Standards of Care for the Health of Transgender and Gender Diverse People, Version 8.

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

A specialised pollination system using nectar-seeking thynnine wasps in Caladenia nobilis (Orchidaceae).

Caladenia is a diverse Australian genus that is exceptional among orchids in having both species pollinated by food-seeking and sexually deceived insects. Here, we investigated the pollination of Caladenia nobilis, a species predicted to be food-deceptive due to its large, cream-coloured and apparently nectarless flowers. Pollinator observations were made using experimental clumps of flowers. Measurements of floral colour were undertaken with a spectrometer, nectar was tested using GC-MS, and reproductive success was quantified for 2 years. While C. nobilis attracted nine species of insect, only males of the thynnine wasp Rhagigaster discrepans exhibited the correct size and behaviour to remove and deposit pollen. Male R. discrepans attempted to feed from the surface of the labellum, often crawling to multiple flowers, but showed no evidence of sexual attraction. Most flowers produced little or no nectar, although some may provide enough sucrose to act as a meagre reward to pollinators. Floral colouration was similar to a related Caladenia species pollinated by sexual deception, although the sexually deceptive species had a dull-red labellum. Reproductive success was generally low and highly variable between sites and years. In addition to most visitors being of inappropriate size for pollinia removal, the lack of response to the orchid by several co-occurring species of thynnine wasp suggests filtering of potential pollinators at the attraction phase. Our discovery of a pollination strategy that may be intermediate between food deception and food reward raises the question, how many putatively rewardless orchids actually produce meagre amounts of nectar?

Evolutionary relationships among pollinators and repeated pollinator sharing in sexually deceptive orchids.

The mechanism of pollinator attraction is predicted to strongly influence both plant diversification and the extent of pollinator sharing between species. Sexually deceptive orchids rely on mimicry of species-specific sex pheromones to attract their insect pollinators. Given that sex pheromones tend to be conserved among related species, we predicted that in sexually deceptive orchids, (i) pollinator sharing is rare, (ii) closely related orchids use closely related pollinators and (iii) there is strong bias in the wasp lineages exploited by orchids. We focused on species that are pollinated by sexual deception of thynnine wasps in the distantly related genera Caladenia and Drakaea, including new field observations for 45 species of Caladenia. Specialization was extreme with most orchids using a single pollinator species. Unexpectedly, seven cases of pollinator sharing were found, including two between Caladenia and Drakaea, which exhibit strikingly different floral morphology. Phylogenetic analysis of pollinators using four nuclear sequence loci demonstrated that although orchids within major clades primarily use closely related pollinator species, up to 17% of orchids within these clades are pollinated by a member of a phylogenetically distant wasp genus. Further, compared to the total diversity of thynnine wasps within the study region, orchids show a strong bias towards exploiting certain genera. Although these patterns may arise through conservatism in the chemical classes used in sex pheromones, apparent switches between wasp clades suggest unexpected flexibility in floral semiochemical production. Alternatively, wasp sex pheromones within lineages may exhibit greater chemical diversity than currently appreciated.

Steroid hormones, stress and the adolescent brain: a comparative perspective.

Steroid hormones, including those produced by the gonads and the adrenal glands, are known to influence brain development during sensitive periods of life. Until recently, most brain organisation was assumed to take place during early stages of development, with relatively little neurogenesis or brain re-organisation during later stages. However, an increasing body of research has shown that the developing brain is also sensitive to steroid hormone exposure during adolescence (broadly defined as the period from nutritional independence to sexual maturity). In this review, we examine how steroid hormones that are produced by the gonads and adrenal glands vary across the lifespan in a range of mammalian and bird species, and we summarise the evidence that steroid hormone exposure influences behavioural and brain development during early stages of life and during adolescence in these two taxonomic groups. Taking a cross-species, comparative perspective reveals that the effects of early exposure to steroid hormones depend upon the stage of development at birth or hatching, as measured along the altricial-precocial dimension. We then review the evidence that exposure to stress during adolescence impacts upon the developing neuroendocrine systems, the brain and behaviour. Current research suggests that the effects of adolescent stress vary depending upon the sex of the individual and type of stressor, and the effects of stress could involve several neural systems, including the serotonergic and dopaminergic systems. Experience of stressors during adolescence could also influence brain development via the close interactions between the stress hormone and gonadal hormone axes. While sensitivity of the brain to steroid hormones during early life and adolescence potentially leaves the developing organism vulnerable to external adversities, developmental plasticity also provides an opportunity for the developing organism to respond to current circumstances and for behavioural responses to influence the future life history of the individual.

Toxicity and characterization of cotton expressing Bacillus thuringiensis Cry1Ac and Cry2Ab2 proteins for control of lepidopteran pests.

Cry1Ac protoxin (the active insecticidal toxin in both Bollgard and Bollgard II cotton [Gossypium hirsutum L.]), and Cry2Ab2 toxin (the second insecticidal toxin in Bollgard II cotton) were bioassayed against five of the primary lepidopteran pests of cotton by using diet incorporation. Cry1Ac was the most toxic to Heliothis virescens (F.) and Pectinophora gossypiella (Saunders), demonstrated good activity against Helicoverpa zea (Boddie), and had negligible toxicity against Spodoptera exigua (Hübner) and Spodoptera frugiperda (J. E. Smith). Cry2Ab2 was the most toxic to P. gossypiella and least toxic to S. frugiperda. Cry2Ab2 was more toxic to S. exigua and S. frugiperda than Cry1Ac. Of the three insect species most sensitive to both Bacillus thuringiensis (Bt) proteins (including H. zea), P. gossypiella was only three-fold less sensitive to Cry2Ab2 than Cry1Ac, whereas H. virescens was 40-fold less sensitive to Cry2Ab2 compared with CrylAc. Cotton plants expressing Cry1Ac only and both Cry1Ac and Cry2Ab2 proteins were characterized for toxicity against H. zea and S.frugiperda larvae in the laboratory and H. zea larvae in an environmental chamber. In no-choice assays on excised squares from plants of different ages, second instar H. zea larvae were controlled by Cry1Ac/Cry2Ab2 cotton with mortality levels of 90% and greater at 5 d compared with 30-80% mortality for Cry1Ac-only cotton, depending on plant age. Similarly, feeding on leaf discs from Cry1Ac/Cry2Ab2 cotton resulted in mortality of second instars of S.frugiperda ranging from 69 to 93%, whereas exposure to Cry1Ac-only cotton yielded 20-69% mortality, depending on plant age. When cotton blooms were infested in situ in an environmental chamber with neonate H. zea larvae previously fed on synthetic diet for 0, 24, or 48 h, 7-d flower abortion levels for Cry1Ac-only cotton were 15, 41, and 63%, respectively, whereas for Cry1Ac/Cry2Ab2 cotton, flower abortion levels were 0, 0, and 5%, respectively. Cry1Ac and Cry2Ab2 concentrations were measured within various cotton tissues of Cry1Ac-only and Cry1Ac/Cry2Ab2 plants, respectively, by using enzyme-linked immunosorbent assay. Terminal leaves significantly expressed the highest, and large leaves, calyx, and bracts expressed significantly the lowest concentrations of Cry1Ac, respectively. Ovules expressed significantly the highest, and terminal leaves, large leaves, bracts, and calyx expressed significantly (P < 0.05) the lowest concentrations of Cry2Ab2. These results help explain the observed differences between Bollgard and Bollgard II mortality against the primary lepidopteran cotton pests, and they may lead to improved scouting and resistance management practices, and to more effective control of these pests with Bt transgenic crops in the future.

Combination therapy for the treatment of hepatitis C in the veteran population: higher than expected rates of therapy discontinuation.

AIM: To compare the efficacy of high-dose induction with standard dose interferon therapy for the treatment of chronic hepatitis C virus at the Dallas Veterans Affairs Medical Center. METHODS: Patients were randomized to receive 5 million units daily interferon-alpha2b for 4-weeks followed by 44-weeks for genotype 1 or 20 weeks for non-genotype 1 of standard dose therapy (3 million units three times a week) or standard dose therapy for total treatment duration. Daily weight-based ribavirin was used for entire therapy interval. RESULTS: Forty-five patients were enrolled in the trial with genotype 1 comprising 75.6% of the sample. Cirrhosis or bridging-fibrosis was present in 69% of the patients. Of the 29 liver biopsies available for Knodell scoring, 41% and 51% had scores of 6-10 and 11-15, respectively. Rates of sustained virological response did not differ significantly between the two treatment groups. Therapy type and/or early intervention for depression did not affect the rate of therapy discontinuation, which was 26.6%. CONCLUSION: The rate of sustained virological response was similar between the two treatment groups and higher than anticipated among patients with cirrhosis or bridging-fibrosis. The rate of therapy discontinuation was also higher than anticipated but was not attributable to therapy type or untreated depression.

Comparing EST-based genetic maps between Pinus sylvestris and Pinus taeda.

A genetic map of Pinus sylvestris was constructed using ESTP (expressed sequence tag polymorphism) markers and other gene-based markers, AFLP markers and microsatellites. Part of the ESTP markers (40) were developed and mapped earlier in Pinus taeda, and additional markers were generated based on P. sylvestris sequences or sequences from other pine species. The mapping in P. sylvestris was based on 94 F(1) progeny from a cross between plus-tree parents E635C and E1101. AFLP framework maps for the parent trees were first constructed. The ESTP and other gene sequence-based markers were added to the framework maps, as well as five published microsatellite loci. The separate maps were then integrated with the aid of AFLPs segregating in both trees (dominant segregation ratios 3:1) as well as gene markers and microsatellites segregating in both parent trees (segregation ratios 1:1:1:1 or 1:2:1). The integrated map consisted of 12 groups corresponding to the P. taeda linkage groups, and additionally three and six smaller groups for E1101 and E635C, respectively. The number of framework AFLP markers in the integrated map is altogether 194 and the number of gene markers 61. The total length of the integrated map was 1,314 cM. The set of markers developed for P. sylvestris was also added to existing maps of two P. taeda pedigrees. Starting with a mapped marker from one pedigree in the source species resulted in a mapped marker in a pedigree of the other species in more than 40% of the cases, with about equal success in both directions. The maps of the two species are largely colinear, even if the species have diverged more than 70 MYA. Most cases of different locations were probably due to problems in identifying the orthologous members of gene families. These data provide a first ESTP-containing map of P. sylvestris, which can also be used for comparing this species to additional species mapped with the same markers.

Potassium uptake and retention by Oceanomonas baumannii at low water activity in the presence of phenol.

Oceanomonas baumannii(T) (ATCC 700832) is a halotolerant bacterium capable of degrading phenol, which requires potassium in order for turgor growth to occur in minimal medium containing 5% NaCl (w/v). However, at this salinity growth can be inhibited by reduced potassium concentrations. The affinity for potassium (K(S)) was determined to be 219 microM and 408 microM for cultures utilising phenol and succinate respectively as the sole carbon source for growth. Rubidium but not caesium could substitute for potassium in alleviating growth inhibition due to potassium limitation. The effect of elevated phenol on potassium retention was studied, and it was shown that contrary to expectations, as external phenol concentration was increased the levels of intracellular potassium were significantly elevated. This observation correlated with changes in the cytoplasmic membrane, particularly the increase in the saturated:unsaturated fatty acid ratio from 0.47 to 1.44, and the decrease in the zwitterionic:anionic phospholipid ratio from 2.23 to 1.22. Both these changes promote membrane bilayer configurations and increase lipid ordering of the membrane reducing its permeability and inhibiting cation efflux.

Anchored reference loci in loblolly pine (Pinus taeda L.) for integrating pine genomics.

Anchored reference loci provide a framework for comparative mapping. They are landmarks to denote conserved chromosomal segments, allowing the synthesis of genetic maps from multiple sources. We evaluated 90 expressed sequence tag polymorphisms (ESTPs) from loblolly pine (Pinus taeda L.) for this function. Primer sets were assayed for amplification and polymorphism in six pedigrees, representing two subgenera of Pinus and a distant member of the Pinaceae, Douglas-fir (Pseudotsuga menziesii [Mirb.] Franco). On average, 89% of primer sets amplified in four species of subgenus Pinus, 49% in one species of subgenus Strobus, and 22% in Douglas-fir. Polymorphisms were detected for 37-61% of the ESTPs within each pedigree. Comparative mapping in loblolly and slash pine (P. elliottii Englm.) revealed that ESTPs mapped to the same location. Disrupted synteny or significant disruptions in colinearity were not detected. Thirty-five ESTPs met criteria established for anchor loci. The majority of those that did not meet these criteria were excluded when map location was known in only a single species. Anchor loci provide a unifying tool for the community, facilitating the creation of a "generic" pine map and serving as a foundation for studies on genome organization and evolution.

Using proximity measures to describe mother-infant relationships.

What are the relative roles of mothers and infants in maintaining proximity with one another? How do the relative roles of the mother and infant change over time? What do proximity measures tell us about the mother-infant relationship? Questions such as these have been addressed using proximity indices devised by Hinde and coworkers in the 1960s. In this paper, I review how these indices are derived and discuss what they do, and do not, infer about the nature of the mother-infant relationship. An additional index is proposed which indicates whether the mother or the infant is responsible for the majority of changes in proximity.

Novel 4-piperidinopyridine inhibitors of oxidosqualene cyclase-lanosterol synthase derived by consideration of inhibitor pK(a).

Potent inhibition of rat microsomal oxidosqualene cyclase-lanosterol synthase (OSC) was maintained after structural modification of the 4-piperidinopyridine OSC inhibitor series. These novel analogues with a much lower pK(a) range (5.8-6.7) gave potent oral inhibition of rat cholesterol biosynthesis (8 ED(80) 0.7 mg/kg), and diminished effects on rat feeding after a 100 mg/kg oral dose.

Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms.

Cell-mediated cytotoxicity plays an important role in the clearance of noncytopathic viruses from infected tissues. Perforin-dependent cytotoxic mechanisms have been noted to play an important role in the clearance of infections from multiple extrahepatic organs. In contrast, mice with defects in the Fas/Fas ligand (FasL)-mediated cytotoxicity pathway exhibit delayed clearance of adenovirus from the liver without apparent delay in the clearance of viral infections from extrahepatic organs. The present studies examined the role of cytotoxic effector mechanisms in intrahepatic immune responses to a replication-defective, recombinant beta-galactosidase-encoding adenovirus (AdCMV-lacZ). Delayed clearance of AdCMV-lacZ from the livers of FasL-defective B6.gld mice, but not perforin-deficient B6.pfp(-/-) mice, was noted despite no significant differences in initial hepatic CD8(+) T cell IFN-gamma or TNF responses or in activation of intrahepatic cytotoxic lymphocytes cells capable of killing AdCMV-lacZ-infected fibroblast targets. In contrast, AdCMV-lacZ-infected hepatocyte targets were far more sensitive to killing by intrahepatic cytotoxic lymphocytes from B6.pfp(-/-) than from B6.gld mice, and residual levels of virus-specific killing of hepatocyte targets by FasL-defective B6.gld CTL were blocked by TNF inhibition. These results suggest that inherent resistance of hepatocytes to cytotoxicity mediated by perforin-dependent mechanisms leaves Fas/FasL-dependent, cell-mediated cytotoxicity as the major pathway for CTL-mediated killing of virally infected hepatocytes and accounts for the more prominent role of perforin-independent anti-viral mechanisms in immune responses in the liver.

Reclassification of [Pseudomonas] doudoroffii (Baumann et al. 1983) into the genus Oceanomonas gen. nov. as Oceanomonas doudoroffii comb. nov., and description of a phenol-degrading bacterium from estuarine water as Oceanomonas baumannii sp. nov.

A bacterium, isolate GB6T, capable of degrading phenol in the presence of elevated salinity was isolated from the estuary of the River Wear, UK. The bacterium was subjected to biochemical and molecular analysis to determine its taxonomic status. These studies indicated that the bacterium was a distinct species closely related to [Pseudomonas] doudoroffii. However, the phylogenetic analysis indicated that [Pseudomonas] doudoroffii was misclassified, as noted previously. Analysis of the characteristics of isolate GB6T and the type strain of [Pseudomonas] doudoroffii confirmed that these bacteria belonged to the same novel genus, which we have named Oceanomonas gen. nov. The type strain of Oceanomonas doudoroffii (Baumann et al. 1983) comb. nov. is ATCC 27123T (= DSM 7028T. The DNA-DNA homology between isolate GB6T and [Pseudomonas] doudoroffii is low and phenotypic differences between the two organisms are evident. Isolate GB6T (= ATCC 700832T = NCIMB 13685T) is therefore proposed as the type strain of a new species, Oceanomonas baumannii sp. nov.

Enhancement of MHC class I-stimulated alloresponses by TNF/TNF receptor (TNFR)1 interactions and of MHC class II-stimulated alloresponses by TNF/TNFR2 interactions.

In vivo TNF inhibition has been observed to ameliorate the disease process attributed to T cell-dependent immune responses such as those generated during graft-vs.-host disease. The present studies were designed to evaluate whether TNF/TNF receptor (TNFR)1 and TNF/TNFR2 interactions were involved in the generation of allospecific T cell responses. Splenic lymphocyte populations were obtained from TNFR1- or TNFR2-deficient B6 mice and from control B6 mice. These responder cells were cultured with irradiated MHC class II-disparate B6.C-H-2bm12 (bm12) or MHC class I-disparate B6.C-H-2bm1 (bm1) or irradiated syngeneic stimulator cells for 3 days before assay of [3H]thymidine incorporation. IL-2 levels of the mixed lymphocyte culture (MLC) supernatants were assessed by enzyme-linked immunosorbent assay. With MHC class II-disparate bm12 stimulator cells, a significant reduction in T cell proliferation was observed utilizing TNFR2-deficient CD4+ responder T cells, but not when using TNFR1 -deficient CD4+ responder T cells. A significant decrease in proliferation of TNFR1-deficient CD8+ responder cells, but not of TNFR2-deficient CD8 responder T cells was observed after stimulation with MHC class I-disparate bm1 stimulator cells. IL-2 levels were lower in MLC utilizing MHC class I stimulators and TNFR1-deficient responders or MHC class II stimulators and TNFR2-deficient responders. These results indicate that TNF/TNFR2 interactions promote MHC class II-stimulated alloresponses, while TNF/TNFR1 interactions promote MHC class I-stimulated alloresponses.

T-cell activation and differentiation are regulated by TNF during murine DBA/2-->B6D2F1 intestinal graft-versus-host disease.

Administration of a tumor necrosis factor (TNF) inhibitor-encoding adenoviral vector decreases the severity of colonic inflammation in a DBA/2-->B6D2F1 murine model of colonic graft-versus-host disease (GVHD). The present studies evaluated the effect of TNF blockade on the splenic and colonic T-cell responses. cDNA encoding an artificial fusion protein consisting of the extracellular domain of the human 55-kDa receptor for TNF fused to a mouse IgG heavy chain was subcloned into an E1a-deficient adenoviral vector. Following transfer of DBA/2 T cells and bone marrow cells into irradiated B6D2F1 mice, the mice then received either the control adenovirus or the TNF inhibitor-encoding adenovirus. Splenic and colonic lymphocytes were isolated, stained with anti-H-2b, anti-H-2d, anti-CD3, anti-CD4, anti-CD8, and anti-CD45RB antibodies, and analyzed by flow cytometry. Splenic and colonic lymphocyte cytokine profiles also were assessed. More colonic T cells of donor origin were isolated from the control adenovirus recipients than from recipients of the TNF inhibitor encoding adenovirus (P = .027). Fewer CD4+ and CD8+ T cells were observed in colon but not in the spleen in the TNF inhibitor recipients. Fewer CD45RBlow (memory) T cells were observed in the CD4+ colonic lymphocytes isolated from the TNF inhibitor recipients than from controls. Importantly, lower levels of interleukin-2(IL-2) and interferon-gamma (INF-gamma) but not of IL-4 were observed in the lamina propria lymphocyte RNA isolated from the TNF inhibitor recipients. Infiltration and expansion of donor T cells and T-cell activation in the colon appear to be regulated by TNF during murine DBA/2 --> B6D2F1 gut GVHD.

The modification of the membrane of Oceanomonas baumannii when subjected to both osmotic and organic solvent stress.

Oceanomonas baumanniioff a novel halotolerant bacterium which was isolated from the estuary of the river Wear (Sunderland, UK). When grown in tryptone soya broth it can tolerate high levels of phenol, which is not utilised as a carbon source in this medium. However, the level of tolerance was reduced from 35 mM to 3 mM phenol as salinity increased from 1% to 12% NaCl (w/v). Increasing salinity up to 12% NaCl also decreased the growth rate 8-fold and caused modifications to the cytoplasmic membrane particularly anionic phosphatidylglycerol levels, which doubled at the expense of zwitterionic phosphatidylethanolamine. In addition, changes in the phospholipid fatty acid composition were noted, cis-vaccenic acid decreased significantly at higher salinities. Intracellular solute levels also increased with increasing salinity and there was an accumulation of the compatible solutes ectoine, glycine betaine and glutamate. The addition of phenol to osmotically compromised cultures led to a further modification of the cytoplasmic membrane phospholipid composition, in particular, that the decrease in zwitterionic phosphatidylethanolamine and the increase of anionic phospholipid species was much less pronounced. A further decrease in unsaturation, particularly in the proportion of cis-vaccenic acid, and the mean chain length of the fatty acids suggested that this response was important in maintaining membrane integrity in the presence of phenol.

Naphthyl ketones: a new class of Janus kinase 3 inhibitors.

Potent inhibition of Janus kinase 3 was found for a series of naphthyl(beta-aminoethyl)ketones (e.g. 7, pIC50 = 7.1+/-0.3). Further studies indicated that these compounds fragment in less than 1 h by retro-Michael reaction in the Jak3 in vitro ELISA assay procedure. The breakdown product of 7, 2-naphthylvinyl ketone (22, pIC50 = 6.8+/-0.3) showed very similar inhibitory activity to 7. Compounds 7 (in neutral buffer) and 22 will be useful pharmacological tools for the investigation of the Janus tyrosine kinase Jak3.

A novel series of 4-piperidinopyridine and 4-piperidinopyrimidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase.

A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.

Diaphragmatic hernia seen as a late complication of laparoscopic cholecystectomy.

Laparoscopic surgery has emerged as the standard of care for the elective operative management of symptomatic gallbladder disease. The surgical literature is now beginning to accumulate sufficient case numbers that more clearly define the associated morbidity of this type of surgery. This article reports an instance of iatrogenic injury to the right muscular hemidiaphragm and subsequent hernia after laparoscopic cholecystectomy.

Manipulation of postnatal testosterone levels affects phallic and clitoral development in infant rhesus monkeys.

Male primates exhibit marked elevation of circulating testosterone levels during the early postnatal period. The aim of this project was to test whether experimental manipulation of circulating testosterone levels in male and female infant rhesus monkeys affected development of the external genitalia during the first six months of life. Four groups of infants were studied. Seven control male infants exhibited high circulating testosterone levels during the first three months of life. Seven males were treated with a GnRH agonist (avorelin) from the first week of life onwards, which suppressed the postnatal testosterone surge. Ten control females exhibited low circulating testosterone levels during the early postnatal period. Administration of testosterone to 10 females resulted in high circulating levels in these infants. Fortnightly blood samples and genital measurements were taken from all infants during the first six months of life. Growth of the penis of avorelin-treated males was significantly retarded when compared to control males. Average length of the penis at six months of age was significantly (p = 0.012) smaller for avorelin-treated males (25.2 +/- 2.8 mm) than for control males (37.3 +/- 3.0 mm). Avorelin-treated males attained only around 50% detachment of the prepuce from the glans of the penis, while control males averaged 90% detachment. Treatment of females with testosterone resulted in significant growth of the clitoris in comparison to control females. The growth rates of the penis of control males and clitorides of testosterone-treated females were similar and greatest during the first two months of life. Gain in body weight was not affected by either hormonal manipulation. It is concluded that manipulation of circulating testosterone levels during the early postnatal period affects penile and clitoral development of infant rhesus monkeys. This postnatal period may therefore represent an important stage in penile development in primates.