A Review of the Economic Evidence of Typhoid Fever and Typhoid Vaccines.

Typhoid places a substantial economic burden on low- and middle-income countries. We performed a literature review and critical overview of typhoid-related economic issues to inform vaccine introduction. We searched 4 literature databases, covering 2000-2017, to identify typhoid-related cost-of-illness (COI) studies, cost-of-delivery studies, cost-effectiveness analyses (CEAs), and demand forecast studies. Manual bibliographic searches of reviews revealed studies in the gray literature. Planned studies were identified in conference proceedings and through partner organization outreach. We identified 29 published, unpublished, and planned studies. Published COI studies revealed a substantial burden in Asia, with hospitalization costs alone ranging from $159 to $636 (in 2016 US$) in India, but there was less evidence for the burden in Africa. Cost-of-delivery studies are largely unpublished, but 1 study found that $671 000 in government investments would avert $60 000 in public treatment costs. CEA evidence was limited, but generally found targeted vaccination programs to be cost-effective. This review revealed insufficient economic evidence for vaccine introduction. Countries considering vaccine introduction should have access to relevant economic evidence to aid in decision-making and planning. Planned studies will fill many of the existing gaps in the literature.

Antibodies that cross-neutralize the tier-2 pseudoviruses are produced in antiretroviral-naïve HIV-1-infected children from northern India.

In this cross-sectional study, we evaluated the efficiency of the plasma of 38 antiretroviral-naïve HIV-1-infected children from northern India against a standard panel of pseudoviruses (3 clade C and 3 clade B) by TZM-bl assay. Neutralization potential was observed to a variable extent, with a potency ranging up to reciprocal ID(50) titers of 1967. Cross-neutralization was observed in 28.9 % (11/38) of the children. There was a significant positive correlation between viremia and neutralization efficiency against two of the viruses studied (Du172 r = 0.49; p = 0.007 and RHPA r = 0.47; p = 0.01), suggesting that persistent antigenic stimulation is necessary for the generation of broadly neutralizing antibody responses in these children. Further mapping of the epitope specificities of the neutralization determinants in the polyclonal plasma would provide important information for immunogen design.

Pneumocystis jirovecii dihydropteroate synthase (DHPS) genotypes in non-HIV-immunocompromised patients: a tertiary care reference health centre study.

Studies on Pneumocystis jirovecii dihydropteroate synthase (DHPS) genotypes among non-HIV immunocompromised patients from developing countries are rare. In the present prospective investigation, 24 (11.8%) cases were found to be positive for Pneumocystis jirovecii out of 203 non-HIV patients with a clinical suspicion of Pneumocystis pneumonia (PCP). Dihydropteroate synthase (DHPS) genotype 1 (Thr55+Pro57) was noted in 95.8% P. jirovecii isolates in the present study in contrast to only 4.1% of patients with DHPS genotype 4 (Thr55Ala + Pro57Ser).

DC-SIGN and DC-SIGNR polymorphic variants in Northern Asian Indians.

Dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin-related protein (DC-SIGNR), along with DC-SIGN, is suggested to facilitate HIV infection of T cells in trans through binding with HIV gp120. We studied the repeat region polymorphisms in DC-SIGN and DC-SIGNR in 100 healthy HIV-1 seronegative individuals among Northern Asian Indians. Each variant polymorphism obtained by polymerase chain reaction (PCR) was confirmed by cloning and sequencing. Fifty-four per cent of the healthy seronegative individuals were homozygous for the DC-SIGNR 7/7 repeat. The heterozygous 7/5 variant was found in 25%, while the 5/5 homozygous genotype was found in 17% of the subjects. Allele 8 was rare and accounted for 4% of the heterozygous genotype (8/7) in the sample population. DC-SIGN polymorphism was rare, and the genotype 7/7 was most frequent in this study population. Further studies are warranted in a large sample size including high-risk and seropositive HIV patients to confirm the association of DC-SIGNR polymorphisms with HIV-1 susceptibility.

18F-FDG uptakes in leptomeningeal metastases from carcinoma of the breast on a positron emission tomography/computerized tomography study.

Leptomeningeal metastases (LM) are most commonly observed in hematological malignancies. With prolonged survival in solid tumors, an increased frequency of metastases is noted in these tumors too. Early diagnosis, when the patient has minimal neurological disability, is associated with prolonged survival and improved functional outcome although the therapy is palliative. The diagnosis of LM is difficult, and the demonstration of tumor cells in the cerebrospinal fluid remains the gold standard. This can also be done by definitive neuroimaging. MRI is routinely used in this aspect. We discuss here a case where 18F-FDG PET/CT (Fluoro-de-oxy glucose positron emission tomography/computerized tomography) study helped us in the diagnosis of LM. Whole-body PET/CT imaging could be a useful tool in identifying the possibility of metastases of breast carcinoma in the usual sites and the not-so-usual sites of metastases.

High prevalence of insulin resistance in postpubertal Asian Indian children is associated with adverse truncal body fat patterning, abdominal adiposity and excess body fat.

OBJECTIVE: The objectives were to study the relationships of insulin resistance with generalized and abdominal obesity, and body fat patterning in urban postpubertal Asian Indian children. DESIGN: Cross-sectional, population-based epidemiological study. SUBJECTS: In all, 250 (155 males and 95 females) healthy urban postpubertal children. MEASUREMENTS: Anthropometric profile, percentage of body fat (%BF), fasting serum insulin, and lipoprotein profile. RESULTS: Fasting insulin correlated significantly with body mass index (BMI), %BF, waist circumference (WC), central and peripheral skinfold thicknesses and sum of four skinfold thicknesses (Sigma 4SF) in both sexes, and with systolic blood pressure and waist-to hip circumference ratio (W-HR) in males only. Consistent increase in fasting insulin was noted with increasing values of central skinfold thickness at each tertile of peripheral skinfold thickness, WC, and %BF. Central skinfold thickness correlated with fasting insulin even after adjusting for WC, W-HR, and %BF. The odds ratios (OR) (95% CI) of hyperinsulinemia (fasting insulin concentrations in the highest quartile) were 4.7 (2.4-9.4) in overweight subjects, 8 (4.1-15.5) with high %BF, 6.4 (3.2-12.9) with high WC, 3.7 (1.9-7.3) with high W-HR, 6.8 (3.3-13.9) with high triceps skinfold thickness, 8 (4.1-15.7) with high subscapular skinfold thickness, and 10.1 (5-20.5) with high Sigma 4SF. In step-wise multiple logistic regression analysis, %BF [OR (95% CI): 3.2 (1.4-7.8)] and Sigma 4SF [OR (95% CI): 4.5 (1.8-11.3)] were independent predictors of hyperinsulinemia, similar to insulin resistance assessed by HOMA (homeostatic model of assessment) in the study. CONCLUSION: A high prevalence of insulin resistance in postpubertal urban Asian Indian children was associated with excess body fat, abdominal adiposity, and excess truncal subcutaneous fat. Primary prevention strategies for coronary heart disease and diabetes mellitus in Asian Indians should focus on the abnormal body composition profile in childhood.

Differential expression of CXCR4 receptor in early and term human placenta.

Chemokines and their receptors play a crucial role in regulation of T-cell migration and differentiation. Recent findings suggest that these proteins can also regulate cell functions such as angiogenesis and proliferation. Besides, CXCR4, a chemokine receptor, is one of the two major co-receptors for entry of the HIV virus during the late stages of HIV infection. We have studied the expression of CXCR4 in early (8-10 weeks) and term human placenta. Immunofluorescence staining and RT-PCR analysis revealed a differential expression of the CXCR4 receptor. Densitometric analysis revealed a two fold higher expression of the CXCR4 mRNA in early as compared to term placenta. This finding suggests that the expression of CXCR4 receptor may be developmentally regulated and its role in the early stages of pregnancy is implicated, when embryogenesis and organogenesis takes place. The fact that only 1-2 per cent of the placental transmission of the HIV virus takes place in the early placenta may also be correlated with our findings, suggesting that CXCR4 may not have a direct role in the transmission of HIV infection in the placenta.

Study of apolipoproteinc3 Sstl polymorphism in healthy volunteers from Northern India.

Several studies including a small case-control (hypertriglyceridemic/normotriglyceridemic individuals) study by us revealed close association between rare S2 allele ofAPOC3 Sstl polymorphism and hypertriglyceridemia. With the understanding that Asian Indians are highly vulnerable to the adverse effects of hypertriglyceridemia, we extended the investigation and studied the frequency distribution of this polymorphism in 216 healthy volunteers from Northern plains of India. We found that more than 50% of the study population had one or two S2 allele. This may suggest that a larger fraction of this population is genetically predisposed to hypertriglyceridemia.

Apolipoprotein E gene polymorphism in cerebrovascular disease: a case-control study.

The association between apolipoprotein E (apo E) polymorphism and stroke has been controversial. So far there are no studies reported on the polymorphism of apolipoprotein E in cerebrovascular diseases in the Asian Indians. A blinded case-control study was therefore undertaken and the apo E genotypes and lipid profile of a total of 120 subjects (63 stroke patients and 57 healthy controls) were done. The frequency distribution of apo E alleles and genotypes were assessed and their relation with the occurrence of stroke in Asian Indian subjects was determined. A significantly high frequency of apo epsilon4 allele (30%) was observed in the stroke patients than the controls (11%) (p < 0.005), and patients with epsilon4 allele had a fourfold higher odds to develop stroke OR (95%CI) 4.2 (1.8-10.1) (p < 0.005). On multivariate analysis, after adjusting for age, triglycerides and hypertension, the association of epsilon4 allele with stroke was found to be no longer statistically significant, OR (95%CI) 1.2 (0.4-4.5) (p = NS). On multiple logistic regression analysis age, OR (95%CI) 1.1 (1.1-1.2) (p < 0.001), and hypertension OR (95%CI) 15.1 (2.6-89.1) (p < 0.005) were found to be independent risk factors for development of stroke. This is the first report to have examined the association of apo E gene polymorphism with stroke in the Asian Indians. This study suggests that apo epsilon4 allele, triglycerides, age and hypertension are the predictors for stroke development.

Use of complement receptor 1 (CD35) assay in the diagnosis and prognosis of immune complex mediated glomerulopathies.

Complement Receptor 1 (CR1) is a polymorphic glycoprotein expressed on erythrocytes, leukocytes and glomerular podocytes and has a major role in immune complex processing. In addition, it regulates the complement cascade activation by preventing formation of classical and alternative pathway convertases and by acting as a cofactor for Factor I mediated cleavage of C3. In this study, we have examined the expression of erythrocyte CR1 (E-CR1) and glomerular CR1 (G-CR1) in different kinds of nephropathies using ELISA and immunofluorescence microscopy to understand their role in immune complex (IC) mediated renal diseases. E-CR1 was significantly reduced in all categories of lupus nephritis in comparison to normal subjects and non-IC renal diseases. However, other IC mediated diseases like IgA nephropathy and membranoproliferative glomerulonephritis had normal E-CR1 levels. G-CR1 showed distinct differences between IC and non-IC mediated diseases. G-CR1 was virtually absent in lupus kidneys. In other IC mediated diseases, there was a correlation of G-CR1 expression to the IC and complement fragment deposition. G-CR1 serves as a useful diagnostic marker for IC mediated diseases while E-CR1 is useful as a prognostic marker to monitor the course of disease after the treatment has initiated.

A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer.

Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1; vincristine 1 mg/m2 on day 8; and ifosfamide 1.2 gm/m2 on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.

Relation between plasma leptin and anthropometric and metabolic covariates in lean and obese diabetic and hyperlipidaemic Asian Northern Indian subjects.

This study investigated the relationship of plasma leptin to obesity, diabetes and hyperlipidaemia in Asian Northern Indian subjects, considered to have a predisposition to abdominal obesity and metabolic syndrome. A total of 72 subjects, subcategorised into lean and obese healthy subjects, lean and obese Type 2 diabetic and lean and obese non-diabetic hyperlipidaemic subjects were recruited. High leptin values were observed in all obese groups, and obese diabetic patients showed the highest levels. In lean and obese diabetic subjects, plasma leptin did not show any correlation to any index of glycaemia. When all lean and all obese subjects were analysed in two separate groups, body mass index (BMI), percent total body fat, and body density significantly correlated with the plasma leptin levels (p<0.05). Leptin values, when correlated to all variables in all patients taken together, showed the greatest magnitude of correlation with BMI (r=0.64), percent total body fat (r=0.67), and waist circumference (r=0.51). Strong inverse correlation was seen with body density (r=-0.67). Levels of serum insulin did not show any correlation with leptin levels in all subjects combined, and separately in various groups. Multiple linear regression analysis performed in obese, non-diabetic and normolipidaemic subjects, all Type 2 diabetic and all non-diabetic hyperlipidaemic subjects separately showed that percent total body fat is the only significant predictor of plasma leptin concentration in all the 3 groups. The present study suggests that plasma leptin has a strong positive correlation with percent total body fat in Asian Northern Indian subjects. Among other components of metabolic syndrome, only abdominal obesity is weakly correlated to serum leptin levels.

Oncogene expression as detected by immunocytochemical staining in hormonally induced ovarian cell lines.

To understand the nature and extent of oncogene involvement in the development of neoplasia, an experimental model of goat ovarian granulosa cells stimulated by LH was chosen. In the course of these studies, several cell lines were developed which were essentially non-tumorigenic primary cell lines. One of them, however, was spontaneously transformed being immortalized and tumorigenic. These cell lines, transformed and non-transformed, should serve as contralateral cell lines to study differential oncogene expression in hormonally induced cell proliferation, and elucidate possible hormone-oncogene nexus which may be operative in the genesis of cancer. In the present report, we have studied expression of c-myc, c-ras, c-myb, c-fos and c-sis cellular oncogenes in the cell lines by immunocytochemistry using monoclonal antibodies. In the rest of our text we refer to these cellular oncogenes as oncogenes. The results reveal differential expression of the oncogenes. The striking difference between the non-transformed AIMS/GRXII cells and the transformed AIMS/GRXVIII cells was the absence of ras protein expression in the transformed AIMS/GRXVIII cells which intensely expressed the c-myc, c-myb, c-fos, and c-sis proteins. c-ras protein was expressed in the non-transformed AIMS/GRXVIII cell line and primary cultures. c-myc protein was expressed exclusively in the AIMS/GRXVIII transformed cells. The myc activity seen in the transformed cell line may be correlated to cell proliferation. These results show the variation of phenotype in cell lines derived from a single tissue source.

Problem based learning as a curricular strategy for medical undergraduates: a tutor's experience.

This article focuses on the experiences and role of a tutor while conducting a problem based learning (PBL) exercise to facilitate the learning of biochemistry and molecular biology. A case presentation of sickle cell anemia was used to frame a module. The objective of this experimental exercise was to assess the suitability and effectiveness of problem based learning in the first year of undergraduate medical course and to practice self-assessment by tutors in this new role of a facilitator of learning through small group discussion. A tutor during such a learning session encouraged the students to apply their reasoning to analyze the problem and to develop self-directed learning skills in acquiring the knowledge appropriate to their perceived needs to work on a problem. The tutors ensured that they apply this knowledge in their work with other similar problems that they would encounter later in life.

LP(a) phenotypes and levels in angiographically proven coronary heart disease patients and controls.

Lipoprotein Lp(a) excess has been identified as a powerful predictor of premature atherosclerotic vascular diseases. To evaluate this in a North-Indian population, 130 CAD patients and 130 controls were analyzed. The size of the apo(a) phenotypic isoforms was inversely proportional to Lp(a) concentrations. The mean concentration of Lp(a) in the CAD patients was 42±34 mg/dl whereas in the normal subjects it was much lower, 27±27 mg/dl. 157 subjects out of the total 260 subjects showed plasma levels of >20mg/dl. The frequency of high Lp(a) levels was much higher in patients(73%) than controls (43%). These data suggest (1) that there is heterogeneity of the Lp(a) polymorphism, (2) Higher Lp(a) levels were found in patients than in the controls, (3) Patients showed 1.5 fold increase in Lp(a) levels as compared to the controls. We conclude that low molecular weight apo(a) isoforms are significantly associated with increased risk of CAD in the North-Indian population.

Differential expression of multidrug resistance gene product, P-glycoprotein, in normal, dysplastic and malignant oral mucosa in India.

Multidrug resistance (MDR) in human cancer is often associated with over-expression of the mdr-1 gene, which encodes a 170-kDa transmembrane protein, termed P-glycoprotein (P-gp). We evaluated the immunoreactivity of P-gp in oral tissues at different stages of tumorigenesis in the Indian population by flow cytometry, using the MRK-16 monoclonal antibody, which recognizes an external epitope of P-gp. The expression of P-gp was studied in human oral normal tissues (12 cases), dysplastic lesions (13 cases), primary untreated squamous-cell carcinomas (12 cases) and recurrent tumors (18 cases). Quantitative flow-cytometric analysis of P-gp expression showed a significant increase in P-gp levels in untreated primary oral tumors (p < 0.01) and in dysplastic lesions (p < 0.05) as compared with normal oral tissues. A marked significant increase in P-gp expression was observed in recurrent oral carcinomas as compared with normal oral tissues (p < 0.001) and dysplastic lesions (p < 0.01). Among recurrent tumors, a significant increase in the level of P-gp was observed in T4-stage tumors as compared with T3-stage tumors (p < 0.01). We conclude that P-gp is differentially expressed during oral tumorigenesis, and may be an indicator of the biological behavior of oral malignancies.