De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Pregnancy outcomes in type 2 diabetic patients as compared with type 1 diabetic patients and nondiabetic controls.

OBJECTIVE: To characterize the neonatal and maternal outcomes of type 2 diabetic patients as compared with type 1 diabetic patients and nondiabetic controls. STUDY DESIGN: We performed a retrospective cohort study reviewing perinatal outcomes of type 1 and type 2 diabetic patients and nondiabetic controls from July 2000 to August 2006. Analysis of variance, t testing and chi2 analysis were used to compare groups. Post hoc power analysis indicated 80% power was necessary to detect a 15% difference in composite poor neonatal outcomes. RESULTS: A total of 64 type 2 and 64 type 1 diabetic patients were compared with 256 controls. Type 1 diabetic patients had higher incidences of composite poor neonatal outcome and congenital anomalies than did type 2 diabetic and control patients. Both diabetic groups had similarly higher incidences of cesarean delivery, preeclampsia, preterm delivery, polyhydramnios and macrosomia than did controls. CONCLUSION: Type 2 diabetic patients have a decreased incidence of adverse neonatal outcomes when compared with that of type 1 diabetic patients. No difference was observed between the diabetic groups in the incidence of a majority of the adverse maternal outcomes examined, however both diabetic groups had overall worse outcomes that did nondiabetic controls.

Maternal serum alpha-fetoprotein values in type 1 and type 2 diabetic patients.

OBJECTIVE: Maternal serum alpha-fetoprotein (MSAFP) values are reported to be lower in type 1 diabetic patients, and a correction factor is often applied. We sought to determine whether type 2 diabetic patients require the same MSAFP adjustments as type 1 diabetic patients. STUDY DESIGN: We performed a retrospective review of MSAFP levels from a university laboratory in type 1 and type 2 diabetic patients between July 2000 and August 2006, matched 1:2 with controls. Groups were compared using analysis of variance and Student t testing. RESULTS: Seventy-seven type 1 and 75 type 2 diabetic patients were compared with 304 controls. Type 1 and type 2 diabetic patients differed significantly from each other and controls before corrections. Diabetic patients were similar to each other, but significantly lower than controls, after weight corrections. These differences were eliminated by a 10% correction factor. CONCLUSION: Type 1 and type 2 diabetic patients require both weight and diabetes corrections to adjust MSAFP values to nondiabetic levels.

What are patients seeking when they turn to the Internet? Qualitative content analysis of questions asked by visitors to an orthopaedics Web site.

BACKGROUND: More people than ever are turning to the Internet for health-related information, and recent studies indicate that the information patients find online directly affects the decisions they make about their health care. Little is known about the information needs or actual search behavior of people who use the Internet for health information. OBJECTIVE: This study analyzes what people search for when they use a health-education Web site offering information about arthritis, orthopaedics, and sports-medicine topics. Additionally, it determines who is performing these searches: is it patients, friends or relatives of patients, or neither? Finally, it examines the similarities and differences among questions submitted by Web site visitors from different countries. METHODS: Content analysis was performed on 793 free-text search queries submitted to a patient-education Web site owned and operated by the Department of Orthopaedics and Sports Medicine at the University of Washington Medical Center. The 793-query data set was coded into 3 schemes: (1) the purpose of the query, (2) the topic of the query, and (3) the relationship between the asker of the query and the patient. We determined the country from which each query was submitted by analyzing the Internet Protocol addresses associated with the queries. RESULTS: The 5 most frequent reasons visitors searched the Web site were to seek: (1) information about a condition, (2) information about treatment, (3) information about symptoms, (4) advice about symptoms, and (5) advice about treatment. We were able to determine the relationship between the person submitting the query and the patient in question for 178 queries. Of these, the asker was the patient in 140 cases, and the asker was a friend or relative of the patient in 38 cases. The queries were submitted from 34 nations, with most coming from the United States, Australia, the United Kingdom, and Canada. When comparing questions submitted from the United States versus those from all other countries, the 3 most frequent types of questions were the same for both groups (and were the top 3 question types listed above). CONCLUSIONS: These results provide the University of Washington Department of Orthopaedics and Sports Medicine, as well as other organizations that provide health-information Web sites, with data about what people around the world are seeking when they turn to the Internet for health information. If Web site managers can adapt their health-information Web sites in response to these findings, patients may be able to find and use Internet-based health information more successfully, enabling them to participate more actively in their health care.

Re-evaluation of the subgroup analysis from the Royal College of Obstetricians and Gynaecologists randomized controlled trial of cervical cerclage.

History-indicated cervical cerclage is offered to patients who are at risk of spontaneous preterm birth (SPTB), though the indications are controversial. A common practice of offering cerclage after three prior SPTBs or midtrimester losses (MTLs) is based on findings of the subgroup analysis of the 1993 Royal College of Obstetricians and Gynaecologists (RCOG) randomized trial of cervical cerclage. The subgroup analysis was performed by repeating the primary analysis within individual subgroups, which can lead to erroneous conclusions. We repeated the subgroup analysis by evaluating the interaction between the characteristic of interest and treatment allocation in a regression model. The interaction between cerclage and any prior PTB as a binary variable was non-significant. Among subjects delivering at <37 weeks, there was a significant interaction between cerclage and prior PTBs as a continuous variable or ≥ 3 (p-values 0.04 and 0.03, respectively). There were no significant interactions between cerclage and the aforementioned outcomes among women who delivered at <33 weeks, though this may have been secondary to a smaller number of SPTB in this range. Our findings lend credence to the current recommendations regarding the use of history-indicated cerclage, though they remain subject to the inherent limitations of subgroup analyses.

Perinatal outcomes in type 2 diabetic patients compared with non-diabetic patients matched by body mass index.

OBJECTIVE: Given that both type 2 diabetes and obesity are associated with adverse pregnancy outcomes and often coexist, we sought to determine if outcomes in type 2 diabetic patients are related to the presence of diabetes or to maternal obesity. METHODS: This retrospective cohort study examined perinatal outcomes of type 2 diabetic and nondiabetic patients matched by prepregnancy body mass index January 2000 to July 2008. Chi-square, Fisher's exact test, Mann-Whitney U and t-tests were used to compare groups. The association between type 2 diabetes and adverse perinatal outcomes was evaluated through logistic regression with adjustment for potential confounders. RESULTS: 213 pairs of type 2 and non-diabetic patients were compared. Diabetic patients had overall worse composite pregnancy, delivery, fetal, and neonatal outcomes. Specifically, diabetic patients had higher rates of preeclampsia, poly- and oligohydramnios, cesarean delivery, shoulder dystocia, postpartum hemorrhage, preterm delivery, LGA infant, fetal anomaly, and neonatal hypoglycemia, hyperbilirubinemia, RDS, sepsis, intubation, and admission to the NICU. Diabetes remained a significant predictor of adverse delivery, fetal and neonatal composite outcomes when adjusted for confounders in logistic regression. CONCLUSIONS: Type 2 diabetic patients have a higher incidence of adverse perinatal outcomes than nondiabetic patients independent of obesity.

The effect of intrapartum clindamycin on vaginal group B streptococcus colony counts.

OBJECTIVE: To determine the temporal relationship between intrapartum clindamycin and vaginal Group B Streptococcus (GBS) colony counts. METHODS: In this prospective observational study, women with GBS-positive, clindamycin-sensitive, antenatal rectovaginal cultures, intrapartum vaginal cultures were collected just before the first clindamycin dose (T(0)) and then every 2 h for 8 h or until delivery. Colony counts were quantified using serial dilution. Results were standardized as percent of initial colony count and analyzed using sequential Friedman tests. RESULTS: Twenty-one women had positive intrapartum vaginal GBS cultures at T(0). With T(0) colony counts standardized to 100%, subsequent percents-of-baseline fell rapidly and significantly by T(2) and fell further at each subsequent point, reaching 0% by T(6). For 12 women cultured for the full 8 hours, the decline in GBS was significant at p < 0.001. CONCLUSIONS: Vaginal GBS colony counts fall rapidly after intrapartum clindamycin administration, similar to declines after penicillin. This represents a possible mechanism for efficacy of chemoprophylaxis.