E2 sequence variations of HPV 16 among patients with cervical neoplasia seen in the Indian subcontinent

OBJECTIVES: Specific nucleotide variations in the E2 DNA sequence were looked for in samples with an intact human papillomavirus (HPV) 16 episomal E2 DNA. METHODS: Ninety-two women, 76 with invasive cervical carcinoma and 16 with cervical intraepithelial neoplasia (CIN) were recruited. HPV DNA typing was performed by polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). Intact episomal E2 DNA of HPV 16 was detected by PCR. Important nucleotide variations in samples with amplifiable E2 DNA were detected by RFLP. Nucleotide sequencing was performed on representative samples to confirm RFLP findings. RESULTS: A total of 89 (96.7%) women were positive for HPV DNA. Of these, 56 (63%) were positive for HPV 16, and of these, 38 (68%) were positive for intact episomal HPV 16 E2 DNA while 18 (32%) were negative. Samples with intact episomal HPV 16 E2 DNA sequences were grouped into four different digestion profiles I to IV based on RFLP patterns. Digestion patterns revealed absence of any sequence variations in samples with digestion profile I and presence of a 2983 A-G variation in those with profile II. Samples with digestion profiles III and IV revealed three variations in the hinge region (3516 C-A, 3538 A-C, 3566 T-G) and two in the DNA binding domain (3684 C-A, 3694 T-A) of the E2 sequence. Sequencing performed on representative samples confirmed RFLP findings. CONCLUSIONS: PCR-RFLP helped in the identification of important HPV 16 E2 sequence variations, circumventing the need for sequencing. The presence of the nucleotide variations in positions that could alter the biological and immunological functions of the E2 protein combined with its increased occurrence in this study bring out the importance of these variations.     

Multiple structural features of steroids mediate subtype-selective effects on human alpha4beta3delta GABAA receptors

Neurosteroids have been shown to mediate some of their physiological effects via a modulatory site on type A inhibitory gamma-aminobutyric acid (GABAA) receptors. In particular, recent evidence has implicated selective potentiation of the delta subunit of GABAA receptors as an important mediator of in vitro and in vivo neurosteroid activity. However, this has been demonstrated for only a very small number of steroids, so both the generality of this finding, and the structural features of steroids which mediate functional delta-selectivity, are unclear. We have used a potentiometric assay based on fluorescence resonance energy transfer to measure GABA-activated responses in L(tk-) cells stably transfected with human GABAA receptor alpha4beta3delta and alpha4beta3gamma2 receptor subtypes. A set of 28 steroids were evaluated on these subtypes to characterise their functional potency and efficacy in modulating GABA responses. For most compounds there was a clear separation of their efficacy profiles between the receptor subtypes, with a substantially larger maximal response at the alpha4beta3delta receptor. 5beta-Pregnan-3beta-ol-20-one, 5beta-pregnane-3alpha,20beta-diol and 5beta-pregnane-3alpha,17alpha-diol-11,20-dione showed particularly high efficacy for alpha4beta3delta. No compounds were identified that simply inhibited responses at delta-containing receptors. However, 5beta-pregnane-3alpha,17alpha,20beta-triol, prednisolone 21-acetate, 4-pregnene-17alpha,20alpha-diol-3-one-20-acetate, 4-pregnen-20alpha-ol-3-one, and 5beta-pregnane-3alpha,17alpha,21-triol-20-one inhibited, though did not abolish, GABA responses at the alpha4beta3gamma2 subtype, while evoking modest-amplitude potentiation of alpha4beta3delta responses. Molecular modelling on this compound series using principal components analysis indicates that several structural features of steroids underlie their relative functional selectivity for potentiation of delta-containing GABAA receptors.     

Antinociceptive,anti-inflammatory,and antipyretic properties of an aqueous extract of <Emphasis Type="Italic">Dicranopteris linearis</Emphasis> leaves in experimental animal models

This study was performed out to establish the antinociceptive, anti-inflammatory, and antipyretic properties of an aqueous extract of Dicranopteris linearis leaves in experimental animals. The antinociceptive activity was measured using the abdominal constriction, hot plate, and formalin tests. The anti-inflammatory and antipyretic activities were measured using the carrageenan-induced paw edema and brewer’s yeast-induced pyrexia tests, respectively. The extract, obtained after 72 h soaking of the air-dried leaves in distilled water and then prepared in the doses of 13.2, 66.0, 132.0, and 660.0 mg/kg, was administered subcutaneously 30 min before subjecting the animals to the assays mentioned above. Generally, the extract, at all doses used, was found to have significant (P < 0.05) concentration-independent antinociceptive, anti-inflammatory, and anti-pyretic activity. In conclusion, the aqueous extract of D. linearis has antinociceptive, anti-inflammatory, and antipyretic activity, supporting previous claims of its traditional use by the Malays to treat various ailments, particularly fever.     

Phase II clinical trial with Praneem polyherbal tablets for assessment of their efficacy in symptomatic women with abnormal vaginal discharge (an ICMR task force study)

Abnormal vaginal discharge syndrome (AVDS) is a commonly observed gynaecological complaint for which women seek medical attention. The present study was conducted in six Indian Council of Medical Research centres with Praneem polyherbal tablets (PPT), to determine their efficacy in the treatment of symptomatic women with AVDS. Data are given on 141 subjects investigated. In total, 137 women (97%) reported complete (n=62, 44%) and partial (n=75, 53%) relief from symptoms after use of PPT for seven consecutive days. On speculum examination, 71 (74%) women were confirmed to be cured of AVDS. Microbiological tests could only be conducted microscopically for Trichomonas vaginalis, Candida albicans and bacterial vaginosis. It was observed that all women with T. vaginalis had this infection cured by PPT, and the cure rate was 77% for C. albicans and 68% for bacterial vaginosis. Seventy-eight women (55%) reported a transient burning sensation, mostly on the first 2 d of intake of PPT; however, they continued to use the tablets for the prescribed 7 d. This study lays the basis for an extended Phase II/III clinical trial, preferably randomized and comparing a larger number of women to confirm the safety and efficacy of PPT.     

Technical efficiency of peripheral health units in Pujehun district of Sierra Leone: a DEA application

Background  

The Data Envelopment Analysis (DEA) method has been fruitfully used in many countries in Asia, Europe and North America to shed light on the efficiency of health facilities and programmes. There is, however, a dearth of such studies in countries in sub-Saharan Africa. Since hospitals and health centres are important instruments in the efforts to scale up pro-poor cost-effective interventions aimed at achieving the United Nations Millennium Development Goals, decision-makers need to ensure that these health facilities provide efficient services. The objective of this study was to measure the technical efficiency (TE) and scale efficiency (SE) of a sample of public peripheral health units (PHUs) in Sierra Leone.     

Use of fermented foods to combat stunting and failure to thrive

OBJECTIVES: With the adoption of vigorous child survival strategies, infant and child mortalities in India have declined significantly, even among the poorest, most undernourished segments of the population. Of the surviving infants and children, however, many remain stunted and undernourished. The present study was based on the hypothesis that failure to thrive is the result of damage to the gut epithelium incurred during repeated bouts of gastrointestinal infections. Promoting the regeneration of the damaged gut epithelium through the use of lactobacillus-rich fermented foods may yield beneficial results. This low-cost procedure can be widely used, even in poor communities. The objectives of this study were to investigate the effect in poor Indian communities of supplementation with a probiotic on the growth of children (aged 2 to 5 years) with growth retardation and assess the difference in morbidity between those receiving the supplement (n = 50) and the control group (n = 50), mainly with respect to the frequency, severity, and duration of diarrheal episodes. METHODS: One hundred children aged 2 to 5 y from an urban slum of New Delhi were matched for their age (+/-36 d), sex and weight (+/-1 kg) and assigned to one of two groups (experimental n= 50 and control n= 50). The experimental group received a probiotic supplement (50 ml curd containing Lactobacillus acidophilus) and the control group received an isocaloric supplement daily for 6 mo. Weight, height, and morbidity profile with respect to diarrhea, fever, cough, and cold was recorded. RESULTS: Increases in weight (P < 0.002) and height (P < 0.001) were significantly greater in the experimental group than in the control group. In addition, after 6 mo, of supplementation, there were fewer cases of diarrhea (P < 0.005) and fever (P < 0.001) in the intervention group then in the control group. CONCLUSIONS: From this study, it can be concluded that 6 mo of probiotic supplementation may be beneficial with respect to decrease in diarrheal morbidity and accelerated growth in the experimental group.     

Progesterone receptor expression in medroxyprogesterone acetate-induced murine mammary carcinomas and response to endocrine treatment

Using medroxyprogesterone acetate (MPA) as a carcinogen, we were able to induce in BALB/c female mice, several progestin-dependent mammary ductal carcinomas that regress completely with estrogen or antiprogestins and are maintained by serial transplantations in syngeneic mice. Progestin-independent variants were subsequently generated or appeared spontaneously. Based on their response to estrogen or antiprogestins, we subdivided them into responsive progestin-independent (R-PI) variants which regress completely and unresponsive progestin-independent (UR-PI) carcinomas which are resistant to both families of compounds. In this study we have investigated progesterone receptor (PR) expression in six responsive progestin-dependent, six R-PI, and three UR-PI tumors. Progestin-dependent and R-PI tumors disclosed a higher expression of the PR_A isoform as compared with PR_B, as well as an additional band of 78 kDa that was not detected in uterine tissue; all were down-regulated by progestins. UR-PI tumors expressed lower levels of all bands in western blots, but were highly reactive by immunohistochemistry. PR RNA expression was detected in both, UR-PI and R-PI tumors. PR binding was comparable in progestin-dependent and R-PI tumors. In the three UR-PI tumors, only 29/61 (48%) of the samples evaluated showed low binding levels, the rest were negative. This report is the first to describe in an experimental model of breast cancer the expression of PR isoforms and their distribution. Our results suggest the expression of functionally altered isoforms in a subgroup of mammary carcinomas, which may explain their lack of hormone response.     

Identification of an Orally Bioavailable,Potent, and Selective Inhibitor of GlyT1

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Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome

Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.