Interaction and simulation studies suggest the possible molecular targets of intrinsically disordered amyloidogenic antimicrobial peptides in Acinetobacter baumannii.

Acinetobacter baumannii is one of the causing agents of nosocomial infections. A wide range of antibiotics fails to work against these pathogens. Hence, there is an urgent requirement to develop other therapeutics to solve this problem. Antimicrobial peptides (AMPs) are a diverse group of naturally occurring peptides that have the ability to kill diverse groups of microorganisms. The major challenge of using AMPs as therapeutics is their unstable nature and the fact that most of their molecular targets are still unknown. In this study, we have selected intrinsically disordered and amyloidogenic AMPs, showing activity against A. baumannii, that is, Bactenecin, Cath BF, Citropin 1.1, DP7, NA-CATH, Tachyplesin, and WAM-1. To identify the probable target of these AMPs in A. baumannii, calculation of docking score, binding energy, dissociation constant, and molecular dynamics analysis was performed with selected seventeen possible molecular targets. The result showed that the most probable molecular targets of most of the intrinsically disordered amyloidogenic AMPs were UDP-N-acetylenol-pyruvoyl-glucosamine reductase (MurB), followed by 33-36 kDa outer membrane protein (Omp 33-36), UDP-N-acetylmuramoyl-l-alanyl-d-glutamate-2,6-diaminopimelate ligase (MurE), and porin Subfamily Protein (PorinSubF). Further, molecular dynamics analysis concluded that the target of antimicrobial peptide Bactenecin is MurB of A. baumannii, and identified other molecular targets of selected AMPs. Additionally, the oligomerization capacity of the selected AMPs was also investigated, and it was shown that the selected AMPs form oligomeric states, and interact with their molecular targets in that state. Experimental validation using purified AMPs and molecular targets needs to be done to confirm the interaction.Communicated by Ramaswamy H. Sarma.

Comparison of intracervical Foley catheter combined with a single dose of vaginal misoprostol tablet or intracervical dinoprostone gel for cervical ripening: a randomised study.

We compared two combined methods for cervical ripening before induction of labour (IOL) Women (n = 150) were randomised into Foley's-misoprostol (n = 75) and Foley's-dinoprostone (n = 75) groups. A single dose of vaginal misoprostol tablet (25 µg) or intracervical dinoprostone gel (0.5 mg) were used alongwith intracervical Foley's. The primary outcome was induction-delivery interval (IDI) and secondary outcomes were change in Bishop's score, oxytocin requirement, caesarean section (CS) rate, chorioamnionitis and neonatal outcome. The mean parity, gestation and indications for IOL were similar in the two groups. The IDI (19 h 37 min and 19 h 20 min; p = .683), cervical ripening time, oxytocin requirement, CS rate (18.7 and 25.4%, p = .322) and neonatal outcome were similar. Hyperstimulation developed in 2.7% women with Foley's-misoprostol and in 1.3% with Foley's-dinoprostone (p = .55). No woman had chorioamnionitis. Thus, these two combined methods of cervical ripening and IOL were observed to be similarly efficacious. A low incidence of hyperstimulation and no chorioamnionitis may be attributed to using a single dose of prostaglandins. Misoprostol may be substituted for dinoprostone in resource limited countries.Impact statementWhat is already known on this subject? Combined methods for cervical ripening (intracervical Foley's plus prostaglandins) before induction of labour (IOL) may be similarly or more efficacious than individual methods. Most studies comparing various combined methods have used repeated doses of prostaglandins. A combined method using repetitive doses of prostaglandins may increase the risk of hyperstimulation and also of infection consequent to repeated vaginal examination to administer prostaglandins. These two concerns may be offset by combining a single dose of prostaglandin with intracervical Foley's catheter.What do the results of this study add? Two combined methods for cervical ripening using a single dose of vaginal misoprostol (25 µg) or intracervical dinoprostone gel (0.5 mg) co-administered with intracervical Foley's catheter were found to be similarly efficacious. The IDI (19 h 37 min and 19 h 20 min; p = .683), cervical ripening time, oxytocin requirement, CS rate (18.7 and 25.4%, p = .322) and neonatal outcome were similar. The incidence of hyperstimulation was low (2.7 and 1.3% with Foley's-misoprostol and Foley's-dinoprostone, respectively) and no woman had chorioamnionitis.What are the implications of these findings for clinical practice and/or further research? Combined methods for cervical ripening using a single dose of prostaglandins (misoprostol or dinoprostone) were observed to be similarly efficacious. Misoprostol is a cheaper alternative to dinoprostone and may be utilised in resource limited countries. These methods may be compared with each other in more number of women in order to identify which combined method is more efficient and safe. Clinical Trials Registry of India: CTRI/2017/12/010738.

Cervical Cancer Screening in HIV-Positive Women in India: Why, When and How?

BACKGROUND: Cervical cancer is an AIDS-defining illness, and HIV-positive women are at high risk. The present study aimed to determine the magnitude of the problem, compare the performance of screening tests and assess factors affecting participation. METHODS: HIV-positive women aged 30-59 years attend the anti-retroviral therapy (ART) clinics were screened by conventional Pap, HPV testing (Hybrid Capture 2) and visual inspection with acetic acid (VIA). A cohort of HIV-negative women from the community matched for age and parity were screened similarly. Screen-positive women underwent colposcopy and biopsy. Factors affecting participation were assessed. RESULTS: Pap, VIA and HPV were positive in 48 (23.8%), 65 (32.2%) and 76 (37.6%) subjects, respectively, among HIV-positive women, and in 12 (5.9%), 10 (4.9%) and 12 (5.9%) subjects, respectively, among HIV-negative women. CIN2 + was present in 12 (6.4%) HIV-positive women and in 1(0.5%) HIV-negative woman (p = < 0.004). Sensitivity of HPV, Pap and VIA for detection of CIN2 + lesions was 91.7%, 75.0% and 75.0%, respectively; specificity was 68.4%, 83.9% and 72.5%, respectively. Lack of availability of screening facilities in the ART clinic and long waiting times were a strong deterrent to participation among HIV-positive women. CONCLUSIONS: There was higher prevalence of HPV infection and CIN2 + lesions in HIV-positive women. VIA showed equivalent sensitivity to Pap and could be a good substitute in low resource settings. Setting up cervical screening services in ART clinics and sensitising physicians can improve outcomes among these women.

A Systematic Study of the Prevalence and Risk Factors of CKD in Uddanam, India.

INTRODUCTION: Despite reports of a high prevalence of chronic kidney disease (CKD) from the coastal Uddanam region of Andhra Pradesh, India, there are no accurate data on the distribution of kidney function abnormalities and CKD risk factors in this region. METHODS: A total of 2419 participants were recruited through multistage cluster random sampling from 67 villages. Serum creatinine and urine protein creatinine ratio were measured using validated methodologies. All abnormal estimated glomerular filtration rate (eGFR) and urine protein creatinine ratio values were reconfirmed after 3 months. A range of sociodemographic factors were evaluated for their association with CKD using Poisson regression. RESULTS: Of 2402 eligible subjects (mean ± SD age, 45.67 ± 13.29 years; 51% female), 506 (21.07%) had CKD (mean ± SD age, 51.79 ± 13.12 years; 41.3% female). A total of 246 (10.24%) had eGFR <60 ml/min/1.73 m2, whereas 371 (15.45%) had an elevated urine protein creatinine ratio (>0.15 g/g). The poststratified estimates, adjusted for age and sex distribution of the region for CKD prevalence, are 18.7% (range, 16.4%-21.0%) overall and 21.3% (range, 18.2%-24.4% ) and 16.2% (range, 13.7%-18.8%) in men and women, respectively. Older age, male sex, tobacco use, hypertension, and family history of CKD were independently associated with CKD. Compared with those with higher eGFR, those with eGFR <60 ml/min/1.73m2 were older, were more likely to be uneducated, manual laborers/farmers, or tobacco users, and were more likely to have hypertension, a family history of CKD, a diagnosis of heart disease, and a lower body mass index. Among those with low eGFR, there was no difference between those with urine protein creatinine ratio <0.15 or >0.15, except a lower frequency of males in the former. CONCLUSION: We confirmed the high prevalence of CKD in the adult population of Uddanam. The cause was not apparent in a majority. Subjects with a low eGFR with or without elevated proteinuria were phenotypically distinct from those with proteinuria and preserved eGFR. Our data suggest the need to apply a population-based approach to screening and prevention and studies to understand the causes of CKD in this region.

Study to Test and Operationalize Preventive Approaches for CKD of Undetermined Etiology in Andhra Pradesh, India.

INTRODUCTION: High prevalence of chronic kidney disease (CKD) not associated with known risk factors has been reported from coastal districts of Andhra Pradesh. The Study to Test and Operationalize Preventive Approaches for Chronic Kidney Disease of Undetermined Etiology in Andhra Pradesh (STOP CKDu AP) aims to ascertain the burden (prevalence and incidence) of CKD, the risk factor profile, and the community perceptions about the disease in the Uddanam area of Andhra Pradesh. METHODS: Study participants will be sampled from the Uddanam area using multistage cluster random sampling. Information will be collected on the demographic profile, occupational history, and presence of conventional as well as nonconventional risk factors. Glomerular filtration rate (GFR) will be estimated using the Chronic Kidney Disease Epidemiology Collaboration equation, and proteinuria will be measured. All abnormal values will be confirmed by repeat testing after 3 months. Cases of CKD not associated with identified etiologies will be identified. Biospecimens will be stored to explore future hypotheses. The entire cohort will be followed up every 6 months to determine the incidence of CKD and to identify risk factors for decline in kidney function. Qualitative studies will be performed to understand the community perceptions and expectations with respect to the interventions. IMPLICATIONS: CKD is an important public health challenge in low- and middle-income countries. This study will establish the prevalence and determine the incidence of CKD not associated with known risk factors in a reported high-burden region, and will provide insights to help design targeted health systems responses. The findings will contribute to the policy development to tackle CKD in the region and will permit international comparisons with other regions with similar high prevalence.

Association of single nucleotide polymorphisms of adiponectin and leptin genes with breast cancer.

Single nucleotide polymorphisms (SNPs) in adiponectin gene [rs1501299 (+276G/T) and rs266729 (-11377C/G)] and one SNP of leptin gene [rs7799039 (-2548G/A)] are known to influence plasma levels of adiponectin and leptin respectively. Literature is scarce on the association of adiponectin gene polymorphism rs266729 with breast cancer. The present study was taken up to study these polymorphisms and their association with breast cancer. Ninety-three patients diagnosed with malignant breast cancer were included as cases along with 186 age matched healthy controls. Adiponectin +276G/T, -11377C/G and leptin -2548G/A polymorphism were studied using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). Adipokine levels in blood were measured using enzyme linked immunosorbent assay. Adiponectin +276G/T and leptin -2548G/A showed a significant increased risk for breast cancer even after adjusting for confounding variables like present age, age at menarche, age at first child birth and age at menopause. In the subset analysis, based on menopausal state, stronger association was observed between SNP in adiponectin gene +276G/T with the breast cancer in post-menopausal women after adjusting for all other variables. No association was found with adiponectin -11377C/G. No association of the gene polymorphisms with adipokine levels was observed. Also, no significant association was seen for the effect of gene-environment interaction i.e. presence of polymorphism with obesity and menopausal state for any of the SNPs studied. Adiponectin +276G/T is strongly associated with breast cancer in postmenopausal women while leptin -2548G/A polymorphisms is significantly associated with breast cancer irrespective of the menopausal state in south Indian subjects.

A Comparison of the Strength of Association of Reid Colposcopic Index and Swede Score With Cervical Histology.

OBJECTIVE: Colposcopic scoring systems provide an objective diagnosis and select patients who require treatment. A new scoring system, Swede score, has added lesion size as a parameter. This study aimed to compare the strength of association of Reid colposcopic index versus Swede score and assess their utility in low-resource settings. METHODS: In this prospective study, 150 women aged 30 to 59 years with abnormal screening result were enrolled. All women underwent colposcopy; the findings were scored by both Reid colposcopic index and Swede score, biopsy taken from all abnormal areas. Performances of both the scores were calculated. RESULTS: A total of 33 (22%) CIN 2+ lesions were detected. Reid colposcopic index at a cutoff of 5 had sensitivity, specificity, positive predictive value, and negative predictive value for detecting CIN2+ lesions of 96.97%, 95.35%, 88.89%, and 98.8%, respectively. Using Swede score at a cutoff of 8, sensitivity, specificity, positive predictive value, and negative predictive value were 42.42%, 100%, 100%, and 81.9%, and with a cutoff of 5, these were 100%, 88.37%, 76.74%, and 100%, respectively. The correlation coefficient (R) was 0.919. By Spearman rank correlation coefficient, the strength of correlation between Swede score and RCI was 0.937 (p < .001). CONCLUSIONS: Swede score can be used flexibly depending on the setting. The lower threshold (5) with high sensitivity can be used for screening, whereas the higher threshold (8) with high specificity can be used for screen-and-treat selection to decrease the overtreatment rate. Thus, it is a more attractive option for cancer prevention programs in low-resource settings.

Novel MntR-independent mechanism of manganese homeostasis in Escherichia coli by the ribosome-associated protein HflX.

Manganese is a micronutrient required for activities of several important enzymes under conditions of oxidative stress and iron starvation. In Escherichia coli, the manganese homeostasis network primarily constitutes a manganese importer (MntH) and an exporter (MntP), which are regulated by the MntR dual regulator. In this study, we find that deletion of E. coli hflX, which encodes a ribosome-associated GTPase with unknown function, renders extreme manganese sensitivity characterized by arrested cell growth, filamentation, lower rate of replication, and DNA damage. We demonstrate that perturbation by manganese induces unprecedented influx of manganese in ΔhflX cells compared to that in the wild-type E. coli strain. Interestingly, our study indicates that the imbalance in manganese homeostasis in the ΔhflX strain is independent of the MntR regulon. Moreover, the influx of manganese leads to a simultaneous influx of zinc and inhibition of iron import in ΔhflX cells. In order to review a possible link of HflX with the λ phage life cycle, we performed a lysis-lysogeny assay to show that the Mn-perturbed ΔhflX strain reduces the frequency of lysogenization of the phage. This observation raises the possibility that the induced zinc influx in the manganese-perturbed ΔhflX strain stimulates the activity of the zinc-metalloprotease HflB, the key determinant of the lysis-lysogeny switch. Finally, we propose that manganese-mediated autophosphorylation of HflX plays a central role in manganese, zinc, and iron homeostasis in E. coli cells.

Sister Mary Joseph's nodule as the first and only sign of recurrence in a case of stage Ia carcinoma ovary.

Sister Mary Joseph's nodule, a term coined by Sir Hamilton Bailey, describes the umbilical nodule associated with advanced intra-abdominal malignancy. It signifies extensive intra-abdominal disease with a poor prognosis and a median survival of 4-14 months. We describe a case in which discharge from umbilical nodule was the first sign of recurrence in carcinoma ovary. On laparotomy, besides extra-abdominal umbilical deposit there was no peritoneal disease.

Bone marrow involvement at presentation in pediatric non-haematological small round cell tumours.

Pediatric small round cell tumors (SRCT) are a group of neoplasms occurring in children, which have in common a cytomorphology of groups of small round cells with scanty cytoplasm. The common SRCT encountered are neuroblastoma, retinoblastoma, Ewing's sarcoma/peripheral neuroectodermal tumor (PNET), rhabdomyosarcoma and lymphoma which show varying degrees of bone marrow involvement and bone marrow evaluation forms a part of the initial staging procedure. This study was undertaken to evaluate marrow involvement at presentation in pediatric non hematological SRCT. 7833 bone marrow aspirates done over a period of three years in different malignancies were analysed and of these 180 aspirates were performed in patients of pediatric non hematological SRCT at presentation. These cases were evaluated in detail for incidence of marrow involvement. Thirty two (17.7%) cases showed marrow involvement and these cases have been analysed with respect to the primary tumor. The SRCT showing involvement of bone marrow included neuroblastoma (48.8%), retinoblastoma (11.1%), Ewing's sarcoma/PNET (8.6%) and rhabdomyosarcoma (3.2%). These findings are discussed in the light of available world literature.

Extreme grandmultiparity: is it an obstetric risk factor?

OBJECTIVE: To examine the perinatal outcome in women of extreme grandmultiparity (EGMP) in a setting with good socio-economic conditions and modern perinatal care. METHODS: About 1015 pregnant women with a parity of 10 and above who delivered at Al-Mafraq hospital, Abu Dhabi between 1992 and 1998 were compared with 2044 women of parity <5 and 1662 with parity of 5-9. RESULTS: Pregnant women with parity of 10 and above had an increased incidence of gestational diabetes (P<0.001) and macrosomia (P<0.001) and a reduced incidence of preterm delivery (P<0.0001) and induction of labor (P<0.0001). There were no significant differences between the groups regarding, antepartum hemorrhage, cesarean section rate and neonatal outcomes. CONCLUSION: Extreme grandmultiparity does not appear to be an independent risk factor for adverse perinatal outcome in the setting of good perinatal care.