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Introduction and Objectives Patients with Inducible laryngeal obstruction (ILO) and Breathing pattern disorder (BPD) can mimic severe asthma. ILO and/or BPD can co-exist in patients with severe asthma. Therefore a multidisciplinary team (MDT) approach from Respiratory Physicians, Respiratory specialist nurses, Speech and Language therapists, Physiotherapists and Psychologists to accurately diagnose and manage these conditions is essential. The MDT optimises the patient outcomes as well as reducing healthcare utilisation and costs of pharmacotherapy. Methods Eighty six patients who attended Bolton complex breathlessness clinic between Apr2017 - July 2019 were involved in this service evaluation. Hospitalisations, Emergency departmental (ED) visits, oral steroid and antibiotic courses 12 months before and after review in the clinic were analysed using paired t-testing with p value Conclusions Accurate diagnosis and appropriate interventions for ILO and BPD undertaken from Specialist Complex breathlessness clinic resulted in significant reduction of hospitalisations, booster courses of oral steroids and antibiotics in our cohort of patients.

Maternal transfer of steroids to eggs can elicit permanent effects on offspring phenotype. Although testosterone was thought to be a key mediator of maternal effects in birds, we now know that vertebrate embryos actively regulate their exposure to maternal testosterone through steroid metabolism, suggesting testosterone metabolites, not testosterone, may elicit the observed phenotypic effects. To address the role steroid metabolism plays in mediating yolk testosterone effects, we used European starling (Sturnus vulgaris) eggs to characterize the timing of testosterone metabolism and determine whether etiocholanolone, a prominent metabolite of testosterone in avian embryos, is capable of affecting early embryonic development. Tritiated testosterone was injected into freshly laid eggs to characterize steroid movement and metabolism during early development. Varying levels of etiocholanolone were also injected into eggs and incubated for either three or five days to test whether etiocholanolone influences the early growth of embryonic tissues. The conversion of testosterone to etiocholanolone is initiated within 12 hours of injection, but the increase in etiocholanolone is transient indicating that etiocholanolone is also subject to metabolism, and that exposure to maternal etiocholanolone is limited to a short period during early development. Exogenous etiocholanolone manipulation had no significant effect on the growth rate of the embryos or extra-embryonic membranes early in development. Thus, the conversion of testosterone to etiocholanolone may be an inactivation pathway that buffers the embryo from maternal steroids, with any effects of yolk testosterone resulting from testosterone that escapes metabolism; alternatively, etiocholanolone may influence processes other than growth or take additional time to manifest.

In recent years, the potential for maternal stress effects to adaptively alter offspring phenotype has received considerable attention. This research has identified offspring traits that are labile in response to maternal stress; however, an understanding of the mechanisms underlying these effects is lagging and is crucial to appreciating the significance of this maternal effect. In the present study, we sought to better understand maternal stress effects by examining the potential for embryonic regulation of corticosterone exposure, determining the phenotypic consequences of elevated corticosterone during development, and characterizing the levels of maternally transferred corticosterone in unmanipulated eggs using Trachemys scripta. By dosing eggs with tritiated corticosterone and tracking the steroid throughout development, we found that most corticosterone is metabolized, and less than 1% of the corticosterone dose reaches the embryo as free corticosterone. We also found that exogenous dosing of corticosterone, in concentrations sufficient to overwhelm embryonic metabolism, reduces embryonic survival and negatively impacts hatchlings traits important to fitness. Lastly, we demonstrate that concentrations of maternal corticosterone in the yolks of unmanipulated eggs are low and are significantly lower than the doses of corticosterone required to elicit phenotypic effects in hatchlings. Taken together, these results provide evidence that both the embryo and the female may minimize corticosterone accumulation in the embryo to avoid reductions in embryonic survival and negative impacts on offspring phenotype and fitness.

All vertebrate embryos are exposed to maternally derived steroids during development. In placental vertebrates, metabolism of maternal steroids by the placenta modulates embryonic exposure, but how exposure is regulated in oviparous vertebrates is less clear. Recent work in oviparous vertebrates has demonstrated that steroids are not static molecules, as they can be converted to more polar steroid sulfates by sulfotransferase enzymes. Importantly, these steroid sulfates can be converted back to the parent compound by the enzyme steroid sulfatase (STS). We investigated when and where STS, was present during embryonic development in the red-eared slider turtle, Trachemys scripta. We report that STS is present during all stages of development and in all tissues we examined. We conclude that STS activity may be particularly important for regulating maternal steroid exposure in oviparous vertebrates.

Free-living vertebrates tend to respond to environmental challenges by increasing circulating glucocorticoid levels. Changes in glucocorticoids can modulate various aspects of physiology and behavior, which can have fitness benefits in the short term but may be detrimental to fitness if elevated levels are frequent, prolonged, or both. The transfer of glucocorticoids from females to offspring might also have fitness consequences, but there is less known about the potential effects of transgenerational glucocorticoid transfer. Our study examined corticosterone levels in female Red-eared Sliders (Trachemys scripta) during the nesting season because of the potential fitness consequences for both females and offspring. Whether caught in aquatic traps or caught during the nesting process, females had similar circulating corticosterone levels that were relatively low. However, when females were subjected to a restraint protocol, corticosterone rose. Therefore, corticosterone levels may be elevated duri...

The leopard gecko (Eublepharis macularius) exhibits temperature-dependent sex determination as well as temperature-influenced polymorphisms. Research suggests that in oviparous reptiles with temperature-dependent sex determination, steroid hormones in the yolk might influence sex determination and sexual differentiation. From captive leopard geckos that were all from the same incubation temperature regime, we gathered freshly laid eggs, incubated them at one of two female-biased incubation temperatures (26 or 34°C), and measured testosterone content in the yolk-albumen at early or late development. No differences in the concentration of testosterone were detected in eggs from different incubation temperatures. We report testosterone concentrations in the yolk-albumen were higher in eggs of late development than early development at 26°C incubation temperatures, a finding opposite that reported in other TSD reptiles studied to date.

Synopsis All vertebrate embryos develop in the presence of maternally derived steroids, and maternal steroids have been hypothesized to link phenotype of the offspring to maternal physiology. In placental vertebrates, it is known that maternally derived steroids are metabolized during development via the sulfonation pathway. We used eggs from the red-eared slider turtle (Trachemys scripta) to determine whether the same metabolic pathway is used to metabolize maternally derived steroids in an oviparous vertebrate. To examine the relationship between estradiol and estrogen sulfates during development, levels of maternally derived estradiol were compared with levels of estradiol sulfate, estrone sulfate, and estriol sulfate at oviposition and after 20 days of embryonic development. Estrone sulfate was the only detectable estrogen sulfate. At oviposition, levels of both estradiol and estrone sulfate varied seasonally with clutches from later in the nesting season having significantly higher concentrations of both steroids. Levels of estrone sulfate increased during development, demonstrating that the sulfonation of maternally derived steroids occurs in oviparous vertebrates as well as in placental vertebrates. We also found that exogenous estrone sulfate increases the production of female hatchlings, thereby demonstrating the ability of this metabolite to influence embryonic development. To examine the role of sulfonation in the metabolism of maternal progesterone and testosterone, we characterized the metabolic fate of both steroids by applying tritiated forms of each steroid at oviposition and characterizing metabolites after 20 days of incubation. Similar to what was demonstrated for estradiol, both progesterone and testosterone are converted to sulfonated metabolites during embryonic development. These data suggest that steroid sulfates, both those that are maternally derived and those resulting from the metabolism of maternal steroids, are a key component of the mechanism underlying steroid-mediated maternal effects.

Glucocorticoids circulating in breeding birds during egg production accumulate within eggs, and may provide a potent form of maternal effect on offspring phenotype. However, whether these steroids affect offspring development remains unclear. Here, we employed a non-invasive technique that experimentally elevated the maternal transfer of corticosterone to eggs in a wild population of house wrens. Feeding corticosterone-injected mealworms to free-living females prior to and during egg production increased the number of eggs that females produced and increased corticosterone concentrations in egg yolks. This treatment also resulted in an increase in the amount of yolk allocated to eggs. Offspring hatching from these eggs begged for food at a higher rate than control offspring and eventually attained increased prefledging body condition, a trait predictive of their probability of recruitment as breeding adults in the study population. Our results indicate that an increase in maternal glucocorticoids within the physiological range can enhance maternal investment and offspring development.

Early embryonic exposure to maternal glucocorticoids can broadly impact physiology and behaviour across phylogenetically diverse taxa. The transfer of maternal glucocorticoids to offspring may be an inevitable cost associated with poor environmental conditions, or serve as a maternal effect that alters offspring phenotype in preparation for a stressful environment. Regardless, maternal glucocorticoids are likely to have both costs and benefits that are paid and collected over different developmental time periods. We manipulated yolk corticosterone (cort) in domestic chickens ( Gallus domesticus ) to examine the potential impacts of embryonic exposure to maternal stress on the juvenile stress response and cellular ageing. Here, we report that juveniles exposed to experimentally increased cort in ovo had a protracted decline in cort during the recovery phase of the stress response. All birds, regardless of treatment group, shifted to oxidative stress during an acute stress response. In addition, embryonic exposure to cort resulted in higher levels of reactive oxygen metabolites and an over-representation of short telomeres compared with the control birds. In many species, individuals with higher levels of oxidative stress and shorter telomeres have the poorest survival prospects. Given this, long-term costs of glucocorticoid-induced phenotypes may include accelerated ageing and increased mortality.

Understanding the many factors that underlie phenotypic variation is of profound importance to evolutionary biologists. The embryonic endocrine environment is one such factor that has received much attention. In placental amniotes, the dynamic interaction of maternal and embryonic steroid production and metabolism is critical to regulating the endocrine environment. Less is known about how embryos of oviparous amniotes regulate their endocrine environment because most studies have focused on relating initial steroid levels in the yolk at oviposition to offspring phenotype. We tested the hypothesis that embryos of oviparous amniotes regulate their endocrine environment by conjugating maternal steroids and subsequently using the metabolites as precursors for steroid production later in development. Using the red-eared slider turtle ( Trachemys scripta ), we first characterized the conjugation of exogenous oestradiol to either oestradiol glucuronide or oestradiol sulphate (E 2 -S) in ovo during the first 15 days of development. Results show that oestradiol is primarily conjugated to E 2 -S. We then examined whether E 2 -S influenced sex determination and report that E 2 -S increases the production of female offspring. These data demonstrate that oviparous amniotes can both sulphonate steroids and respond to sulphonated steroids during embryonic development in a manner similar to placental amniotes.

In birds, maternally derived yolk steroids are a proposed mechanism by which females can adjust individual offspring phenotype to prevailing conditions. However, when interests of mother and offspring differ, parent–offspring conflict will arise and embryonic interests, not those of the mother, should drive offspring response to maternal steroids in eggs. Because of this potential conflict, we investigated the ability of developing bird embryos to process maternally derived yolk steroids. We examined how progesterone, testosterone and oestradiol levels changed in both the yolk/albumen (YA) and the embryo of European starling eggs during the first 10 days of development. Next, we injected tritiated testosterone into eggs at oviposition to characterize potential metabolic pathways during development. Ether extractions separated organic and aqueous metabolites in both the embryo and YA homogenate, after which major steroid metabolites were identified. Results indicate that the concentrations of all three steroids declined during development in the YA homogenate. Exogenous testosterone was primarily metabolized to an aqueous form of etiocholanolone that remained in the YA. These results clearly demonstrate that embryos can modulate their local steroid environment, setting up the potential for parent–offspring conflict. Embryonic regulation must be considered when addressing the evolutionary consequences of maternal steroids in eggs.

During development, embryos utilize steroid signals to direct sexual differentiation of tissues necessary for reproduction. Disruption of these signals by exogenous substances (both natural and synthetic) frequently produce phenotypic effects that can persist into adulthood and influence reproduction. This paper reviews the evidence that during embryonic development, progesterone metabolites and xenobiotic-sensing nuclear receptors may interact to increase the expression of numerous enzymes responsible for steroid metabolism in oviparous and placental amniotes. In these groups, embryonic development is characterized by (1) elevated progesterone concentrations, (2) 5 beta reduction being the primary metabolic pathway of progesterone, (3) the presence of xenobiotic-sensing nuclear receptors that can bind 5 beta metabolites of progesterone, and (4) increased expression of a suite of enzymes responsible for the metabolism of multiple steroids. We propose that xenobiotic-sensing nuclear receptors initially evolved to buffer the developing embryo from the potentially adverse effects of various maternal steroids on sexual differentiation.

Maternally derived yolk steroids have been found to elicit both short-term and long-term effects on offspring phenotype. Paradoxically, their effects can be strikingly specific given the often substantial concentrations present at oviposition, and they do not appear to uniformly affect all steroid-sensitive processes. To better understand the dynamics of yolk steroids across embryonic development, we quantified levels of progesterone, testosterone, and estradiol at 5-day intervals throughout development in eggs of the red-eared slider turtle (Trachemys scripta) incubated at both male- and female-producing temperatures. We also assessed the effect of season on yolk steroid levels. For all steroids assayed, the concentrations in yolk declined significantly by day 15 of embryonic development despite large differences in initial concentrations among steroids. We found that estradiol was the only steroid whose initial concentration varied significantly with season, while only the decline in testosterone was affected by incubation temperature. These findings illustrate the complex nature of yolk steroid dynamics and suggest that maternal steroids may be rapidly degraded or subject to embryonic processing, emphasizing the need for studies aimed at understanding the mechanisms through which yolk steroids may elicit their effects.

Maternal effects are typically thought to enhance rather than reduce offspring performance, but asynchronous hatching (ASH) in birds typically produces a size hierarchy within a clutch that frequently reduces the growth and survival of nestlings from eggs that hatch later. Given that yolk steroids can significantly affect offspring phenotype and that in many species the levels of yolk steroids have been found to increase with laying order, the maternal transfer of steroids to egg yolk has been proposed as a mechanism for females to offset the deleterious effects of ASH. To test this hypothesis, we determined whether yolk steroids varied with laying order or clutch size in Common Grackles (Quiscalus quiscula). Because ASH varies with clutch size (hatching span averages 48 h in five-egg clutches, 24 h in four-egg clutches) and regularly results in the starvation of later hatched nestlings, we predicted: (1) testosterone and 17s-estradiol levels should increase with laying order in both clutch sizes to mitigate the negative effects of ASH on last-hatched nestlings, and (2) the increase should be greater in five-egg clutches due to more pronounced hatching asynchrony. Using a competitive-binding steroid radioimmunoassay, we found no systematic variation in either testosterone or estradiol levels relative to laying order or clutch size. In the absence of evidence that yolk steroids interact adaptively with ASH, research must look elsewhere for potential benefits that might compensate for the costs these steroids impose on nestlings.

The understanding of the timing and development of the recurrence of androgen-independent prostate cancer is limited and has significant clinical implications. The paper by So et al. addresses, for the first time, the concept of recurrence after androgen ablation in an animal model. They show clearly in this well designed and conducted study that the recurrence of an androgen-independent cancer depends on both the initial size of the tumour and the delay leading to castration. These results have significant clinical importance in the understanding and treatment of prostate cancer. OBJECTIVE To use the androgen-dependent Shionogi tumour model in mice to help define the effects of the timing of androgen ablation on the development of androgen resistance in prostate cancer, as the timing of androgen ablation remains controversial. MATERIALS AND METHODS Groups of nine mice were castrated at 1, 3, 6, 10 and 14 days after tumour inoculation, with a similar-sized group of mice castrated before tumour inoculation serving as a control. The time of first palpable tumour recurrence and tumour volume was monitored after castration. RESULTS All mice were observed for ≥ 80 days after castration. Only mice castrated at 10 and 14 days had palpable tumour at the time of castration. Mice castrated at 14 days had the highest rate of early tumour recurrence (all nine) while mice castrated before inoculation or at 1 and 3 days afterward had a significantly lower rate of tumour recurrence (four of nine; P

Daycare parents ( N =37; mean age=30) were interviewed by phone about important aspects of their child's daycare center. Information about the daycare centers' structural and procedural characteristics was obtained through interviews with center directors. Comparisons between parental answers and the data provided by the directors revealed significant gaps in parental knowledge of daycare. On average, parents answered only 45% of questions correctly, and reported a lack of knowledge regarding both general center characteristics ( i.e. ,'turnover rates, caregiver training, and hiring practices) and specific group characteristics ( i.e. , group size, adult-child ratio, and child's daily schedule). Parental knowledge increased with length of involvement with the center, but other variables such as parent education and the number of hours the child spent in care per week did not contribute to prediction of parental knowledge.

This study investigates the potential effects of maternally derived hormones present in the yolk of reptile eggs. Specifically, we ask when are these hormones utilized by developing red-eared slider turtles (Trachemys scripta elegans), a species with temperature-dependent sex determination (TSD). Eggs were incubated at 27 degrees C, a male-producing temperature, and at 31 degrees C, a female-producing temperature. Concentrations of progesterone, testosterone, and 17beta-estradiol were measured at four points during development: at oviposition, at the start of the temperature sensitive period (TSP), at the end of the TSP, and at hatching. No effects of incubation temperature on yolk hormone concentrations were detected. The highest concentrations of all three hormones were measured at oviposition. Hormone-specific patterns of decline occurred throughout development. Each hormone declined between oviposition and the early TSP. Although estradiol was present in detectable quantities at oviposition, it was virtually undetectable by the early TSP. Testosterone showed no further decline after the early TSP. Progesterone continued to decline between the early and post-TSP. These results demonstrate that maternally derived yolk hormones decline at different rates. Alternative explanations for the disappearance of these yolk hormones are presented.

Despite a significant worldwide need for effective microbicides to reduce sexually transmitted diseases (STD) and HIV transmission, none is currently available. C31G, a surface active anti-infective agent that is active in vitro against bacterial and viral STD pathogens, was evaluated in a 3-day, once-daily dosing clinical trial designed to assess multiple formulations for safety and acceptance. The trial used a scoring algorithm that was based on relevant subject reported symptoms and signs observed at follow-up. Differences in tolerance and acceptability between the formulations were demonstrated, as was consistency with the results from a previous 7-day trial that involved two of the formulations (1.2% HEC gel, 2.0% N-9). The 1.0% C31G co-polymer gel was the best tolerated, most acceptable formulation, and will be advanced to longer, more comprehensive trials. Thus, formulation differences are relevant to microbicide tolerance and acceptability, and the 3-day trial design validated in this study can be used to assess formulations.

The actions of circulating hormones, although relatively well understood for adults, are largely unknown for their developing embryos. Transfer of maternal hormones to the egg is known to occur in oviparous species, and recently the presence of hormonally heterogeneous yolk layers has been described in two avian species. To investigate the possibility of a similar phenomenon occurring in chelonian species, egg yolk layers were analyzed in the painted turtle (Chrysemys picta marginata) and the red-eared slider turtle (Trachemys scripta elegans), two species that exhibit temperature-dependent sex determination. There was a similar pattern of hormonally heterogeneous yolk layers in both species: concentrations of progesterone and testosterone were significantly higher in the external yolk layer while concentrations of 17beta-estradiol were significantly higher in the intermediate and internal layers. This pattern of hormone deposition concurs with previously published studies of plasma hormone profiles from females of temperate-zone turtle species. Yolks of freshly laid eggs were also sampled using a biopsy technique to examine the concordance of early yolk hormone concentrations and offspring sex. No relationship was found between yolk hormone concentrations and individual offspring sex. Previous work showing that maternally derived yolk estradiol concentrations are correlated with female-biased sex ratios was, however, replicated. These findings suggest that offspring sex is influenced, in part, by the maternal hormone environment.

Pigtailed macaques (Macaca nemestrina) and longtailed macaques (M. fascicularis) show behavioral, ecological, and possible temperament differences, and their responses to the laboratory environment might therefore be quite different. We tested pigtailed macaques under the same conditions that were investigated in a previous study with longtailed macaques, using the same comprehensive set of physiological and behavioral measures of stress. First, eight adult females' adaptation to a new room in regulation-size cages was monitored, and in the third week their responses to ketamine sedation were measured. Then they spent two weeks singly housed in each of four cage sizes (USDA regulation size, one size larger, one size smaller, and a very small cage). Half of the subjects were in upper-level cages and the remainder in lower-level cages for the entire study. Cage size, ranging from 20% to 148% of USDA regulation floor area, was not significantly related to abnormal behavior, self-grooming, manipulating the environment, eating/drinking, activity cycle, cortisol excretion, or biscuit consumption. Locomotion and frequency of behavior change were significantly reduced in the smallest cage, but did not differ in cage sizes ranging from 77% to 148% of regulation size. The only manipulation to produce an unequivocal stress response, as measured by cortisol elevation and appetite suppression, was ketamine sedation. Room change and cage changes were associated with minimal cortisol elevation and appetite suppression. Wild-born females showed more appetite suppression after room change than captive-born females. No differences were related to cage level. Pigtailed macaques strongly resembled longtailed macaques except they showed weaker responses to the new room and cage change, probably because the pigtails had spent more time in captivity. These findings support the conclusion that increasing cage size to the next regulation size category would not have measurable positive effects on the psychological well-being of two species of laboratory macaques.

During embryonic development, endogenous signals, for example steroid hormones, and exogenous signals, for example endocrine disrupting chemicals (EDCs), have the capacity to produce phenotypic effects that persist into adulthood. As the actions of steroids are mediated through the binding of steroid receptors, most studies of EDCs have assumed that they too elicit their effects by binding steroid receptors. We tested an alternative hypothesis, namely that EDCs elicit their effects during embryonic development by disrupting the metabolism of maternally derived steroids, thereby allowing maternally derived steroids to bind steroid receptors and elicit effects. Specifically, we examined the ability of the EDC, bisphenol-A (BPA) to inhibit the normal metabolism of oestradiol during the first nine days of embryonic development in the red-eared slider turtle ( Trachemys scripta ). We found that, when BPA was present, oestrogen metabolism was inhibited when compared to control eggs. In particular, the formation of oestrone sulfate was blocked in BPA-treated eggs. We postulate that the oestrogenic effects of EDCs may be driven, at least in part, by inappropriate oestrogen signalling. The retention of oestrogens at points of development when they would normally be metabolized to inactive forms might also help explain low-dose effects frequently reported for EDCs.

Tuberculosis (TB) morbidity and mortality have increased substantially since the mid-1980s in areas with a high prevalence of medically underserved populations, human immunodeficiency virus, foreign-born persons, residents of long-term care facilities and crowded correctional institutions, and alcoholics and intravenous-drug abusers. The occupational risk has likewise increased for those exposed to these high-risk people in the course of their work. The magnitude of the occupational hazard is present unclear, although implications are disturbing. We used available data bases containing occupational exposure information, and telephone surveys, in an attempt to elucidate the magnitude of risk of occupationally acquired TB. We obtained up-to-date employee conversion rates at high-risk institutions, identified changing rates of TB infection and disease over time, documented high conversion rates following accidental exposures, and revealed a relative lack of reported TB disease and deaths. Numerous barriers to worker protection against TB are identified and recommendations are made to reduce the risk of occupationally acquired tuberculosis.

Eggs of oviparous amniotes can contain substantial quantities of several steroids at the time of oviposition. These maternally derived steroids appear to affect the phenotype of developing offspring, but not all steroid sensitive traits are affected by maternal steroids, and little is known about how these effects may arise. In this study, we applied tritiated estradiol to the eggs of red-eared sliders (Trachemys scripta) at the time of oviposition and characterized the subsequent metabolism and movement throughout embryonic development. Results indicate that very early in development, estradiol is converted to a variety of water-soluble estrogen sulfates that reside in the yolk and extraembryonic fluids until late in development. Within the final stages of development, we observe a significant decline in the total amount of metabolites present in the yolk and extraembryonic fluids and a significant increase in the amount of metabolites present in the embryo. While estradiol metabolism occurs during the early stages of development, the later stages appear to be the most dynamic with regards to the movement of estradiol metabolites. Our findings have important implications for studies investigating the effect of maternally derived steroids on offspring development.

Objective: To present the methodology for speech assessment in the Scandcleft project and discuss issues from a pilot study. Design: Description of methodology and blinded test for speech assessment. Speech samples and instructions for data collection and analysis for comparisons of speech outcomes across five included languages were developed and tested. Participants and Materials: Randomly selected video recordings of 10 5-year-old children from each language (n = 50) were included in the project. Speech material consisted of test consonants in single words, connected speech, and syllable chains with nasal consonants. Five experienced speech and language pathologists participated as observers. Main Outcome Measures: Narrow phonetic transcription of test consonants translated into cleft speech characteristics, ordinal scale rating of resonance, and perceived velopharyngeal closure (VPC). A velopharyngeal composite score (VPC-sum) was extrapolated from raw data. Intra-agreement comparisons were performed. Results: Range for intra-agreement for consonant analysis was 53% to 89%, for hypernasality on high vowels in single words the range was 20% to 80%, and the agreement between the VPC-sum and the overall rating of VPC was 78%. Conclusions: Pooling data of speakers of different languages in the same trial and comparing speech outcome across trials seems possible if the assessment of speech concerns consonants and is confined to speech units that are phonetically similar across languages. Agreed conventions and rules are important. A composite variable for perceptual assessment of velopharyngeal function during speech seems usable; whereas, the method for hypernasality evaluation requires further testing.

The organization and chemical development of the area postrema (AP) in the macaque monkey was studied by immunohistochemistry imaged with conventional and confocal microscopy from day 40 of gestation to adulthood. The thin ependyma of the adult was found to develop from a thick continuous structure beginning in the second trimester. It was later invaded by tyrosine hydroxylase immunoreactive (TH+) and dopamine beta-hydroxylase immunoreactive (DBH+) cells and fibers, suggesting a possible route for release of neurotransmitter directly into ventricular cerebrospinal fluid. Other TH+ and/or DBH+ fibers were found in close approximation to blood vessels. Prominent vascularity of the parenchyma of AP was present late in the first trimester (fetal day (Fd)57 in the macaque) and increased further until birth. By contrast, the underlying solitary nucleus was hypervascular at Fd57, but its vascularity rapidly declined by late in the second trimester. TH+ neurons first appeared late in the first trimester, and DBH+ neurons appeared in the second trimester; these findings are consistent with the view that catecholaminergic cells in AP are the earliest members of the A2 noradrenergic group. Catecholaminergic cells or fibers in AP contained little labeling for synaptic vesicular proteins, suggesting that the release of neurotransmitter there may not involve a synaptic mechanism. Synapses were first observed in mid-second trimester, and most were associated with GABA+ fibers.

The objectives of this study were to examine the respiratory irritancy of boron trifluoride (BF3) and fluorosulfonic acid (FSA) following acute inhalation exposure. Testing was conducted using groups of 10 male and 10 female rats (BF3) or groups of 6 male rats (FSA). Rats were exposed for a single 4-h period (BF3) or a single 1-h period (FSA) and necropsied 1 or 14 days after exposure (BF3) or 14 days after exposure (FSA). Measurements consisted of clinical signs, body weight, kidney and lung weight, histopathology (BF3), and breathing parameters (FSA) and were used to evaluate the possible irritating effects of these compounds. The results indicated treatment-related findings in the larynx and trachea in the rats exposed to 74.4 mg/m3 BF3, consisting of ventral cartilage necrosis, hemorrhage, and an increase in ventral epithelial hyperplasia and ventral inflammatory cell inflammation 24 h postexposure. In the animals sacrificed 14 days postexposure, the only notable observation was ventral cartilage necrosis, present in 2 animals. The next lower level tested, 24.6 mg/m3 BF, was considered a no-observed-adverse-effects level (NOAEL). A concentration of 4125 mg/m3 FSA resulted in a clearly decreased breathing rate during and shortly after exposure with 67% (4/6) mortality on days 5-9 after exposure. A concentration of 845 mg/m3 FSA resulted in only minor signs of irritation, consisting of slight changes in breathing pattern shorlty after exposure. The results of the present 4-h inhalation study with BF3 indicated that respiratory irritation was present at a level of 74.4 mg/m3 whereas 24.6 mg/m3 was a NOAEL. A single 1-h exposure to 845 mg/m3 FSA resulted in only minor signs of respiratory irritation, indicating that on a mass basis FSA is no more toxic or irritating than hydrogen fluoride (HF) or sulfuric acid. Copyright © Informa Healthcare USA, Inc.

Ethanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5, 3.3 or 4.1 gm/kg from the 5th week. Mean maternal peak plasma ethanol concentrations (MPPEC's) ranged from 24 +/- 6 mg/dl at the 0.3 g/kg dose to 549 +/- 71 mg/dl at the 4.1 g/kg dose. Thirty-three live born infants were assessed for abnormalities of physical and behavioral development. Ocular pathology, neuropathologic and neurochemical assessements were done on 31 animals at 6 months postnatal age. Microphthalmia was noted in three of the 26 animals exposed to ethanol. Retinal ganglion cell loss was significantly associated with intra-uterine ethanol exposure. Microphthalmia and retinal ganglion cell loss was observed in both the delayed and full-gestational exposed animals. No structural anomalies were found in the brains via gross inspection or light microscopy. Chemical abnormalities in the striatal nuclei were identified. Striatal dopamine concentrations increased with increasing MPPEC exposure (0-249 mg/dl) among animals exposed weekly to ethanol throughout gestation. Striatal dopamine concentrations decreased with increasing MPPEC exposure (260-540 mg/dl) among animals whose weekly exposure to ethanol was delayed until the 5th week of gestation. The same pattern of association was also noted between MPPEC and ultrastructural alterations in the caudate nucleus. The extent of ultrastructural alterations increased with increasing MPPEC among the full-gestational exposed animals and decreased with increasing MPPEC among the delayed-dose animals.

To develop a battery of innocuous tests measuring individual differences in the rate of biological aging, longitudinal data were gathered on 28 biochemical, physiological, and morphological characteristics of 40 adult female pigtailed macaques. The change in each variable over time, i.e., the beta coefficient of linear regression, was calculated for each animal, and a matrix of correlations among the variables was constructed. Eight variables correlated well with the first principal component of the matrix. These variables (rate of fingernail growth, blood lymphocytes, mean corpuscular hemoglobin, immunoglobulin A, and serum sodium, chloride, total protein, and creatinine) represented the best subset of the potential biomarkers analyzed to produce an index covering a range of morphologic and functional systems that change with age. A similar set representing a wider range of systems and measured over a larger fraction of the life span should provide a valid index of an individual's rate of biological aging.

Vertebrate embryos develop in the presence of maternally derived steroids. While these steroids can influence development, embryonic enzymes are thought to buffer some steroid sensitive processes, such as gonadal differentiation, from the effects of maternal steroids. Many of these same enzymes may also buffer the embryo from chemicals present in the environment, but this may alter their capacity to metabolize maternal steroids. Here, we characterized the ability of red-eared slider ( Trachemys scripta ) embryos to metabolize oestrone immediately following oviposition and tested whether a prevalent environmental chemical, Bisphenol A (BPA), would affect the in ovo conversion of oestrone to oestrone sulfate. We found that tritiated oestrone applied at the time of oviposition is mostly converted to oestrone sulfate within 6 h. However, when BPA is present, that conversion is inhibited, resulting in elevated oestrone levels. Our finding of rapid in ovo metabolism of steroids suggests that maternally derived enzymes are present in the egg and can alter embryonic exposure to exogenous chemicals. The disruption of this metabolism by BPA demonstrates how environmental chemicals might change embryonic exposure to endogenous substances within the egg. Taken together, these findings highlight the dynamic nature of the early endocrine environment in developing vertebrates.

The transfer of hormones from a female to her offspring is known to occur in egg laying vertebrates, and the potential for these early, maternally derived hormones to influence sex determination in reptiles with temperature-dependent sex determination is intriguing. In the present study, we examine variation in the concentrations of progesterone, testosterone, and estradiol among three follicle size classes within a female painted turtle (Chrysemys picta) and among females across four periods that span the pre- to post-nesting season. Females were collected, and both follicles and shelled eggs (when present) were harvested for hormone analysis. Progesterone levels did not vary seasonally. However, the concentration of progesterone did vary among and within follicle classes, and was primarily dependent upon ovulatory state: Recently ovulated follicles (as yolks within shelled eggs) contained significantly more progesterone than unovulated follicles. Concentrations of testosterone were low and did not vary either among size classes or across the season. Estradiol levels decreased with increasing follicle size and were higher later in the nesting season. Thus, hormone concentrations varied among follicle sizes and states but in patterns that differed among hormones. This variation has the potential to influence sex determination.

Introduction. Data from the 2010 British Gambling Prevalence Survey (BGPS) estimated that in the United Kingdom, the prevalence of problem gambling was about 0.9%. Amongst the general population, the most popular types of gambling are poker, dog races, slot machines and casino games. Previous international research emphasized that some forms of gambling are more “addictive” than others, with online gambling and gaming machines presenting with a higher association to gambling disorder. More recently, in the last year, research has shown that we should shift our attention from type of gambling to level of involvement in a number of different types of gambling activities. Method. We analyzed data from 736 patients assessed at the National Problem Gambling Clinic during a period of two years (2011–2012) and report the characteristics of the treatment seeking population. Result. We compare gamblers' activities and the level of involvement in relation to the severity of presentation of gambling symptoms.

Measurements were made in 29 adult baboons that were housed in social groups, allowing the occurrence of the full range of species-specific behavioral interactions. The cardiovascular variables measured included blood pressure, heart rate, renal blood flow, lower limb blood flow, and occasionally mesenteric blood flow. The data were telemetered from backpacks worn by the animals and were recorded in analogue form on a polygraph, digitally on a computer and were also recorded on the audio channels of videotape being made of the behavior and social interactions of the baboons. The video and the computer recordings were synchronized by a timing system that made it possible to relate the cardiovascular responses to the behavioral responses. A numerically based behavioral code was developed that allowed the categorization of the totality of the behavior, including postural and locomotor changes. Comparisons between baseline cardiovascular values and those occurring 1 s before the initiation of a movement or posture change gave no evidence of anticipatory cardiovascular responses unless the movement was associated with behavior that included emotional content. Hypothalamic perifornical lesions reduced or eliminated these anticipatory changes.

Most hypotheses that have been put forward in order to explain the persistence of environmental sex determination (ESD) in reptiles assume a relatively fixed association of sex with temperature-induced phenotype and no maternal influence on offspring sex. Here we demonstrate the association of maternally derived yolk hormone levels with the offspring sex ratio and describe two new aspects of temperature-dependent sex determination (TSD), i.e. seasonal variation in both thermal response and yolk steroid levels. Eggs from painted turtles (Chrysemys picta) were incubated at 28 degrees C. The hatchling sex ratio at 28 degrees C (i.e. the phenotypic reaction norm for sex at 28 degrees C) shifted seasonally from ca. 72% male to ca. 76% female. Yolk oestradiol (E2) increased seasonally while testosterone (T) decreased. The proportion of males in a clutch decreased as E2 levels increased and the E2:T ratio increased. These new findings are discussed in relation to heritability and adaptive explanations for the persistence of ESD in reptiles. Maternally derived yolk hormones may provide a mechanism for the seasonal shift in the sex ratio which in turn may help explain the persistence of ESD in reptiles. They may also explain those clutches of other reptiles with TSD that fail to yield only males at maximally masculinizing conditions.

The effect of antioxidant activity on the rate of biological aging was studied in 39 pigtailed macaques (Macaca nemestrina) 7-30 years of age. Scores of seven antioxidant compounds (vitamins C and E, carotenoids, urate, bilirubin, ceruloplasmin, and albumin) were combined to produce an antioxidant variable (AOx) that was tested for correlation with a second composite variable, rate of biological aging (RBA). RBA was formed from seven physiological variables that met a stringent set of criteria as biomarkers of aging. Potential effects of disease on RBA and AOx were excluded by experimental design and by statistical control using a composite index of disease (Dis) that was based on four measures of clinical history and pathology. The study produced three salient findings: (1) there was a significant inverse relation between AOx and RBA (i.e., animals that had high AOx scores had low RBA scores and vice versa); (2) the relation was independent of Dis effects, and (3) there was no significant relation between AOx and Dis independent of RBA (i.e., the correlation between AOx and Dis was dependent on the correlation of AOx with RBA). These results further validated the RBA variable as a measure of the rate of biological aging and supported the concept that antioxidant activity influences both the rate of biological aging and vulnerability to disease.

Recently developed biosensor technology, which allows near real-time measurement in situ of gas tension (pCO2 and pO2) and of pH, was applied to arterial blood, cerebrospinal fluid (CSF), and brain parenchyma during intravenous lactate infusion in monkeys. Comparison of simultaneous biosensor measurements and discrete arterial blood sampling for traditional blood gas analyses indicated a high level of correlation for pCO2, pO2, and pH. Arterial pO2 and pH values were significantly higher and pCO2 significantly lower than corresponding CSF and brain parenchyma values at baseline, during and following lactate infusion. There was a divergence between arterial and brain parenchyma pH and pO2 measurements. Lactate infusion was associated with progressive arterial pH rises, consistent with the production of a metabolic alkalosis. Cerebrospinal fluid pCO2 remained unchanged during and following lactate infusion. Brain parenchyma exhibited a complex pattern of response characterized by a trend for pO2 and pH to decrease during lactate infusion, which reversed following completion of the infusion. These observations are suggestive of a transient hypoxia from decreased cerebral blood flow and/or reduced oxyhemoglobin dissociation during lactate infusion, but verification of these results is required.

Heart rate, arterial blood pressure, and renal and mesenteric or femoral blood flow were telemetered from 11 Papio hamadryas in an untethered free-ranging situation. The animals' behavior was recorded on videotape, and the cardiovascular (CV) data were recorded on the audio channels of the tape. The behavior was coded, and the codes were linked to the CV data via a time-code generator and computer control. The CV data were digitized into 1-s intervals, and the static relations between CV measures and the postures/locomotions (P/Ls) associated with the behavior were analyzed. The total frequency distributions for heart rate, blood pressure, and renal conductance approximated Gaussian distributions, whereas femoral conductance was positively skewed. The distribution for renal conductance suggested that during normal waking conditions the kidney is not maximally dilated and may increase or decrease its blood flow. All distributions were highly influenced by the Sit category, which occupied 80% of the total time. The CV measures for all P/Ls had wide ranges, and the CV values associated with each P/L overlapped those for the other P/Ls. The heart rate and renal conductance associated with the various P/Ls showed the largest deviations from the grand means and therefore contributed the most to the ability to discriminate one P/L from another. Blood pressure varied little from one P/L to another. The patterns of CV variables served to distinguish particular P/Ls very effectively. The frequency distributions were separated best when they were parceled on the basis of the intensity of behavior associated with a particular P/L. These variations in intensity were the major cause of the overlaps in the frequency distributions associated with P/Ls.

Urinary free cortisol responses to five cage sizes, cage level, room change, tethering adaptation, chronic catheterization, and ketamine sedation were measured in 14 female and 14 male wild-born adult Macaca fascicularis. Urinary free cortisol, a physiological measure of psychological well-being that can be collected unobtrusively, provided a measure of the animals' general adrenocortical response to various conditions over a time course of hours. Urinary free cortisol values in response to stimulation with adrenocorticotropic hormone (ACTH) validated the measure as a reflection of blood values. Cortisol values were expressed as a ratio to creatinine, which normalized for differences in urinary output and body weight (muscle mass). Cage size (20-140% of regulation floor area) and housing level (upper vs. lower cage) had no effect on stress, as measured by cortisol excretion. Room change elicited a slight increase in cortisol excretion for the first day, but not to a level suggesting stress. Sedation, surgery, some aspects of tethering adaptation, and chronic catheterization produced urinary cortisol evidence of stress. Even so, animals varied in their responses and all showed adaptation. Males and females did not differ in normal mean values but females tended to have higher cortisol levels in response to potential stressors investigated in this study. Cortisol levels continued to decline gradually throughout the study. © 1993 Wiley-Liss, Inc.

Methods of examining and diagnosing damage to nerves commonly involved in leprosy are described. The equipment used is inexpensive, gives reliable and repeatable results and is useful in making objective assessments in terms of function in everyday living.

Raman microscopy--the analysis of scattered photons after excitation--is well established in non-biological sciences for the identification of crystals. It shows promise in biological (clinical) specimens also, as demonstrated here in studies of synovial fluid, synovium, and gouty tophus, selected for their known content of sodium urate and calcium pyrophosphate crystals.

This journal offers reviews of key neuropsychiatric topics for clinicians, with the aim of tying research findings to the needs of clinical practice. It strives to "unite theory, findings, and therapies in cohesive, comprehensive presentations." The first three issues we examined did contain important, timely, and interesting topics that included advances in neuroimaging, neuropsychiatric syndromes in the developmentally disabled, and brain damage and legal responsibility. Each issue includes a brief introduction from the editor, followed by a few pages from a guest editor who has been invited to solicit submissions from others on the featured topic. Each issue has six to nine reviews organized around the central theme. The guest editor comments on how each of the articles in the issue conforms to or amplifies the theme. Authors attempt to present information in a readable format that may serve as a springboard for further investigation. Most articles summarize the

The Journal of Neuropsychiatry and Clinical Neurosciences is of interest for what it says about one of the major directions in American psychiatry as well as for what it offers to the medical field. An increasing number of psychiatrists see their primary interest as lying in the biomedical mainstream of medicine, with a focus on diseases of the brain, or the central nervous system component of systemic diseases. This journal, the official publication of the American Neuropsychiatric Association, is an effort to address this evolving field of psychiatry. Its focus is on those psychiatric disorders in which there is an organic substrate, especially in the brain. These include strokes, delirium, alcohol-induced mental disorders, schizophrenia, and similar conditions. The journal tends to concentrate on those aspects of disease that are medically observable rather than strictly inferential. Thus, for schizophrenia, one finds articles about electroencephalographic patterns and attentional states and higher cortical

We have detected, in monkey caudate nucleus and putamen, neuronal cell bodies containing tyrosine hydroxylase-like immunoreactivity, as revealed by peroxidase-antiperoxidase immunohistochemistry. Many of these cells are distributed in an outer rim of 1–2 mm throughout the anterior-posterior extent of the neostriatum near its borders with the corona radiata; others are embedded in the adjacent white matter, especially near the ventral putamen and nucleus accumbens. Light and electron microscopy indicate that they are small (8–12 μm), bipolar cells with large nuclei. Such neostriatal neurons, containing tyrosine hydroxylase-like immunoreactivity, number in the tens of thousands.

A juvenile male Saimiri sciureus died of a tumor diagnosed as a histiocytic type of malignant lymphoma. The neoplasm presented as a thoracic mass occupying the posterior mediastinum and infiltrating the contiguous structures without involving distant nodes, the liver or spleen. The tumor tissue consisted of sheets or poorly defined clusters of fairly large cells with a vesicular nucleus and a variably abundant cytoplasm. The tumor cells were laid out in a poorly developed stroma of fine argyrophilic fibers. This is the first report of a spontaneous malignant lymphoma in a primate of this species. The speculation is put forth that the reported tumor is probably the first known example of the long sought after correlate of squirrel monkeys to Burkitt lymphoma in man.

A nonhuman primate on a periodic ethanol dosing schedule should provide a model of fetal alcohol syndrome (FAS) most relevant to the majority of pregnant women who are "social drinkers" and can exercise reasonable control over their ethanol intake. In this pilot study, four pregnant pig-tailed macaques (Macaca nemestrina) received ethanol once a week from 40 days' gestation. Doses were 2.5 gm/kg for three moderate-dose animals (MDAs) and 4.1 gm/kg for one high-dose animal (HDA). Peak blood ethanol levels reached a mean of 240-256 mg/dl for the MDAs and averaged 379 mg/dl for the HDA. Peak acetaldehyde did not vary with dose. One MDA aborted after the first dose. The other three pregnancies were compared with eight to ten control pregnancies, and the infants' development over the first six months was compared with that of the control offspring. Nutritional status of the pregnant females was normal. The fetal heart rate response to maternal restraint was absent in the HDA. Gestational duration and simian Apgar scores were normal. All three infants were abnormally large, and two were also abnormally heavy, with body weight appropriate to skeletal size. Skeletal maturation, judged by ossification and tooth eruption, was not accelerated. The high-dose infant (HDI) was scaphocephalic, with an underdeveloped cranial base and midface, and its brain was small and dysplastic; its reflex, motor, and cognitive development were retarded. One moderate-dose infant (MDI) had some brain abnormalities; it was hyperkinetic and showed developmental retardation on several behavioral measures. The other MDI was normal. We conclude that the periodic model offers an effective means of investigating FAS in M. nemestrina. Furthermore, when nutrition is maintained, intermittent intake of ethanol by the pregnant primate does not necessarily reatard fetal growth.