Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

PROSPECTIVE OBSERVATIONAL STUDY ON ANTIBIOTIC-PRESCRIBING PATTERN AND MEDICATION ERRORS IN SURGICAL PROPHYLAXIS IN A SPECIALTY HOSPITAL

Objective: The objective was to study the antibiotic-prescribing patterns, identify the medication errors and impact of surgical antimicrobial prophylaxis (SAP) in preventing surgical site infection (SSI), and to understand the prescribers’ adherence to surgical prophylaxis guidelines. Methods: The study was conducted for a period of 6 months in all surgical departments of a specialty hospital. Data were collected from inpatients records. Australian guideline for SAP was used to assess the appropriateness in prescribing pattern. The sample size was calculated using Raosoft sample size calculator. Results: A prospective observational study was carried out among 178 patients. Of which, 100 were male and 78 were female. Four hundred and thirty-three antimicrobials were prescribed as pre- and post-operative surgical prophylaxis, among that 87% prescribed by brand name and 13% by generic. Seventy-one percent received single antimicrobial agent preoperatively, of which 99.5% prescribed as parenteral and 0.5% as oral formulation. Most often prescribed antibiotic was cefoperazone (28%) of cephalosporin group. Only 5.6% of cases had compliance with SAP guidelines. In this study, 11 patients affected with SSI due to inappropriate antibiotic selection and non-adherence to prophylactic antibiotic guidelines. Conclusion: The present study revealed that there is a poor compliance to SAP guidelines in terms of inappropriateness in antibiotic drug selection, dose, duration, and omission of drugs. Inappropriateness and non-compliance are mainly due to unavailability of clinical pharmacist to assist the physicians in the selection and administration of correct choice of prophylactic drug and unavailability of proper national or local guidelines. Hence, there is dire need to make local SAP guidelines to improve SAP-prescribing pattern

Estrogen receptor (ER)-β isoforms: A key to understanding ER-β signaling

Estrogen receptor beta (ER-β) regulates diverse physiological functions in the human body. Current studies are confined to ER-β1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-β4 and -β5 isoforms were obtained from a prostate cell line, and they exhibit differential expression in a wide variety of human tissues/cell lines. Through molecular modeling, we established that only ER-β1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-β2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-β4 and -β5 completely lack helix 12. We further demonstrated that ER-β1 is the only fully functional isoform, whereas ER-β2, -β4, and -β5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-β1 and enhance its transactivation in a ligand-dependent manner. ER-β1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (i) ER-β1 is the obligatory partner of an ER-β dimer, whereas the other isoforms function as variable dimer partners with enhancer activity, and (ii) a single functional helix 12 in a dimer is sufficient for gene transactivation. Thus, ER-β behaves like a noncanonical type-I receptor, and its action may depend on differential amounts of ER-β1 homo- and heterodimers formed upon stimulation by a specific ligand. Our findings have provided previously unrecognized directions for studying ER-β signaling and design of ER-β-based therapies

Kinetic analysis of estrogen receptor/ligand interactions

Surface plasmon resonance biosensor technology was used to directly measure the binding interactions of small molecules to the ligand-binding domain of human estrogen receptor. In a screening mode, specific ligands of the receptor were easily discerned from nonligands. In a high-resolution mode, the association and dissociation phase binding responses were shown to be reproducible and could be fit globally to a simple interaction model to extract reaction rate constants. On average, antagonist ligands (such as tamoxifen and nafoxidine) were observed to bind to the receptor with association rates that were 500-fold slower than agonists (such as estriol and β-estradiol). This finding is consistent with these antagonists binding to an altered conformation of the receptor. The biosensor assay also could identify subtle differences in how the same ligand interacted with two different isoforms of the receptor (α and β). The biosensor's ability to determine kinetic rate constants for small molecule/protein interactions provides unique opportunities to understand the mechanisms associated with complex formation as well as new information to drive the optimization of drug candidates