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International audience; The prevalence of neonatal mortality is high in the canine species and far from well-studied. In most domestic neonates, an appropriate colostrum intake is a key element of the control of neonatal mortality. The aim of this study was to evaluate the impact of passive immune transfer on puppy mortality, assessed through serum immunoglobulin G (IgG) concentration at 2 days of age. Factors impacting passive immune transfer and the value of an oral immunoglobulin supplementation to prevent it were also analyzed. A total of 149 puppies from 34 litters (12 breeds) within one breeding kennel were included. Blood samples were collected at 2 days of age and colostrum was collected from their dams 1 day after whelping to assay IgG concentration. Puppies were weighed at birth and at 2 days of age for calculation of growth rate. Mortality was recorded until 3 weeks of age. Seventy randomly assigned puppies were orally supplemented with hyper-immunized adult plasma twice within the first 8h of life. IgG concentration at 2 days of age was significantly correlated with weight gain during the first 2 days of life. The multivariable model with litter as a random effect demonstrated that neonatal mortality was not influenced by breed size, sex, supplementation, litter size, nor colostrum IgG concentration, but by puppy IgG concentration at 2 days of age. According to the ROC curve, the minimal IgG concentration at and below which puppies were at higher risk of death was determined at 230mg/dl. Puppy IgG concentration was significantly associated with growth rate, but not with breed size, sex, supplementation, litter size or colostrum IgG concentration in a multivariable model with litter as a random effect. This study demonstrates that neonatal mortality in puppies is related to the quality of passive immune transfer. The oral supplementation with hyper-immunized canine plasma neither decreased risk of mortality, nor improved serum IgG concentration at 2 days of age in puppies. Attention must thus be paid to early colostrum intake to control the neonatal mortality in puppies.

Obtaining FeNO levels routinely in clinical practice adds to the burden of asthma care and resource utilisation. On the other hand, routine use of FeNO levels to guide therapy may improve asthma control and reduce exacerbations and hospitalisations related to asthma. The objective of this Cochrane review was to evaluate the efficacy of tailoring asthma therapy based on FeNO levels, in comparison with not using FeNO (i.e. management based on clinical symptoms and/or asthma guidelines), for asthma related outcomes in children. In our original review, we found that the use of FeNO strategy did not confer any benefit. Methods: The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Collaborative Review Group Specialised Trials Register, MEDLINE, EMBASE and CINAHL databases were searched by the Cochrane Airways Group. The latest search was performed in January 2016. All RCT9s comparing adjustment of asthma medications based on FeNO levels with clinical symptoms were eligible to be included. Results of searches were reviewed against pre-determined criteria for inclusion. Results: Nine studies were included. Three studies reported significant reduction in asthma exacerbations when treatment was based on FeNO levels in comparison to clinical symptoms and 6 did not. Combining all studies, 1426 participants were randomised and 1370 completed the trial. The meta-analyses using GIV showed that use of FeNO for guiding treatment significantly reduced asthma exacerbations OR 0.63 (95% CI 0.49 to 0.83). Conclusion: Tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreases the frequency of asthma exacerbations in children.

Noninvasive measures of fetal and neonatal body composition may provide early identification of children at risk for obesity. Air displacement plethysmography provides a safe, precise measure of adiposity and has recently been validated in infants. Therefore, we explored relationships between term newborn percent body fat (%BF) measured by air displacement plethysmography to 2-dimensional ultrasound (2-D US) biometric measures of fetal growth and maternal and umbilical cord endocrine activity. A total of 47 mother/infant pairs were studied. Fetal biometrics by 2-D US and maternal blood samples were collected during late gestation (35 wk postmenstrual age); infants were measured within 72 h of birth. Fetal biometrics included biparietal diameter, femur length, head circumference, abdominal circumference (AC), and estimated fetal weight (EFW). Serum insulin, insulin-like growth factor (IGF) 1, IGF binding protein-3, and leptin concentrations were measured in umbilical cord and maternal serum. The mean %BF determined by plethysmography was 10.9 +/- 4.8%. EFW and fetal AC had the largest correlations with newborn %BF (R(2) = 0.14 and 0.10, respectively; P < 0.05); however, stepwise linear regression modeling did not identify any fetal biometric parameters as a significant predictor of newborn %BF. Newborn mid-thigh circumference (MTC; cm) and ponderal index (PI; weight, kg/length, cm(3)) explained 21.8 and 14.4% of the variability in %BF, respectively, and gave the best stepwise linear regression model (%BF = 0.446 MTC + 0.347 PI -29.692; P < 0.001). We conclude that fetal growth biometrics determined by 2-D US do not provide a reliable assessment of %BF in term infants.

Community paediatrics strives to integrate the biology of health into the social and psychological worlds within which children grow and develop. Consumer demand for limited community paediatric clinical services is increasing and medico-legal pressures escalate professional and personal concern. Meanwhile, the profession, through training and professional support, has struggled to keep up. Research into community paediatrics and its integration into policy and clinical practice remains limited, raising the perception that it is a 'soft' science. Our viewpoint is that necessary progress in this field requires leadership, apprenticeship and research. We argue that to build firm foundations for the future requires structures to enable clinical specialisation and continuing professional development in this area.

Objective: To compare the outcomes of two models for the management of children admitted to hospital with suspected child abuse: routine early case conferencing versus standard evaluation. Methods: Between March 2001 and February 2002 professionals from the Royal Children's Hospital, Melbourne, Victoria Police and Child Protection services collaborated on a randomized controlled study involving children admitted to hospital with suspected child abuse. The intervention group (n = 13) received a case conference within 24 h of the child's admission to hospital. The control group (n = 12) were managed according to standard procedures whereby each organization conducted their own evaluation (and a case conference might or might not have been held). Patients were followed for 3 months with data collected from all three professional groups. Results: The process of evaluation, the eventual diagnosis of child abuse and the confidence with which professionals made this diagnosis was not significantly different between the groups. Case conferences were judged to be useful regardless of their timing. Mean length of stay in the intervention group was significantly less than in controls (42.4 h vs 99.7 h, P = 0.01). Conclusion: Early case conferences appear to shorten the period of time children spend in hospital when child abuse is suspected. This has significant implications for reducing costs for all organizations involved in the evaluation of suspected child abuse.

SUMMARYThis study describes the first investigations of the physiological signals involved in activating the newly discovered cyclostome renin–angiotensin system (RAS) and its role in the river lamprey Lampetra fluviatilis. Experimental manipulation showed that volume depletion (removal of 40% blood volume) rapidly activated the RAS of lampreys acclimated to water at 576 mOsm kg–1 (21 p.p.t.), significantly increasing plasma angiotensin concentrations after 30 min and 60 min. In agreement with these results, a rapid change in environmental salinity (758 mOsm kg–1 to freshwater (FW) and FW to 605 mOsm kg–1), resulted in a rapid decrease and increase in plasma [angiotensin], respectively. Intraperitoneal(i.p.) injection of FW-acclimated river lampreys with 1% body mass by volume of nominally isosmotic saline (120 mmol l–1 NaCl; 233 mOsm kg–1) resulted in a significant decrease in the plasma angiotensin concentration within 15 min. In contrast, i.p. injection of hyperosmotic saline (4 mol l–1 NaCl) at 1% body mass by volume, which significantly increased plasma osmolality, had no significant effect on plasma [angiotensin], suggesting that volume/pressure receptors and osmoreceptors interact in regulating the lamprey RAS. These results indicate an important role for volume/pressor receptors, as in teleosts, but with an additional osmoreceptor mechanism, such that circulatory [angiotensin] is determined by interaction of volume/pressure and osmoreceptors and their relative sensitivities. The volume/pressure sensitivity is in keeping with the recent evidence of a vasoconstrictor action of homologous lamprey angiotensin and provides evidence that the fundamental role of the RAS in maintaining volume and pressure is an ancient function conserved over 500 million years of vertebrate evolution.

To present a case report of anesthesia for pericardial window surgery for acute cardiac tamponade in a patient with an anterior mediastinal mass in late pregnancy.A 34-yr-old gravida 2, para 1 patient presented at 29 weeks gestation with dyspnea, orthopnea, chest pain, and cough. Investigations showed an anterior mediastinal mass due to Hodgkin's disease. A course of vinblastine at 31 weeks gestation resulted in symptomatic improvement but at 34 weeks gestation she developed an acute cardiac tamponade for which pericardial window drainage was required. Additional help and equipment were assembled in case of cardiopulmonary deterioration. Intra-arterial pressure and continuous fetal monitoring were established and iv access was secured in both arms and the left foot. After awake fibreoptic intubation, spontaneous ventilation was maintained. Anesthesia consisted of local anesthetic infiltration of the anterior chest wall, supplemented with fentanyl, midazolam, and ketamine. The patient remained stable, was extubated fully awake, and then monitored in an intensive care area.This patient presented with acute cardiac tamponade and an anterior mediastinal mass in late pregnancy, an unusual combination of challenges that requires a careful approach to anesthetic management.

Most mammals use changing annual day-length cycles to regulate pineal melatonin secretion and thereby drive many physiological rhythms including reproduction, metabolism, immune function, and pelage. Prolonged exposure to short winter day lengths results in refractoriness, a spontaneous reversion to long-day physiological status. Despite its critical role in the timing of seasonal rhythms, refractoriness remains poorly understood. The aim of this study was therefore to describe cellular and molecular mechanisms driving the seasonal secretion of a key hormone, prolactin, in refractory Syrian hamsters. We used recently developed single cell hybridization and reporter assays to show that this process is initiated by timed reactivation of endocrine signaling from the pars tuberalis (PT) region of the pituitary gland, a well-defined melatonin target site, causing renewed activation of prolactin gene expression. This timed signaling is independent of per1 clock gene expression in the suprachiasmatic nuclei and PT and of melatonin secretion, which continue to track day length. Within the PT, there is also a continued short day-like profile of ICER expression, suggesting that the change in hormone secretion is independent of cAMP signaling. Our data thus identify the PT as a key anatomical structure involved in endogenous seasonal timing mechanisms, which breaks from prevailing day length-induced gene expression.

In seasonal mammals, photoperiod change is associated with a suite of alterations in physiology. It has recently been proposed that the immune response is one of the systems regulated by changes in photoperiod, although this hypothesis has not been rigorously challenged by assays of functional immune responses. The aim of this study was to test the hypothesis that photoperiod modulates immune responsiveness in Syrian ( Mesocricetus auratus) and Siberian ( Phodopus sungorus) hamsters. Consistent with previously reported data, short-day-housed (SD) animals exhibited a significant increase in lymph node cell (LNC) numbers and increased cellular proliferation in response to the polyclonal mitogen concanavalin Acompared to long-day-housed (LD) animals. In contrast, LNC numbers from intact or gonadectomized SD animals that had been sensitized with the antigen dinitrofluorobenzene (DNFB) exhibited a reduced ex vivo proliferative response and reduced production of interleukin-6 (IL-6) compared to LD animals. In vivo studies of the contact hypersensitivity response of animals that had previously been sensitized, and subsequently challenged, with DNFB were similar in SD and LD animals, as was the proliferative activity of LNC recovered from these animals. There were also no photoperiodic differences in the antidinitrophenyl antibody response of animals sensitized with DNFB, or the anti–sheep red blood cell (srbc) response of animals immunized with srbc. Furthermore, no differences could be detected in the activity of natural killer cells from spleens of LD and SD Siberian hamsters, or in lipopolysaccharide-induced IL-6 production by LD and SD Syrian hamsters in vivo. Thus, although photoperiod is able to influence factors regulating the gross number and non-antigen-specific proliferation of lymphocytes in seasonally breeding mammals, day length does not directly influence activation of an effective immune response. The authors conclude, therefore, that expression of the immune response is not directly modified or compromised by photoperiod in these seasonally breeding hamster species.

Seasonal Siberian hamsters lose fat reserves, decrease body weight and leptin concentrations, and suppress reproduction on short-day photoperiod (SD). Chronic leptin infusion at physiological doses caused body weight and fat loss in SD animals but was ineffective in long-day (LD) hamsters. Using ovariectomized estrogen-treated females, we tested the hypothesis that responsiveness to leptin is regulated by photoperiod. On SD, hypothalamic neuropeptide Y, agouti-related peptide, and cocaine- and amphetamine-regulated transcript gene expression in the arcuate nucleus did not exhibit significant changes, and despite SD-induced fat loss, the catabolic peptide proopiomelanocortin was down-regulated. Food restriction of LD-housed animals caused significant reduction of fat reserves and serum leptin concentrations to SD levels, suppressed serum gonadotropins, and induced increased anabolic (neuropeptide Y, agouti-related peptide) and decreased catabolic (proopiomelanocortin, cocaine- and amphetamine-regulated transcript) gene expression in the arcuate nucleus. Leptin infusion in food-restricted animals had no effect on fat reserves or gonadotropins and did not modulate neuropeptide gene expression. Also, leptin treatment did not blunt the refeeding responses or weight and fat gain in LD-housed food-restricted animals. In conclusion, our results strongly suggest that hypothalamic responses to leptin are regulated primarily by photoperiod, rather than seasonal changes in fat reserves, sex steroids, or leptin concentrations.

Angiotensin converting enzyme (ACE) or kininase II is a dipeptidyl-carboxypeptidase that converts angiotensin I (Ang I) to angiotensin II (Ang II) in the renin–angiotensin system (RAS) and inactivates bradykinin in the kallikrein–kinin system (KKS). Angiotensin converting enzyme-like activity (ACELA) has been demonstrated in a wide range of vertebrates, and only in lampreys is a lack of ACELA still suggested. Though long controversial, a lamprey RAS has recently been identified by isolation and sequencing of lamprey Ang I and the measurement of circulating plasma angiotensins. We therefore re-investigated the presence of ACE in tissues from the river lamprey or lampern, Lampetra fluviatilis , using a highly sensitive fluorimetric assay. Significant detection of ACELA was found in a wide range of lamprey tissues (brain, gill, gonad, gut, heart, liver, skeletal muscle, skin, kidney, and plasma). The mammalian ACE inhibitor captopril at 10 −5 M was an effective, but variable inhibitor of the ACELA found in most lamprey tissues. The brain contained the highest ACELA, while kidney (including urinary duct), skin, gonads, and heart only contained very low ACELA. In most tissues, ACELA was similar in lampreys acclimated to freshwater (FW) and seawater (SW). However, gut ACELA was significantly higher in lampreys acclimated to SW than in FW-acclimated lampreys. Liver, skin, and gonad ACELA was significantly lower in lampreys acclimated to SW than in FW lampreys. Male and female lampreys acclimated to FW showed similar ACELA in all tissues except the kidney (including the urinary duct), where ACELA was significantly higher in male than in female lampreys. These results indicate that ACELA, a component of the RAS and KKS, is present in tissues from one of the earliest evolved groups of vertebrates.

Objective: To validate use of chip-based immunoaffinity capillary electrophoresis on dried blood spot samples (DBSS) to measure obesity-related hormones. Methods: Chip-based immunoaffinity capillary electrophoresis was used to measure adiponectin, leptin and insulin in capillary serum and DBSS in pregnant women and infant heelstick at birth and six weeks. Concordance of measurements was determined with Pearson's correlation and Bland-Altman plots. Results: We report high concordance between results obtained from serum and DBSS. Conclusions: Ease of sample collection and storage makes DBSS an optimal method for use in studies involving neonates and young children, as well as studies conducted in areas where freezer storage is not available. Am. J. Hum. Biol., 2011. © 2011 Wiley-Liss, Inc.

Background: Anxiety disorders increase risk of future cardiovascular disease (CVD) and mortality, even after controlling for confounds including smoking, lifestyle, and socioeconomic status, and irrespective of a history of medical disorders. While impaired vagal function, indicated by reductions in heart rate variability (HRV), may be one mechanism linking anxiety disorders to CVD, prior studies have reported inconsistent findings highlighting the need for meta-analysis. Methods: Studies comparing resting-state HRV recordings in patients with an anxiety disorder as a primary diagnosis and healthy controls were considered for meta-analysis. Results: Meta-analyses were based on 36 articles, including 2086 patients with an anxiety disorder and 2294 controls. Overall, anxiety disorders were characterized by lower HRV [high frequency (HF): Hedges’ g = -0.29. 95% CI: -0.41 to -0.17, p < 0.001; time domain: Hedges’ g = -0.45, 95% CI: -0.57 to -0.33, p < 0.001] than controls. Panic disorder (n = 447), post-traumatic stress disorder (n = 192), generalized anxiety disorder (n = 68), and social anxiety disorder (n = 90), but not obsessive–compulsive disorder (n = 40), displayed reductions in HF HRV relative to controls (all ps < 0.001). Conclusion: Anxiety disorders are associated with reduced HRV, findings associated with a small-to-moderate effect size. Findings have important implications for future physical health and well-being of patients, highlighting a need for comprehensive cardiovascular risk reduction.

BACKGROUND This study was conducted to document the rate, duration, and type of objective response to active specific immunotherapy with a polyvalent melanoma cell vaccine (PMCV) for patients with in-transit melanoma metastases and to identify any acute or chronic toxic effects of PMCV treatment. METHODS An analysis was conducted of all in-transit melanoma patients seen at the John Wayne Cancer Institute in Santa Monica, California, during the period 1985–1997 who were enrolled in prospective PMCV protocols in the absence of other therapies with possible antitumor activity (n = 54). Clinical response to PMCV was assessed by standard criteria. Survival curves were estimated by the Kaplan–Meier method. Toxicity was graded according to the Eastern Cooperative Oncology Group standard. RESULTS PMCV produced a 17% (9 of 54 patients) objective response rate with a 13% rate (7 of 54 patients) of complete remission (CR). The median duration of CR was >22 months. Complete response lasting more than 1 year was observed in 4 patients (7.2%); 1 patient remained in remission over 9 years. Median survival was >53 months (i.e., not reached) for responders, 42 months for nonresponders, and 53 months overall. Salvage interventions allowed reinduction with PMCV in 23 of 25 patients, who subsequently remained clinically free of disease for a median of 14 months. Overall toxicity was mild, easily tolerable, and did not significantly change the quality of life. There were no toxic deaths. CONCLUSIONS PMCV can cause objective complete regression of measurable in-transit metastatic melanoma with minimal toxicity, and may prolong patients' median survival. Cancer 1999;85:2160–9. © 1999 American Cancer Society.

Cannulated brown trout, Salmo trutta, were exposed for 36 h to synthetic water with a low calcium content of pH 5 and similar synthetic water dosed with aluminium to raise the filterable A1 from 5 to 290 μg 1−1 over the 36-h period. There were no significant disturbances of plasma concentrations of glucose, cortisol or catecholamine (adrenaline and noradrenaline) in fish held in water of pH 5. The addition of aluminium to this acidic synthetic water resulted in a generalized endocrine stress response with a four-fold increase in plasma glucose concentration after 18 h and a significant increase in plasma cortisol concentration from 24 h onwards when filterable A1 exceeded 200 μg 1−1. Plasma catecholamine concentration indicated an adrenergic stress response in aluminium-exposed brown trout. A transient doubling in noradrenaline after 6 h in A1 was followed by a larger increase in both plasma adrenaline and noradrenaline concentrations in fish surviving the 36-h exposure to A1.

Specific binding of 125 1-[Asn 1 , Val 5 ]-angiotensin II to isolated glomeruli of freshwater-adapted and seawater-adapted rainbow trout, Oncorhynchus mykiss , reached a plateau after 20 min at 10° and was displaced by nonradiolabelled [Asn 1 , Val 5 ]-angiotensin II. Seawater adaptation increased the rate of dissociation of 125 1-[Asn 1 , Val 5 ]-angiotensin II from putative receptors. Competitive binding experiments revealed a single population of high-affinity receptors with a K D 0.3-0.4 × 10 -10 M , which was unchanged by seawater adaptation. Seawater adaptation did, however, reduce the density ( B max ) of the binding sites, which may reflect down-regulation by the higher plasma concentration of angiotensin II in seawater-adapted trout.

Isolated glomeruli from the rainbow trout Oncorhynchus mykiss have been examined for the presence of receptors specific for angiotensin II (AII). Specific binding of 125 I-Asp 1 Val 5 -AII was saturable, plateaued after 20 min, and increased with glomerular protein. Saralasin (Sar 1 Val 5 Ala 8 -AII), a nonselective peptide AII receptor antagonist of AII binding to mammalian tissues, was a poor inhibitor of 125 I-Asn 1 Val 5 -AII binding to trout glomeruli. However, the nonpeptide antagonist, Losartan (= DuP 753), which is specific for AII subtype AT 1 receptors in mammalian tissues, was an effective inhibitor of binding of both 125 I-Asp 1 Val 5 -AII and 125 I-Asn 1 Val 5 -AII to trout glomeruli. The IC 50 for Losartan inhibition of binding of Asp 1 Val 5 -AII was 1.25 ± 0.07 × 10-8 M while that for inhibition of binding of Asn 1 Val 5 -AII was 2.73 ± 0.45 × 10-8 M . Statistical analysis of logistic curve fits confirmed the easier displacement of Asp 1 Val 5 -AII than of Asn 1 Val 5 -AII. PD 123177, a nonpeptide antagonist specific for AII subtype AT 2 receptors in mammalian systems, was ineffective as an antagonist of All binding to trout glomeruli. These results are consistent with the presence of a specific AII receptor in the trout glomerulus and imply a novel receptor configuration.

Prostaglandins in kidney, gills, and urinary bladder of freshwater-adapted and seawater-adapted rainbow trout, Oncorhynchus mykiss (= Salmo gairdneri), and European eel, Anguilla anguilla, were determined by solid-phase extraction of tissue homogenates and high-pressure liquid chromatography. Prostaglandins E2, E1, F1 alpha, F2 alpha, and D2 and the more stable metabolite of prostacyclin, 6-keto F1 alpha, occurred in these osmoregulatory tissues. In gill filaments and kidneys of both eel and trout, prostaglandins D2 and 6-keto F1 alpha were major prostaglandins. Concentrations of these prostaglandins were significantly lower in the eel after seawater adaptation, but not in the trout. The urinary bladder of the trout contained the highest levels of prostaglandins; bladders of seawater-adapted trout contained prostaglandin D2 at 6.7 ng/mg wet tissue, the highest level of any prostaglandin determined in the present studies. Prostaglandin D2 was not detected in bladders of freshwater-adapted trout.

Isolated glomeruli of the rainbow trout have been exposed in vitro to125I-angiotensin II (0.88 × 10−9 M) and binding sites located by light-microscopic autoradiography. These studies provide evidence of specific binding of angiotensin II by glomeruli. Binding was significantly inhibited by excess (10−5 M) unlabelled angiotensin II, but a high degree of non-specific binding also occurred. The mammalian competitive antagonist, saralasin (3 × 10−7 M) did not influence125I-angiotensin II binding to fish glomeruli. Intense binding of125I-angiotensin II was noted at the vascular pole of some glomeruli.

The importance of thyroid hormones in regulating early developmental processes of many amphibian and fish species is well known, but the impacts of exposure to disrupters of thyroid homeostasis during the embryo-larval-juvenile transitions are unclear. To investigate these impacts, fathead minnows, Pimephales promelas, were exposed to a model thyroid axis disrupter, methimazole, an inhibitor of thyroid hormone synthesis, at control (0), 32, 100, and 320 mug/l, starting at

Perchlorate is a known environmental contaminant, largely due to widespread military use as a propellant. Perchlorate acts pharmacologically as a competitive inhibitor of thyroidal iodide uptake in mammals, but the impacts of perchlorate contamination in aquatic ecosystems and, in particular, the effects on fish are unclear. Our studies aimed to investigate the effects of concentrations of ammonium perchlorate that can occur in the environment (1, 10, and 100 mg/L) on the development of fathead minnows, Pimephales promelas. For these studies, exposures started with embryos of < 24-hr postfertilization and were terminated after 28 days. Serial sectioning of thyroid follicles showed thyroid hyperplasia with increased follicular epithelial cell height and reduced colloid in all groups of fish that had been exposed to perchlorate for 28 days, compared with control fish. Whole-body thyroxine (T4) content (a measure of total circulating T4) in fish exposed to 100 mg/L perchlorate was elevated compared with the T4 content of control fish, but 3,5,3′-triiodothyronine (T3) content was not significantly affected in any exposure group. Despite the apparent regulation of T3, after 28 days of exposure to ammonium perchlorate, fish exposed to the two higher levels (10 and 100 mg/L) were developmentally retarded, with a lack of scales and poor pigmentation, and significantly lower wet weight and standard length than were control fish. Our study indicates that environmental levels of ammonium perchlorate affect thyroid function in fish and that in the early life stages these effects may be associated with developmental retardation.

The fathead minnow is widely used in ecotoxicological studies and such investigations have begun to focus on potential disruption of the thyroid axis. However, normal levels of thyroxine (T 4 ) and 3,5,3′-triiodothyronine (T 3 ) and their developmental patterns are unknown. To provide these baseline data, radioimmunoassays were developed and validated for analysis of T 4 and T 3 after extraction from plasma or whole fish. Female fish showed consistently higher plasma levels of T 4 than male fish. Analysis of thyroid hormones during development showed a significant rise in both T 4 and T 3 during the pre-hatch period, indicating embryonic production of both thyroid hormones. After hatching, whole-body content of both T 4 and T 3 significantly increased in early development, peaking at 16 days post-hatch (dph) and 9 dph, respectively, when T 4 reached 32.88 ± 3.30 ng g −1 body weight and T 3 reached 24.17 ± 3.15 ng g −1 body weight. Thyroid hormones subsequently declined to a low plateau in later development with approximately 5 ng g −1 body weight T 4 and 2 ng g −1 body weight T 3 . These data suggest a prominent role for thyroid hormones in early developmental processes when we predict that the ecotoxicological effects of thyroid disrupters will be most significant.

Using a highly sensitive fluorimetric assay, significant levels of angiotensin I -converting enzyme-like activity (ACELA) were detected in a range of tissues (branchial heart, gill, kidney with associated vasculature and archinephric duct, liver, whole brain and gut) from the Atlantic hagfish ( Myxine glutinosa ). The highest ACELA occurred in heart and gill (1.8 and 1.5 nmol His–Leu min −1 mg protein −1 , respectively). The mammalian angiotensin I-converting enzyme (ACE) inhibitor, captopril, at 10 −5 M was a potent inhibitor of the ACELA found in all hagfish tissues. Radioimmunoassay showed that immunoreactive angiotensins (251.8±11.8 pM) were detectable in hagfish plasma. The validity of the assay for measurement of hagfish angiotensins was indicated by the parallelism of the angiotensin II standard curve against serially diluted hagfish plasma. Measurement of immunoreactive plasma angiotensins and detection of significant levels of ACELA in a wide range of tissues gives indirect evidence for the presence of a renin–angiotensin system in hagfishes, the earliest evolved group of craniates.

In many mammals, changes in daylength (photoperiod) regulate multiple aspects of physiology, including the synthesis and secretion of the anterior pituitary hormone prolactin. Here, we tested the hypothesis that individual lactotroph cells exhibit a heterogeneous response to changes in photoperiod, by exploiting a recently developed assay for prolactin gene expression in single pars distalis (PD) cells. Male Syrian hamsters were exposed to either long (LD; 16 h light: 8 h dark) or short (SD; 8 h light: 16 h dark) photoperiods for 12 weeks. Response of the lactotrophic axis to photoperiod was confirmed by the significantly (P0.01) lower plasma prolactin concentrations in SD than LD hamsters. Analysis of freshly dispersed PD cells by in situ hybridisation demonstrated that photoperiod has no effect (P0.05) on the proportion of PD cells (approximately 25%) that expressed prolactin mRNA. Heterogeneity of prolactin mRNA expression was observed in both LD and SD. A similar proportion of cells expressed low levels of prolactin mRNA in both photoperiods, suggesting that they may be unresponsive to photoperiod change. In contrast, the remaining PD cells that expressed prolactin mRNA exhibited markedly increased gene expression in LD, consistent with the selective recruitment of a lactotroph subpopulation to a more transcriptionally active state in this photoperiod.

Objective To determine whether adjuvant postoperative active specific immunotherapy with a therapeutic polyvalent vaccine (PV) called Canvaxin can prolong survival following complete resection of melanoma metastatic to regional nodes (American Joint Committee on Cancer [AJCC] stage III melanoma). Background Data Despite complete lymphadenectomy, 5-year overall survival (OS) for patients with melanoma metastatic to regional lymph nodes is only 20% to 50%, depending on the number of tumor-involved nodes. In 1984, the authors began phase II trials of Canvaxin PV as postsurgical adjuvant therapy for AJCC stage III melanoma. Methods Patients who received PV between 1984 and 1998 were compared with patients who did not receive PV postsurgical therapy between 1971 and 1998. The seven covariates recently defined by the AJCC Melanoma Staging Committee (number of metastatic nodes, palpable status, ulceration, age, primary site, pT stage, and gender) were included by Cox regression in a multivariate model of OS. A computerized program matched PV and non-PV patients by these covariates. Results Of 2,602 patients who underwent complete lymphadenectomy for AJCC stage III melanoma with regional nodal metastases and were followed up by the same team of oncologists between 1971 and 1998, 935 received PV and 1,667 did not. Median OS and 5-year OS were significantly higher in PV than non-PV patients (56.4 vs. 31.9 months and 49% vs. 37%, respectively; P =.0001). When the non-PV patients were matched by the four most significant covariates, 447 matched pairs were formed between patients seen before or after January 1, 1985, and the OS was not different between the two time periods (P =.789). However, when the PV patients were matched with non-PV patients by six covariates forming 739 pairs, the PV patients survived longer (P =.0001). Detailed analysis of the 1,505 patients who were seen or who began vaccine therapy within 4 months after lymphadenectomy, and who had more complete data on the seven prognostic covariates showed that median OS and 5-year OS were higher in 445 PV patients than in 1,060 non-PV patients: 70.4 versus 31 months and 52% versus 37%, respectively (P =.0001). Multivariate Cox regression analysis identified six significant prognostic factors: number of metastatic nodes, size of metastatic nodes, pT stage, ulceration, age, and PV therapy. PV therapy reduced the relative risk of death to 0.64 (95% confidence interval, 0.55-0.76) (P =.0001); sex and site of primary were of borderline significance. Conclusions This large single-institution study independently confirmed the significance of prognostic covariates in the new AJCC staging system. By using modern statistical methods that controlled for all known prognostic factors, it also demonstrated PV's ability to significantly enhance OS. A multicenter phase III randomized trial is underway to validate the efficacy of PV as a postsurgical adjuvant.

Objectives.To determine the neurodevelopmental outcome of infants treated with head cooling with systemic hypothermia after hypoxic-ischemic encephalopathy.Study Group.Infants ≥37 weeks' gestation, who had an umbilical artery pH ≤7.09 or Apgar score ≤6 at 5 minutes, plus clinical encephalopathy. Infants with major congenital abnormalities were excluded.Trial Design.Infants were allocated to either no cooling (rectal temperature = 37.0 ± 0.2°C, n= 15), or, sequentially, to head cooling accompanied by different levels of systemic hypothermia, including minimal cooling, rectal temperature 36.5°C to 36°C (n = 6), and mild cooling, to either 35.9°C to 35.5°C (n = 6), 35 ± 0.5°C (n = 6) or 34.5 ± 0.5°C (n = 7). Head cooling was accomplished by circulating cooled water through a coil of tubing wrapped around the head for up to 72 hours. Survivors were followed up with regular neurologic examination by a neonatologist until 18 months of age, then with blinded developmental testing using the revised Bayley Scales.Results.A total of 40 term infants were enrolled from 2 to 5 hours after birth. The control and the cooled groups were not significantly different for gestation, birth weight, Apgar score, and initial pH. There were 6 early neonatal deaths (3 normothermic and 3 cooled), and 1 death in infancy associated with severe spastic cerebral palsy in a normothermic infant. Six normothermic, 1 minimally cooled, and 4 mildly cooled infants had early stage 1 encephalopathy; all but 1 had a good outcome. Among infants with early stage 2 or 3 encephalopathy, an adverse outcome was found in 4 of 9 normothermic infants (44%) and 4 of 5 minimally cooled infants (80%), whereas in the combined mildly cooled groups, an adverse outcome was found in 4 of 15 infants (26%, odds ratio 0.46 [0.08, 2.56] vs normothermia).Conclusions.The present study supports the safety of hypothermia, with no evidence of late adverse effects in any infant. Among infants with moderate to severe encephalopathy at enrollment, there was a tendency toward better outcome. These results emphasize the relatively wide range of outcomes using purely clinical criteria for enrollment. Therapeutic hypothermia should not be used outside of stringent, multicenter trials.

The tau mutation of Syrian hamsters induces a robust reduction in the period of circadian activity rhythms, from 24 h (wild-type; tau++) to 22 h (heterozygote; tauS+) and 20 h (homozygous mutant, tauSS). Here, we examine the effect of this mutation on circadian rhythms of LH, melatonin, and cortisol in ovariectomized hamsters. Free running circadian rhythms were observed in all three hormones. In each genotype, endocrine rhythms were synchronized with concurrently assessed activity rhythms, suggesting a shared period around 20 h in tauSS, 22 h in tausS+, and 24 h in tau++. Phasing with respect to the activity rhythm was generally similar in tau++ and mutant genotypes. However, melatonin concentrations rose significantly earlier in tauSS than in tau++ animals. Explanted pineals from both genotypes exhibited a similar time course of response to norepinephrine administration, suggesting that the phase advance of melatonin production observed in tauSS in vivo is not a direct effect of the tau mutation within the pinealocyte. The demonstration of reduced period endocrine rhythms in the mutant genotypes extends previous behavioral studies and, together with recent work on rhythmicity in the isolated retina, suggests an ubiquitous influence of the tau mutation on the processes of circadian rhythm generation in this species.

Generalized endocrine responses to stress, common to a wide variety of stressors, involve activation of (i) the hypothalamo-pituitary-interrenal axis (HPI), resulting in release of corticosteroids, and (ii) activation of the adrenergic system resulting in release of catecholamines (Mazeaud et al, 1977; Donaldson, 1981; Mazeaud and Mazeaud, 1981). The primary release of hormones will inevitably lead to secondary physiological and biochemical events. Some of these, such as alterations in energy metabolism, may be immediately beneficial to the fish, and as such are in line with the general adaptation syndrome described by Selye (1950), but it is equally clear that this is not always the case, and maladaptive effects such as disturbed ionoregulation, immunosuppression, and in the longer term, depressed growth and reproductive function, have more recently become apparent.

Infantile fibrosarcoma (IF) has traditionally been treated with surgery, which may have considerable morbidity. Chemotherapy has been suggested in order to reduce the need for extensive surgery. Nine children with histologically confirmed IF who received chemotherapy are described. Six children were treated with chemotherapy initially, two following conservative surgery, and one following recurrence after surgery. All received vincristine (V) and actinomycin D (A), and six received additional drugs including ifosfamide (I), cyclophosphamide (C), adriamycin (Ad), etoposide (E), and cis-platinum (CDDP). Objective responses were achieved in eight: three responded completely (CR), two responded partially (PR), which allowed conservative surgery, one had stable disease, one had an initial PR, but subsequently had tumour recurrence 1 month after cessation of treatment, necessitating further surgery and chemotherapy, and one had an initial PR but died following local and regional metastases. One child had no response to chemotherapy but is alive with stable residual disease. Thus, five of nine children achieved a CR—three with chemotherapy alone. With the inclusion of chemotherapy as part of their treatment, five children, for whom curative surgery may have resulted in amputation, remain alive with limbs intact. Chemotherapy including V and A should be given to infants with fibrosarcoma in whom curative surgery would be mutilating. © 1993 Wiley-Liss, Inc.

An evaluation of general immunologic reactivity was performed in 116 patients with malignant melanoma and in 40 patients with skeletal and soft tissue sarcoma who received adjunctive immunotherapy. An excellent correlation was observed between delayed cutaneous hypersensitivity to DNCB and the clinical extent of malignancy. Eighty percent of patients with Stage I disease were DNCB positive, whereas only 37% of Stage III patients were reactive on initial testing. A method for sequential evaluation of DNCB response was established, and revealed that variations in immune reactivity occurred that also correlated with the patient's clinical course. Persistence of nonreactivity to DNCB or conversion from a reactive to an anergic status was associated with postoperative recurrence in more than 80% of the patients. Conversely, conversion from an anergic to a reactive status was observed if tumor control was achieved. These results indicate that the defect in systemic immunity is closely associated with tumor cell burden, and that sequential evaluation of DNCB reactivity is a clinically useful monitor of disease progression.

1. Monoamine oxidase (MAO) activity was determined fluorometrically in brain, intestine, kidney and liver tissues of the rainbow trout, Salmo gairdneri . 2. MAO activity was inhibited by various drugs in a concentration-related manner, with single sigmoid inhibition curves, the inhibitors of type A MAO, harmaline and clorgyline being more effective than deprenyl, an inhibitor of type B MAO. 3. Intestine exhibited greatest MAO activity followed by liver and brain with kidney showing least activity. The Michaelis constants ( K m ) also showed variability between tissues. 4. Inhibition of MAO by harmaline was non-competitive and dependent on the concentration of substrate present.

Between April 1971 and January 1985, the University of California at Los Angeles (UCLA) Division of Surgical Oncology has seen 649 patients diagnosed with thin primary melanomas, as defined by a Clark level less than IV and Breslow depth less than 0.76 mm. Thirty-six patients, whose primary diagnosis was confirmed by UCLA pathologists, presented with or subsequently developed melanoma metastases. Twenty-four (67%) had Clark level II lesions, whereas the remaining 12 (33%) had Clark level III lesions. Metastases were noted more frequently in men than in women, with a man-to-woman ratio of 3 to 2. The site of the primary lesion in this group was most frequently on the trunk (16 of 36 cases, 44%), followed by the head and neck (9 of 36 cases, 25%) and arm and shoulder (7 of 36 cases, 19%). Metastasizing thin lesions were least likely to occur on the leg and hip (4 of 36 cases, 11%). Twenty of these lesions were recently reexamined, and 17 of 20 cases (85%) demonstrated evidence of regression. Twenty-eight patients (78%) had their first metastases to regional lymph nodes. Fifteen remained alive with no evidence of disease at a median follow-up of 99 months. Twenty patients died from systemic metastases, and one patient was alive with brain metastasis at the time of this article. Although infrequent, metastases from thin melanomas do occur, suggesting the need for careful long-term follow-up and immediate investigation of adenopathy even in low-risk patients.

A boy with agammaglobulinaemia diagnosed and treated from the age of 3 years 2 months developed encephalitis at 4 years 3 months. The illness showed a remitting but deteriorating course until death aged 6 years 5 months. Echo virus type 27 was isolated from the cerebrospinal fluid during the terminal illness. The virus was not isolated from five earlier cerebrospinal fluid samples nor was virus detected in a temporal lobe biopsy.

This study examined the reported association between cerebral palsy and cryptorchidism. A comparison was made among 25 boys with cerebral palsy under the age of 2 years and 6 months, 25 boys with cerebral palsy aged between 5 and 10 years, and age-matched controls. The testes remained in the same position with age in boys with cerebral palsy, whereas in normal children the testes were slightly lower initially (P less than .005) and became lower still with growth (P less than .001). This result, taken in conjunction with previous studies, casts doubts on the theories of early damage to the hypothalamic-pituitary-gonadal axis as the cause of maldescent in cerebral palsy. It is postulated that any apparent increase in cryptorchidism in older patients with cerebral palsy may be caused by spasticity of the cremaster muscle leading to pathologic retraction of the testis out of the scrotum.

The effect of angiotensin infusion on the glomerular ultrastructure of freshwater- and seawater-adapted rainbow trout. Salmo gairdneri, has been examined by scanning and transmission electron microscopy. Adaptation of trout to seawater resulted in epithelial podocyte flattening, primary process broadening and apparent loss of foot processes in almost all glomeruli, features which were uncommon in freshwater-adapted trout. Similar changes were induced by infusion of freshwater-adapted animals with angiotensin, suggesting that the renin-angiotensin system plays a role in the modification of glomerular epithelial ultrastructure. Adaptation of trout to seawater also reduced glomerular diameter, but infusion of freshwater-adapted animals with angiotensin did not mirror this effect. Infusion of angiotensin into seawater-adapted animals increased the overall thickness of glomerular basement membrane by increasing the lamina rara interna and lamina densa. This did not occur when freshwater-adapted fish were either infused with angiotensin or adapted to seawater. These findings suggest that other humoral systems are involved in the control of glomerular diameter and basement membrane thickness as part of an integrated response to increased environmental salinity.

Over the past 15 years in Aberdeen, there has been an extensive screening programme for chemical gestational diabetes, and a number of these mothers have been treated during pregnancy with chlorpropamide, with insulin, or without the use of drugs. (Stowers and Sutherland, 1975).