State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS)

PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available) adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy

Targeting condom distribution at high risk places increases condom utilization-evidence from an intervention study in Livingstone, Zambia

Background: The PLACE-method presumes that targeting HIV preventive activities at high risk places is effective in settings with major epidemics. Livingstone, Zambia, has a major HIV epidemic despite many preventive efforts in the city. A baseline survey conducted in 2005 in places where people meet new sexual partners found high partner turnover and unprotected sex to be common among guests. In addition, there were major gaps in on-site condom availability. This study aimed to assess the impact of a condom distribution and peer education intervention targeting places where people meet new sexual partners on condom use and sexual risk taking among people socializing there. Methods: The 2005 baseline survey assessed the presence of HIV preventive activities and sexual risk taking in places where people meet new sexual partners in Livingstone. One township was selected for a non-randomised intervention study on condom distribution and peer education in high risk venues in 2009. The presence of HIV preventive activities in the venues during the intervention was monitored by an external person. The intervention was evaluated after one year with a follow-up survey in the intervention township and a comparison township. In addition, qualitative interviews and focus group discussions were conducted. Results: Young people between 17-32 years of age were recruited as peer educators, and 40% were females. Out of 72 persons trained before the intervention, 38 quit, and another 11 had to be recruited. The percentage of venues where condoms were reported to always be available at least doubled in both townships, but was significantly higher in the intervention vs. the control venues in both surveys (84% vs. 33% in the follow-up). There was a reduction in reported sexual risk taking among guests socializing in the venues in both areas, but reporting of recent condom use increased more among people interviewed in the intervention (57% to 84%) than in the control community (55% to 68%). Conclusions: It is likely that the substantial increase in reported condom use in the intervention venues was partially due to the condom distribution and peer education intervention targeting these places. However, substantial changes were observed also in the comparison community over the five year period, and this indicates that major changes had occurred in overall risk taking among people socializing in venues where people meet new sexual partners in Livingstone

Conserving the Stage: Climate Change and the Geophysical Underpinnings of Species Diversity

Conservationists have proposed methods for adapting to climate change that assume species distributions are primarily explained by climate variables. The key idea is to use the understanding of species-climate relationships to map corridors and to identify regions of faunal stability or high species turnover. An alternative approach is to adopt an evolutionary timescale and ask ultimately what factors control total diversity, so that over the long run the major drivers of total species richness can be protected. Within a single climatic region, the temperate area encompassing all of the Northeastern U.S. and Maritime Canada, we hypothesized that geologic factors may take precedence over climate in explaining diversity patterns. If geophysical diversity does drive regional diversity, then conserving geophysical settings may offer an approach to conservation that protects diversity under both current and future climates. Here we tested how well geology predicts the species diversity of 14 US states and three Canadian provinces, using a comprehensive new spatial dataset. Results of linear regressions of species diversity on all possible combinations of 23 geophysical and climatic variables indicated that four geophysical factors; the number of geological classes, latitude, elevation range and the amount of calcareous bedrock, predicted species diversity with certainty (adj. R2 = 0.94). To confirm the species-geology relationships we ran an independent test using 18,700 location points for 885 rare species and found that 40% of the species were restricted to a single geology. Moreover, each geology class supported 5–95 endemic species and chi-square tests confirmed that calcareous bedrock and extreme elevations had significantly more rare species than expected by chance (P<0.0001), strongly corroborating the regression model. Our results suggest that protecting geophysical settings will conserve the stage for current and future biodiversity and may be a robust alternative to species-level predictions

IL28B SNP rs8099917 Is Strongly Associated with Pegylated Interferon-α and Ribavirin Therapy Treatment Failure in HCV/HIV-1 Coinfected Patients

Recent genome-wide association studies report that the SNP rs8099917, located 8.9 kb upstream of the start codon of IL28B, is associated with both disease chronicity and therapeutic response to pegIFN-α and RBV in patients infected with genotype 1 HCV. To determine the effect of rs8099917 variation on the response of HCV to therapy, we genotyped this variant in a cohort of 160 HCV/HIV-1 coinfected patients in our clinic unit who received combined peg-IFN-α/RBV therapy. The rs8099917 T/G or G/G genotypes were observed in 56 patients (35%). Treatment failure occurred in 80% of G-allele carriers versus 48% of non-carriers (P<0.0001). This result reveals that the G allele was strongly associated with treatment failure in this patient cohort. Importantly, a highly significant association was found between the G-allele and response to therapy in HCV genotype 1-infected patients (P<0.0001) but not in HCV genotype 3-infected patients. Multivariate analysis (odds ratio; 95% confidence interval; P value) indicated that the rs8099917 TT genotype was a strong predictor of treatment success (5.83; 1.26–26.92; P = 0.021), independent of baseline plasma HCV-RNA load less than 500 000 IU/ml (4.85; 1.18–19.95; P = 0.025) and absence of advanced liver fibrosis (5.24; 1.20–22.91; P = 0.025). These results reveal the high prevalence of the rs8099917 G allele in HCV/HIV-1 coinfected patients as well as its strong association with treatment failure in HCV genotype 1-infected patients. rs8099917 SNP genotyping may be a valid pre-treatment predictor of which patients are likely to respond to treatment in this group of difficult-to-treat HCV/HIV-infected patients

High-Dimensional Coexistence of Temperate Tree Species: Functional Traits, Demographic Rates, Life-History Stages, and Their Physical Context

Theoretical models indicate that trade-offs between growth and survival strategies of tree species can lead to coexistence across life history stages (ontogeny) and physical conditions experienced by individuals. There exist predicted physiological mechanisms regulating these trade-offs, such as an investment in leaf characters that may increase survival in stressful environments at the expense of investment in bole or root growth. Confirming these mechanisms, however, requires that potential environmental, ontogenetic, and trait influences are analyzed together. Here, we infer growth and mortality of tree species given size, site, and light characteristics from forest inventory data from Wisconsin to test hypotheses about growth-survival trade-offs given species functional trait values under different ontogenetic and environmental states. A series of regression analyses including traits and rates their interactions with environmental and ontogenetic stages supported the relationships between traits and vital rates expected from the expectations from tree physiology. A combined model including interactions between all variables indicated that relationships between demographic rates and functional traits supports growth-survival trade-offs and their differences across species in high-dimensional niche space. The combined model explained 65% of the variation in tree growth and supports a concept of community coexistence similar to Hutchinson's n-dimensional hypervolume and not a low-dimensional niche model or neutral model

Comparing sexual risks and patterns of alcohol and drug use between injection drug users (IDUs) and non-IDUs who report sexual partnerships with IDUs in St. Petersburg, Russia

<p>Abstract</p> <p>Background</p> <p>To date, the great majority of Russian HIV infections have been diagnosed among IDUs and concerns about the potential for a sexual transmission of HIV beyond the IDU population have increased. This study investigated differences in the prevalence of sexual risk behaviors between IDUs and non-IDUs in St. Petersburg, Russia and assessed associations between substance use patterns and sexual risks within and between those two groups.</p> <p>Methods</p> <p>Cross-sectional survey data and biological test results from 331 IDUs and 65 non-IDUs who have IDU sex partners were analyzed. Multivariate regression was employed to calculate measures of associations.</p> <p>Results</p> <p>IDUs were less likely than non-IDUs to report multiple sexual partners and unprotected sex with casual partners. The quantity, frequency and intensity of alcohol use did not differ between IDUs and non-IDUs, but non-IDUs were more likely to engage in alcohol use categorized as risky per the alcohol use disorders identification test (AUDIT-C). Risky sexual practices were independently associated with monthly methamphetamine injection among IDUs and with risky alcohol use among non-IDUs. Having sex when high on alcohol or drugs was associated with unprotected sex only among IDUs.</p> <p>Conclusions</p> <p>Greater prevalence of sexual risk among non-IDUs who have IDU sex partners compared to IDUs suggests the potential for sexual transmission of HIV from the high-prevalence IDU population into the general population. HIV prevention programs among IDUs in St. Petersburg owe special attention to risky alcohol use among non-IDUs who have IDU sex partners and the propensity of IDUs to have sex when high on alcohol or drugs and forgo condoms.</p

Nitrated α-Synuclein Induces the Loss of Dopaminergic Neurons in the Substantia Nigra of Rats

BACKGROUND: The pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated alpha-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of alpha-synuclein is relevant to the pathogenesis of PD is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects. CONCLUSIONS/SIGNIFICANCE: Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD

Distribution of GABAergic Interneurons and Dopaminergic Cells in the Functional Territories of the Human Striatum

BACKGROUND: The afferent projections of the striatum (caudate nucleus and putamen) are segregated in three territories: associative, sensorimotor and limbic. Striatal interneurons are in part responsible for the integration of these different types of information. Among them, GABAergic interneurons are the most abundant, and can be sorted in three populations according to their content in the calcium binding proteins calretinin (CR), parvalbumin (PV) and calbindin (CB). Conversely, striatal dopaminergic cells (whose role as interneurons is still unclear) are scarce. This study aims to analyze the interneuron distribution in the striatal functional territories, as well as their organization regarding to the striosomal compartment. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemical methods to visualize CR, PV, CB and tyrosine hydroxylase (TH) positive striatal neurons. The interneuronal distribution was assessed by stereological methods applied to every striatal functional territory. Considering the four cell groups altogether, their density was higher in the associative (2120±91 cells/mm(3)) than in the sensorimotor (959±47 cells/mm(3)) or limbic (633±119 cells/mm(3)) territories. CB- and TH-immunoreactive(-ir) cells were distributed rather homogeneously in the three striatal territories. However, the density of CR and PV interneurons were more abundant in the associative and sensorimotor striatum, respectively. Regarding to their compartmental organization, CR-ir interneurons were frequently found in the border between compartments in the associative and sensorimotor territories, and CB-ir interneurons abounded at the striosome/matrix border in the sensorimotor domain. CONCLUSIONS/SIGNIFICANCE: The present study demonstrates that the architecture of the human striatum in terms of its interneuron composition varies in its three functional territories. Furthermore, our data highlight the importance of CR-ir striatal interneurons in the integration of associative information, and the selective role of PV-ir interneurons in the motor territory. On the other hand, the low density of dopaminergic cells casts doubts about their role in the normal human striatum

Internet Gaming Disorder Behaviors in emergent adulthood: a pilot study examining the interplay between anxiety and family cohesion

Understanding risk and protective factors associated with Internet Gaming Disorder (IGD) has been highlighted as a research priority by the American Psychiatric Association, (2013). The present study focused on the potential IGD risk effect of anxiety and the buffering role of family cohesion on this association. A sample of emerging adults all of whom were massively multiplayer online (MMO) gamers (18–29 years) residing in Australia were assessed longitudinally (face-to-face: N = 61, Mage = 23.02 years, SD = 3.43) and cross-sectionally (online: N = 64, Mage = 23.34 years, SD = 3.39). IGD symptoms were assessed using the nine-item Internet Gaming Disorder Scale-Short Form (IGDS-SF9; Pontes & Griffiths Computers in Human Behavior, 45, 137–143. https://doi.org/10.1016/j.chb.2014.12.006, 2015). The Beck Anxiety Inventory (BAI; Beck and Steer, 1990) and the balanced family cohesion scale (BFC; Olson Journal of Marital & Family Therapy, 3(1) 64–80. https://doi.org/10.1111/j.1752-0606.2009.00175.x, 2011) were applied to assess anxiety and BFC levels, respectively. Linear regressions and moderation analyses confirmed that anxiety increased IGD risk and that BFC weakened the anxiety-related IGD risk