A dynamic covalent approach to [PtnL2n]2n+ cages.

A dynamic covalent approach was exploited to generate a family of homometallic [PtnL2n]2n+ cage (predominantly [Pt2L4]4+ systems) architectures. The family of platinum(II) architectures were characterized using 1H nuclear magnetic resonance (NMR) and diffusion ordered spectroscopy (DOSY), electrospray ionization mass spectrometry (ESI-MS) and the molecular structures of two cages were determined by X-ray crystallography.

Exploiting reduced-symmetry ligands with pyridyl and imidazole donors to construct a second-generation stimuli-responsive heterobimetallic [PdPtL4]4+ cage.

A new sequential metalation strategy that enables the assembly of a new more robust reduced symmetry heterobimetallic [PdPtL4]4+ cage C is reported. By exploiting a low-symmetry ditopic ligand (L) that features imidazole and pyridine donor units we were able to selectively form a [Pt(L)4]2+ "open-cage" complex. When this was treated with Pd(ii) ions the cage C assembled. 1H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the quantitative formation of the cage and the heterobimetallic structure was confirmed by single crystal X-ray crystallography. The cage C was shown to bind anionic guest molecules. NMR studies suggested that these guests interacted with the cavity of the cage in a specific orientation and this was confirmed for the mesylate ion (MsO-) : C host-guest adduct using X-ray crystallography. In addition, the system was shown to be stimulus-responsive and could be opened and closed on demand when treated with appropriate stimuli. If a guest molecule was bound within the cage, the opening and closing was accompanied by the release and re-uptake of the guest molecule.

The Biologically Inspired Abilities of Metallosupramolecular Architectures.

Natural machinery such as proteins and enzymes can bind substrates and perform intricate functions on these molecules. This behaviour is mediated by highly ordered but conformationally flexible structures dictated through favourable intra- and intermolecular interactions. Metallosupramolecular architectures (MSAs) function as synthetic machinery that are responsive to their environment, and display similar, but less impressive, abilities to their biological counterparts. Natural and synthetic systems share the properties of molecular recognition and catalysis facilitated through the often complex structures of these architectures. This article outlines efforts to use metallosupramolecular structures to mimic the properties of biological enzymes and machines using important recent examples from the field.

Relationship of American Indian blood quantum with osteoporosis risk: a cross-sectional study of American Indian women in Oklahoma.

Information regarding the prevalence and risk of osteoporosis among American Indian (AI) women is limited. This study showed that with increasing AI blood quantum, the prevalence of osteoporosis at the hip based on BMD T-scores decreased and this appeared to be independent of other risk factors. INTRODUCTION: This study was designed to investigate the effects of AI blood quantum (BQ) on osteoporosis prevalence and risk in a cohort of AI women in Oklahoma. METHODS: Women (n = 301), aged 50 years and older, were recruited to participate in the Oklahoma American Indian Women's Osteoporosis Study. Baseline bone density, fracture history, bone biochemical markers, and potential risk factors were assessed. Participants were stratified by AI BQ into BQ1 ≤ 25%, BQ2 = 25-49%, BQ3 = 50-74%, and BQ4 = 75-100%. The effects of BQ on the prevalence and risk of osteoporosis were evaluated. RESULTS: Based on T-scores, one in approximately eight women in the study was osteoporotic at one or more sites. The prevalence of osteoporosis decreased (p < 0.05) with increasing BQ, especially at the hip, trochanteric, and intertrochanter regions. No differences in bone-specific alkaline phosphatase and C-telopeptide were observed across BQ that could account for the differences in bone density. 25-OH vitamin D decreased with increasing BQ, but mean for each BQ1-4 was > 40 ng/mL. Fracture history did not differ across BQ, and though 52% of the population consumed less than the RDA for calcium, no effect of BQ was observed. CONCLUSIONS: In this cohort of women who identified as AI, greater Indian BQ was associated with a decrease in the prevalence of osteoporosis.

Preliminary report: Surgical outcomes following genitoplasty in children with moderate to severe genital atypia.

INTRODUCTION: Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. OBJECTIVE: The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. STUDY DESIGN: This 11-site, prospective study included children aged ≤2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. RESULTS: Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. DISCUSSION: In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. CONCLUSION: In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management.

Prospective assessment of cosmesis before and after genital surgery.

INTRODUCTION: Little data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center. OBJECTIVE: The present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery. STUDY DESIGN: This prospective, observational study included children aged <2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children's hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child's genitalia prior to and 6 months after genitoplasty. RESULTS: Of the 37 children meeting eligibility criteria, 20 (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child's genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P < 0.001) and fathers (P ≤ 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P < 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings. DISCUSSION: This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant pre-operatively, they were generally concordant postoperatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life. CONCLUSION: In this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.

Mortality benefit of statin use in traumatic spinal cord injury: a retrospective analysis.

STUDY DESIGN: An observational study based on retrospective review of the medical charts and death records of 163 individuals with traumatic spinal cord injuries (SCI). OBJECTIVES: To determine whether HMG coA Reductase Inhibitor ('statin') use in a cohort of patients with traumatic SCI reduced overall and cause-specific mortality. SETTING: An outpatient clinic designated for veterans with SCI at the Oklahoma City Veterans Administration Hospital. METHODS: Review and analysis of the medical records of 163 veterans with traumatic SCI cared for between the years 2000 and 2014. Data collected included statin use, duration of statin use and intensity of statin therapy, as well as cause-specific mortality. RESULTS: Seventy five participants had taken statins for an average of 5.7 ± 3.7 years, and had greater cardiovascular risk burdens than those who had not taken statins (n = 88). Statin use was associated with a reduced risk of death. The mortality rate for those patients on statins was 33.8-49.9 per 1000 person-years, depending on assumptions made regarding residual effects of statin use. Under most assumptions this was significantly lower than the mortality rate seen in those not on statins (47.4-66.8 deaths per 1000 person-years). Within the statin group, neither duration nor average intensity of statin therapy affected mortality. CONCLUSION: Statin use among a cohort of veterans with traumatic SCI reduced all-cause mortality. This retrospective study ought to spur further investigations into the potential benefits of statin use among people with chronic SCI, and begin a discussion as to whether individuals with injuries should routinely be offered statin therapy.

Complications and urologic risks of neurogenic bladder in veterans with traumatic spinal cord injury.

OBJECTIVES: This observational study aimed to determine the types of urological lesion encountered in veterans with traumatic spinal cord injury (SCI) with neurogenic bladder (NGB), and the usage of bladder management programs to deal with NGB. SETTING: NGB (detrusor muscle and urethral sphincter dysfunction with loss of bladder sensation to void) is common in daily practice; however, information on types of urological lesions encountered in these veterans with NGB and how best to manage their NGB is limited. METHODS: We retrospectively reviewed the electronic charts of veterans with SCI enrolled in our program and regularly followed in our SCI clinic. Demographic data collected included: age, gender, ethnicity and age, level, severity and cause of spinal injury. Also noted was presence of NGB, episodes of urinary tract infection (UTI), bladder program followed and urological lesions found on renal nuclear scans, renal ultrasounds and cystoscopies. RESULTS: Of the 161 veterans with SCI, symptoms of NGB was present in 133 (82.6%). Veterans with NGB had more severe spinal injury and more frequent UTI (P<0.05). Renal atrophy and hydronephrosis were the most common urological lesions seen in patients with UTI. Clean intermittent catheterization (CIC) was the most frequently used bladder program resulting in less frequent occurrence of UTI. CONCLUSION: Renal atrophy and hydronephrosis were the most common urological lesions encountered in veterans with NGB especially in those with UTI. CIC was the most frequently used bladder management program with the least risk for UTI.

A randomized controlled trial adding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients.

Fluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve-to-treatment veterans. Thirty-seven naïve-to-treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention-to-treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve-to-treatment genotype 1 HCV patients.

Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes.

OBJECTIVE: Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. DESIGN: Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. SETTING: Antenatal clinics. POPULATION: Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). METHODS: Maternal serum levels of sRAGE (total circulating pool), N(ε)-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. MAIN OUTCOME MEASURES: Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). RESULTS: In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. CONCLUSIONS: In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.

A randomized trial of dalteparin compared with ibuprofen for the treatment of superficial thrombophlebitis.

BACKGROUND: Superficial thrombophlebitis can produce pain and result in a deep vein thrombosis (DVT) if not treated. Conservative therapies including prescription of non-steroidal anti-inflammatory drugs (NSAID) and heat have been standard care. Recently, studies have been published reporting efficacy and safety of low-molecular-weight heparin for the treatment of superficial thrombophlebitis. However, there are few comparative trials to conservative therapy. We studied the effectiveness and safety of treatment with dalteparin compared with ibuprofen in patients with confirmed superficial thrombophlebitis. METHODS: Consecutive patients were randomized to receive daily dalteparin vs. ibuprofen three times daily for up to 14 days. The primary outcome measure was the incidence of extension of thrombus or new symptomatic venous thromboembolism during the 14-day and 3-month follow-up period. The secondary outcome was a reduction in pain. The outcome measure of safety was the incidence of major and minor bleeding. RESULTS: Of 302 consecutive patients screened, 72 were enrolled. Four patients receiving ibuprofen compared with no patients receiving dalteparin had thrombus extension at 14 days (P = 0.05), however, there was no difference in thrombus extension at 3 months. Both treatments significantly reduced pain. There were no episodes of major or minor bleeding during the treatment period. CONCLUSIONS: Dalteparin is superior to the NSAID ibuprofen in preventing extension of superficial thrombophlebitis during the 14-day treatment period with similar relief of pain and no increase in bleeding. However, questions concerning the optimal treatment duration should be explored in future trials.

A low frequency variant within the GWAS locus of MTNR1B affects fasting glucose concentrations: genetic risk is modulated by obesity.

Two common variants (rs1387153, rs10830963) in MTNR1B have been reported to have independent effects on fasting blood glucose (FBG) levels with increased risk to type 2 diabetes (T2D) in recent genome-wide association studies (GWAS). In this investigation, we report the association of these two variants, and an additional variant (rs1374645) within the GWAS locus of MTNR1B with FBG, 2h glucose, insulin resistance (HOMA IR), ß-cell function (HOMA B), and T2D in our sample of Asian Sikhs from India. Our cohort comprised 2222 subjects [1201 T2D, 1021 controls]. None of these SNPs was associated with T2D in this cohort. Our data also could not confirm association of rs1387153 and rs10830963 with FBG phenotype. However, upon stratifying data according to body mass index (BMI) (low ≤ 25 kg/m(2) and high > 25 kg/m(2)) in normoglycemic subjects (n = 1021), the rs1374645 revealed a strong association with low FBG levels in low BMI group (ß = -0.073, p = 0.002, Bonferroni p = 0.01) compared to the high BMI group (ß = 0.015, p = 0.50). We also detected a strong evidence of interaction between rs1374645 and BMI with respect to FBG levels (p = 0.002). Our data provide new information about the significant impact of another MTNR1B variant on FBG levels that appears to be modulated by BMI. Future confirmation on independent datasets and functional studies will be required to define the role of this variant in fasting glucose variation.

The impact of individual human immunodeficiency virus type 1 protease mutations on drug susceptibility is highly influenced by complex interactions with the background protease sequence.

The requirement for multiple mutations for protease inhibitor (PI) resistance necessitates a better understanding of the molecular basis of resistance development. The novel bioinformatics resistance determination approach presented here elaborates on genetic profiles observed in clinical human immunodeficiency virus type 1 (HIV-1) isolates. Synthetic protease sequences were cloned in a wild-type HIV-1 background to generate a large number of close variants, covering 69 mutation clusters between multi-PI-resistant viruses and their corresponding genetically closely related, but PI-susceptible, counterparts. The vast number of mutants generated facilitates a profound and broad analysis of the influence of the background on the effect of individual PI resistance-associated mutations (PI-RAMs) on PI susceptibility. Within a set of viruses, all PI-RAMs that differed between susceptible and resistant viruses were varied while maintaining the background sequence from the resistant virus. The PI darunavir was used to evaluate PI susceptibility. Single sets allowed delineation of the impact of individual mutations on PI susceptibility, as well as the influence of PI-RAMs on one another. Comparing across sets, it could be inferred how the background influenced the interaction between two mutations, in some cases even changing antagonistic relationships into synergistic ones or vice versa. The approach elaborates on patient data and demonstrates how the specific mutational background greatly influences the impact of individual mutations on PI susceptibility in clinical patterns.

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women.

AIMS/HYPOTHESIS: Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFbeta1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia. METHODS: Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term. RESULTS: Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n = 26) vs those without hypertensive complications (diabetic normotensive, n = 95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p < 0.05) and the normal rise of PlGF during pregnancy was blunted (p < 0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r(2) = 42%, p < 0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p < 0.0001). CONCLUSIONS/INTERPRETATION: Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

Advanced glycation end-products and methionine sulphoxide in skin collagen of patients with type 1 diabetes.

AIMS/HYPOTHESIS: We determined whether oxidative damage in collagen is increased in (1) patients with diabetes; (2) patients with diabetic complications; and (3) subjects from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, with comparison of subjects from the former standard vs intensive treatment groups 4 years after DCCT completion. SUBJECTS, MATERIALS AND METHODS: We quantified the early glycation product fructose-lysine, the two AGEs N (epsilon)-(carboxymethyl)lysine (CML) and pentosidine, and the oxidised amino acid methionine sulphoxide (MetSO) in skin collagen from 96 patients with type 1 diabetes (taken from three groups: DCCT/EDIC patients and clinic patients from South Carolina and Scotland) and from 78 healthy subjects. RESULTS: Fructose-lysine was increased in diabetic patients (p<0.0001), both with or without complications (p<0.0001). Controlling for HbA(1c), rates of accumulation of AGEs were higher in diabetic patients than control subjects, regardless of whether the former had complications (CML and pentosidine given as log(e)[pentosidine]) or not (CML only) (all p<0.0001). MetSO (log(e)[MetSO]) also accumulated more rapidly in diabetic patients with complications than in controls (p<0.0001), but rates were similar in patients without complications and controls. For all three products, rates of accumulation with age were significantly higher in diabetic patients with complications than in those without (all p<0.0001). At 4 years after the end of the DCCT, no differences were found between the previous DCCT management groups for fructose-lysine, AGEs or MetSO. CONCLUSIONS/INTERPRETATION: The findings suggest that in type 1 diabetic patients enhanced oxidative damage to collagen is associated with the presence of vascular complications.

Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder.

Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder.

Constraints to implementing international agreements: the case of the Montreal Protocol in Botswana.

This study addresses the difficulties surrounding effective implementation of the Montreal Protocol in Botswana and provides a general understanding of how best we might advise policy makers when implementing international agreements in the developing world. A questionnaire survey administered to both the formal and informal users of Ozone Depleting Substances (ODSs) revealed that disseminated information on ODSs has little effect on choices that users make about refrigerant gases and this information is skewed in favor of the conventional users of ODSs. As a result, annual statistics of ODS use are probably underestimated. Difficulties exist in changing from old to new technologies in the short term due to high costs associated with the change over. The infrastructure to recover gases and to dispose of unusable hardware is absent or inadequate. Solutions to these difficulties include a comprehensive policy that caters for all users of ODSs and the integration of economic and environmental aspirations.

Transcriptional profiling reveals strict boundaries between hippocampal subregions.

The hippocampus consists of distinct anatomic regions that have been demonstrated to have different biological functions. To explore the molecular differences between hippocampal subregions, we performed transcriptional profiling analysis by using DNA microarray technology. The cRNA derived from the CA1, CA3, and dentate gyrus regions of the hippocampus and from spinal cord was hybridized to Affymetrix high-density oligo arrays. This systematic approach revealed sets of genes that were expressed specifically in subregions of the hippocampus corresponding to predefined cytoarchitectural boundaries, which could be confirmed by in situ hybridization and Real Time quantitative polymerase chain reaction. The relative enrichment and absence of genes in the hippocampal subregions support the conclusion that there is a molecular basis for the previously defined anatomic subregions of the hippocampus and also reveal genes that could be important in defining the unique functions of the hippocampal subfields.

Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.

Both systemic lupus erythematosus (SLE) and vitiligo are autoimmune disorders that have strong evidence of complex genetic contributions to their etiology, but, to date, efforts using genetic linkage to find the susceptibility genes for either phenotype have met with limited success. Since autoimmune diseases are thought to share at least some of their genetic origins, and since only a small minority (16 of 92) of the European-American pedigrees multiplex for SLE in our collection have one or more affected members with vitiligo, we hypothesized that these pedigrees might be more genetically homogeneous at loci important to both SLE and vitiligo and, hence, have increased power for detection of linkage. We therefore evaluated genomewide microsatellite-marker-scan data for markers at an average marker density of approximately 11 cM in these 16 European-American pedigrees and identified a significant linkage at 17p13, where the maximum multipoint parametric LOD score was 3.64 (P<4.3x10(-5)) and the nonparametric linkage score was 4.02 (P<2.8x10(-5)), respectively. The segregation behavior of this linkage suggests a recessive mode of inheritance with a virtually homogeneous genetic effect in these 16 pedigrees. These results support the hypotheses that SLE and vitiligo may share important genetic effects and that sampling on the basis of clinical covariates dramatically improves power to identify genetic effects.

Inconsistent effects of the proline12 --> alanine variant of the peroxisome proliferator-activated receptor-gamma2 gene on body mass index in children and adolescent girls.

OBJECTIVE: To ascertain whether variation in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear ligand-dependent transcription factor affecting both adipocyte differentiation and insulin sensitivity, influences body mass index (BMI). DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Children with premature pubic hair and adolescent girls with hyperandrogenism. INTERVENTION(S): Assay for P12A and P115Q variants and measure BMI. MAIN OUTCOME MEASURE(S): BMI and PPAR-gamma genotypes. RESULT(S): Fourteen subjects were heterozygous for P12A; two were homozygous. None carried the P115Q allele. No significant differences in BMI or basal androstenedione concentrations between P12 carriers and noncarriers were found. Thirty-nine subjects had BMI values at two time points; mean BMI was significantly greater in the P12A carriers at time point 2. Those P12A carriers obese at time point 1 became more obese; lean mutation carriers tended to remain lean. Annual rate of increase in BMI was significantly greater in the P12A carriers than the noncarriers. CONCLUSION(S): Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adolescence. Future studies are needed to determine whether the divergent effects of P12A persist into adulthood, to elucidate the mechanism of this effect, and to replicate our findings in other populations.