx) to absorption. In vitro findings were in consonance with in vivo studies. Besides, there was a significant increase in PG-E levels in enterocytes isolated from STx treated rabbit ileum as compared to control. These findings suggested that STx induced enteritis involves the role of PKC, intracellular calcium stores and prostaglandins. The extracellular calcium pool probably does not play a significant role in this process.

Calcium and protein kinase C play an important role in Campylobacter jejuni-induced changes in Na+ and Cl- transport in rat ileum in vitro.

The pathophysiological mechanism of Campylobacter jejuni (enterotoxigenic) induced secretory diarrhoea remains least understood. To investigate the mechanism(s) involved, the unidirectional fluxes of Na+ and Cl- were measured across the C. jejuni live culture infected and control (non infected) rat ileum (unstriped), in vitro by Ussing technique under short circuit conditions, in the presence or absence of: Ca2+ ionophore A23187 (5 microM), 1-verapamil (100 microM), calmodulin (CaM) antagonist W-7 (100 microM), dantrolene (25 microM), protein kinase C (PKC) activator PMA (100 ng/ml) and H-7 (60 microM), selective inhibitor of PKC. There was net absorption of Na+ and enhanced Cl- secretion in infected animals while in control animals there was net absorption of Na+ and marginal secretion Cl-.Ca2+ ionophore A23187 mimicked the effects of C. jejuni infection whereas 1-verapamil had significant antisecretory effect on Na+ and Cl- secretion in infected animals. In vitro measurement of undirectional 45Ca fluxes in Ussing chamber experiments revealed net absorption of Ca2+ in infected rat ileum as compared to net secretion of Ca2+ in control rat ileum. These observations clearly indicate that there is increased stimulation of Ca2+ uptake from extracellular milieu to the enterocytes during C. jejuni-induced diarrhoea. The intracellular calcium levels (Ca2+]i (as measured by fluorescent probe Fura-2AM) were found to be raised significantly (P < 0.0001) in enterocytes isolated from C. jejuni infected ileum as compared to the enterocytes from control ileum. The observed increase in [Ca2+]i in enterocytes isolated from C. jejuni live culture supernatant treated rat ileum further shows the involvement of enterotoxin in diarrhoeal process. Dantrolene decreased significantly C. jejuni-induced net Na+ and Cl- secretion but it could not reverse it to absorption suggesting the partial involvement of Ca2+ mobilised from intracellular stores in mediating secretion. W-7 failed to inhibit the C. jejuni-induced net Na+ and Cl- secretion. In addition the CaM activity estimated in intestinal microvillar core remained same in both the control and C. jejuni infected animals. This indicates that C. jejuni-induced diarrhoea is not mediated through the activation of Ca(2+)-CaM complex pathway of the Ca2+ messenger system. The PKC activator PMA, induced net secretion of Na+ and Cl- in the control animals but it could not enhance further the C. jejuni-induced Na+ and Cl- secretion, suggesting that there is overlapping effect of PMA and C. jejuni live culture infection.(ABSTRACT TRUNCATED AT 400 WORDS)