Exploring the One Health Paradigm in Male Breast Cancer.

How cancer patterns in humans compare to those of other species remains largely unknown and there is an even bigger knowledge gap for rare cancers like male breast cancer. One Health is a convergence of human and animal healthcare that encourages cross-pollination of medical research uniting human and veterinary medicine. Recognising that breast cancer occurs spontaneously in other male species (e.g. primates, canines, felines), and knowing that no laboratory models exist for male breast cancer, which limits our ability to perform functional studies, we explored the feasibility of applying One Health to breast cancer in men by conducting a narrative review of the topic. Spontaneous development of breast cancer was reported in captive male primates and in companion canines and felines. Some parallels in tumour biology of human male breast cancer with canines and primates were found. The age distribution, pattern of biomarker expression and metastasis were similar, with mammary tumours typically detected after two-thirds of average lifespan. However, instances of triple negative and inflammatory breast cancer, which are rarely observed in human male breast cancer, were found in canines and histological classification was inconsistent between species. These disparities need redressing to enable full exploration of the One Health paradigm in rare cancers.

First direct evidence of adult European eels migrating to their breeding place in the Sargasso Sea.

The European eel (Anguilla anguilla) is critically endangered (according to the most recent IUCN assessment) and has suffered a 95% decline in recruitment since the 1980s, attributed in part to factors occurring during the marine phases of its life-cycle. As an adult, the European eel undertakes the longest spawning migration of all anguillid eels, a distance of 5000 to 10,000 km across the Atlantic Ocean to the Sargasso Sea. However, despite the passage of almost 100 years since Johannes Schmidt proposed the Sargasso Sea as the breeding place of European eels on the basis of larval surveys, no eggs or spawning adults have ever been sampled there to confirm this. Fundamental questions therefore remain about the oceanic migration of adult eels, including navigation mechanisms, the routes taken, timings of arrival, swimming speed and spawning locations. We attached satellite tags to 26 eels from rivers in the Azores archipelago and tracked them for periods between 40 and 366 days at speeds between 3 and 12 km day-1, and provide the first direct evidence of adult European eels reaching their presumed breeding place in the Sargasso Sea.

Long-Term Follow-Up of Autonomic and Enteric Measures in Patients Undergoing Vertical Banded Gastroplasty for Morbid Obesity.

BACKGROUND: A multi-component model of autonomic and enteric factors may correlate with ultimate weight loss or gain after restrictive obesity surgery. This study aimed to determine relevant parameters to predict successful long-term weight loss. METHODS: Thirty-nine patients (four males and 35 females) with a mean age of 37.2 years were followed for over 15 years after vertical banded gastroplasty. Baseline adrenergic: postural adjustment ratio (PAR) and vasoconstriction (VC); cholinergic: electrocardiogram R-to-R interval (RRI) and enteric measure: electrogastrogram (EGG) were utilized by a discriminant function analysis to classify patients as a long-term loser or gainer. Using latest weight compared to baseline, patients were divided as 10 gainers and 29 losers. RESULTS: A discriminate model successfully predicted ultimate weight gain in 8/10 (80%) of patients who subsequently gained weight and weight loss in 24/29 (83%) of patients who lost weight for a total correct classification of 32/39 (82%). The same model with data at 3 months postoperatively predicted weight gain in 9/10 (90%) of patients and weight loss in 24/29 (83%) of patients, for a total correct classification of 34/39 (87%). CONCLUSIONS: A multi-component model at baseline and 3 months postoperative can predict long-term weight outcome from restrictive obesity surgery.

Dysregulation of sterol regulatory element binding protein-1c in livers of morbidly obese women is associated with altered suppressor of cytokine signaling-3 and signal transducer and activator of transcription-1 signaling.

We compared hepatic expression of genes that regulate lipid biosynthesis and metabolic signaling in liver biopsy specimens from women who were undergoing gastric bypass surgery (GBP) for morbid obesity with that in women undergoing ventral hernia repair who had experienced massive weight loss (MWL) after prior GBP. Comprehensive metabolic profiles of morbidly obese (MO) (22 subjects) and MWL (9 subjects) were also compared. Analyses of gene expression in liver biopsies from MO and MWL were accomplished by Affymetrix microarray, real-time polymerase chain reaction, and Western blotting techniques. After GBP, MWL subjects had lost on average 102 lb as compared with MO subjects. This was accompanied by effective reversal of the dyslipidemia and insulin resistance that were present in MO. As compared with MWL, livers of MO subjects exhibited increased expression of sterol regulatory element binding protein (SREBP)-1c and its downstream lipogenic targets, fatty acid synthase and acetyl-coenzyme A-carboxylase-1. Livers of MO subjects also exhibited enhanced expression of suppressor of cytokine signaling-3 protein and attenuated Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling. Consistent with these findings, we found that the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. These data support the hypothesis that suppressor of cytokine signaling-3-mediated attenuation of the STAT signaling pathway and resulting enhanced expression of SREBP-1c, a key regulator of de novo lipid biosynthesis, are mechanistically related to the development of hepatic insulin resistance and dyslipidemia in MO women.

False-Positive Urine Screening for Benzodiazepines: An Association with Sertraline?: A Two-year Retrospective Chart Analysis.

OBJECTIVE: To determine the frequency of false-positive benzodiazepine screens associated with sertraline use at the authors' institution. METHOD: Urine drug screen results spanning a two-year period were data mined to identify those positive for benzodiazepines. When confirmatory gas chromatography-mass spectrometry determined false positives, they were subsequently cross-referenced against pharmacy records to identify patients with active prescriptions for sertraline at the time of the initial urinary drug screen. RESULTS: Of the 522 records reviewed, 160 were later determined to be false positives by confirmatory gas chromatography-mass spectrometry. Sixty-two of those were associated with a concomitant benzodiazepine prescription. Of the 98 remaining, 26 were associated with a concomitant sertraline prescription. CONCLUSION: Our findings suggest that sertraline may be an unreported cause of false-positive benzodiazepine results in a widely used screening assay.

Hepatic gene expression in morbidly obese women: implications for disease susceptibility.

The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women undergoing ventral hernia repair who had experienced massive weight loss (MWL) following prior GBP. Metabolic and hormonal profiles were examined in MO vs. MWL groups. Additionally, we analyzed individual profiles of hepatic gene expression in liver biopsy specimens obtained from MO and MWL subjects. All patients underwent preoperative metabolic profiling. RNAs were extracted from wedge biopsies of livers from MO and MWL subjects, and analysis of mRNA expression was carried out using Affymetrix HG-U133A microarray gene chips. Genes exhibiting greater than twofold differential expression between MO and MWL subjects were organized according to gene ontology and hierarchical clustering, and expression of key genes exhibiting differential regulation was quantified by real-time-polymerase chain reaction (RT-PCR). We discovered 154 genes to be differentially expressed in livers of MWL and MO subjects. A total of 28 candidate disease susceptibility genes were identified that encoded proteins regulating lipid and energy homeostasis (PLIN, ENO3, ELOVL2, APOF, LEPR, IGFBP1, DDIT4), signal transduction (MAP2K6, SOCS-2), postinflammatory tissue repair (HLA-DQB1, SPP1, P4HA1, LUM), bile acid transport (SULT2A, ABCB11), and metabolism of xenobiotics (GSTT2, CYP1A1). Using gene expression profiling, we have identified novel candidate disease susceptibility genes whose expression is altered in livers of MO subjects. The significance of altered expression of these genes to obesity-related disease is discussed.

The development and validation of a computational model to predict rat liver microsomal clearance.

As the cost of discovering and developing new pharmaceutically relevant compounds continues to rise, it is increasingly important to select the right molecules to prosecute very early in drug discovery. The development of high throughput in vitro assays of hepatic metabolic clearance has allowed for vast quantities of data generation; however, these large screens are still costly and remain dependant on animal usage. To further expand the value of these screens and ultimately aid in animal usage reduction, we have developed an in silico model of rat liver microsomal (RLM) clearance. This model combines a large amount of rat clearance data (n = 27,697) generated at multiple Pfizer laboratories to represent the broadest possible chemistry space. The model predicts RLM stability (with 82% accuracy and a kappa value of 0.65 for test data set) based solely on chemical structural inputs, and provides a clear assessment of confidence in the prediction. The current in silico model should help accelerate the drug discovery process by using confidence-based stability-driven prioritization, and reduce cost by filtering out the most unstable/undesirable molecules. The model can also increase efficiency in the evaluation of chemical series by optimizing iterative testing and promoting rational drug design.

Implementing workplace-based assessment across the medical specialties in the United Kingdom.

OBJECTIVES: To evaluate the reliability and feasibility of assessing the performance of medical specialist registrars (SpRs) using three methods: the mini-clinical evaluation exercise (mini-CEX), directly observed procedural skills (DOPS) and multi-source feedback (MSF) to help inform annual decisions about the outcome of SpR training. METHODS: We conducted a feasibility study and generalisability analysis based on the application of these assessment methods and the resulting data. A total of 230 SpRs (from 17 specialties) in 58 UK hospitals took part from 2003 to 2004. Main outcome measures included: time taken for each assessment, and variance component analysis of mean scores and derivation of 95% confidence intervals for individual doctors' scores based on the standard error of measurement. Responses to direct questions on questionnaires were analysed, as were the themes emerging from open-comment responses. RESULTS: The methods can provide reliable scores with appropriate sampling. In our sample, all trainees who completed the number of assessments recommended by the Royal Colleges of Physicians had scores that were 95% certain to be better than unsatisfactory. The mean time taken to complete the mini-CEX (including feedback) was 25 minutes. The DOPS required the duration of the procedure being assessed plus an additional third of this time for feedback. The mean time required for each rater to complete his or her MSF form was 6 minutes. CONCLUSIONS: This is the first attempt to evaluate the use of comprehensive workplace assessment across the medical specialties in the UK. The methods are feasible to conduct and can make reliable distinctions between doctors' performances. With adaptation, they may be appropriate for assessing the workplace performance of other grades and specialties of doctor. This may be helpful in informing foundation assessment.

Surgical caloric restriction ameliorates mitochondrial electron transport dysfunction in obese females.

BACKGROUND: The authors examine the mitochondrial electron transport system (ETS) with regard to caloric restriction and body size in humans. METHODS: The study population included 59 morbidly obese (MO) female subjects with mean body mass index (BMI) 49.6 +/- 1.7 and 40 age-matched previously morbidly obese patients with surgically-induced caloric restriction (SCR) and mean BMI 28.9 +/- 1.1. ETS function in the 2 study groups were made by measuring their lymphocyte mitochondrial ETS complexes I-IV activities and complex III binding kinetics. Linear regression analyses were used to analyze the interactions between ETS function and BMI, energy intake, and metabolic status. RESULTS: The MO, as compared to SCR, subjects had significantly (P < 0.01) higher ETS complexes II-IV activities (complex II = 20.4 +/- 1.9 vs 15.3 +/- 1.1, complex III = 129.4 +/- 10.1 vs 72.3 +/- 4.9, complex IV = 3.1 +/- 0.3 vs 1.4 +/- 0.1 nmol/mg/min for the MO vs SCR, respectively). ETS complexes activities were positively and significantly correlated with subjects' BMI, carbohydrate caloric intake, and fasting plasma insulin levels. Michaelis-Menten kinetic analysis showed that the Km for ubiquinol-2 in complex III of MO patients was 2-fold greater than SCR values, reflecting an apparent reduction in substrate binding capacities producing a resistance to electron flow in the MO population. Caloric consumption, carbohydrate calories, insulin levels, and BMI were also each significantly (P < 0.05) and positively correlated with the Km of Complex III. CONCLUSIONS: ETS function and efficiency are compromised by increasing BMI and caloric consumption in morbidly obese women, and caloric restriction may reduce the potential for excessive oxidative free radical generation via the ETS.

Effects of caffeine, halothane, and 4-chloro-m-cresol on skeletal muscle lactate and pyruvate in malignant hyperthermia-susceptible and normal swine as assessed by microdialysis.

BACKGROUND: Skeletal muscle fibers from malignant hyperthermia (MH)-susceptible humans and swine are markedly more sensitive to ryanodine receptor (RyR1) agonists than those from normal individuals. Reproducible shifts in the dose-response of skeletal muscle to caffeine and halothane are the basis of the current in vitro diagnostic caffeine-halothane contracture test. In an attempt to develop a less invasive MH diagnostic test, the authors determined the effects of RyR1 agonists (caffeine, 4-chloro-m-cresol [4CmC], and halothane) on the adductor muscle with respect to the lactate-pyruvate (L/P) system that was percutaneously dialyzed using a microdialysis technique in homozygous MH-susceptible compared with normal swine. METHODS: Animals were anesthetized (ketamine-propofol) and artificially ventilated. Sets of six CMA/20 microdialysis catheters were implanted; each catheter was perfused with different RyR1 agonist concentrations. After a 30-min equilibration after implantation, one of the catheters was perfused (2 microl/min) with vehicle (0.9% saline or lipid emulsion), and the other five were perfused with caffeine (1-64 mM), 4CmC (0.1-8 mM), or halothane (prepared in lipid emulsion; 10-500 mM). Outflow dialysate fractions collected at 10-min intervals and L/P parameters were measured enzymatically. RESULTS: Only in the MH-susceptible group did all RyR1 agonists increase dialysate L/P in a dose-dependent manner. The dose-effect relations were most prominent with 4CmC. With the halothane lipid emulsion, data scatter was high compared with that of the caffeine group and especially the 4CmC group. There were no signs of global muscle rigidity, systemic hypermetabolism, or a clinical MH episode during microdialysis RyR1 perfusion. CONCLUSIONS: The authors data demonstrate that the in vivo muscle microdialysis of the porcine L/P system reveals distinct differences between MH-susceptible and MH-normal muscle, especially in response to highly specific RyR1 agonists such as 4CmC. The microdialysis L/P technique seems to have an MH diagnostic potential in the clinical setting.

Inhibition of leptin release by atrial natriuretic peptide (ANP) in human adipocytes.

The addition of atrial natriuretic peptide (ANP) to isolated human adipocytes in primary culture from very obese individuals resulted in an inhibition of leptin release after a 24- or 48-hr incubation. There was also an inhibition of leptin release by isoproterenol (ISO) that was partially reversed by insulin, whereas the inhibition due to ANP was unaffected. Similar results were seen with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H-89), which is a cell-permeable inhibitor of protein kinase A. H-89 markedly reduced the effects of ISO on both lipolysis and leptin release without affecting the stimulation of lipolysis or the inhibition of leptin release due to ANP. Inhibition of endogenous nitric oxide formation using N(omega)-nitro-L-arginine resulted in a 20% increase in leptin release over 48 hr, which suggests that the nitric oxide/cyclic GMP pathway might play a small role in the regulation of endogenous leptin release. Similarly, the addition of the nitric oxide donor (Z)-1-[2-aminoethyl)-N-(2-aminoethyl)diazen-1-ium-1,2-diolate (DETA NONOate) at 0.1 or 1 microM to explants of human adipose tissue enhanced lipolysis by 29%. Our data demonstrate that the lipolytic effect of ANP is probably secondary to stimulation of cyclic GMP accumulation in human adipocytes, and this is accompanied by an inhibition of leptin release.

Assessing the performance of specialist registrars.

Assessing the performance of doctors while they are engaged in clinical work is a challenging concept. The introduction of objective-based curricula provides the stimulus and opportunity for the Royal Colleges of Physicians to develop relevant and reliable methods of in-service assessment. We propose to pilot a study investigating the validity, reliability and feasibility of three assessment methods--direct observation of the clinical encounter using an adapted mini-CEX, direct observation of the performance of practical procedures (DOPS), and the doctor's ability to perform effectively as part of a team using 360 degree assessment. The methods will be studied in the setting of routine clinical care. Whilst demanding of time from both trainees and trainers, they will represent a significant advance on the current system which is characterised by a lack of evidence in the assessment process.

Regulation of leptin release by insulin, glucocorticoids, G(i)-coupled receptor agonists, and pertussis toxin in adipocytes and adipose tissue explants from obese humans in primary culture.

The basal release of leptin by adipocytes from massively obese human subjects incubated for 48 hours in serum-free suspension culture was comparable to that by explants of subcutaneous adipose tissue from the same obese individuals. There was no stimulation due to dexamethasone or insulin alone of leptin release by adipocytes. However, the combination of insulin and dexamethasone doubled leptin release by adipocytes. The release of leptin was also stimulated by agonists of G(i)-coupled receptors (prostaglandin E(2) [PGE(2)], brimonidine [an alpha(2) catecholamine agonist] and cyclopentyladenosine [CPA]) in the presence of dexamethasone. Leptin release by these agents was further enhanced by insulin in both adipocytes and adipose tissue. Pertussis toxin, which irreversibly inactivates G(i) heterotrimers, inhibited leptin release and abolished the stimulatory effects of G(i)-coupled receptor agonists. However, pertussis toxin did not block the stimulation of leptin release by insulin in either adipose tissue or adipocytes. These data indicate that the release of leptin by human adipocytes cultured for 48 hours in a serum-free medium is comparable to that by explants of adipose tissue except that dexamethasone stimulation of leptin release requires the presence of insulin.

Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort.

The prevalence of mutations within and in the flanking regions of the gene encoding the melanocortin 4 receptor was investigated in severely obese and normal-weight subjects from the Swedish Obese Subjects study, the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family study, and a Memphis cohort. A total of 433 white and 95 black subjects (94% females) were screened for mutations by direct sequencing. Three previously described missense variants and nine novel (three missense, six silent) variants were detected. None of them showed significant association with obesity or related phenotypes. In addition, two novel deletions were found in two heterozygous obese women: a -65_-64delTG mutation within the 5' noncoding region and a 171delC frameshift mutation predicted to result in a truncated nonfunctional receptor. No pathogenic mutations were found among obese blacks or nonobese controls. Furthermore, none of the null mutations found in other populations was present in this sample. In conclusion, our results do not support the prevailing notion that sequence variation in the melanocortin 4 receptor gene is a frequent cause of human obesity.

Papel da gastroplastia no tratamento da apnéia obstrutiva durante o sono / The role of gastroplasty in the treatment of obstructive sleep apnea

Gastroplastia foi realizada como forma terapêutica auxiliar para reduçäo de peso em 4 pacientes com obesidade severa e apnéia obstrutiva durante o sono (ASO). As idades variavam de 31 a 54 anos e todos eram do sexo masculino. Em três casos a gastroplastia acompanhou-se de traqueostomia. Após a gastroplastia todos tiveram melhora da sonolência diurna e reduçäo de peso em 16,7% a 40,9%. Avaliaçöes polissonográficas de noite inteira realizadas no pré e pós-operatório (3-4 meses). Os registros pós-operatórios foram feitos com traqueostomia fechada e revelaram reduçäo da freqüência das apnéias e aumento dos estágios 3, 4 e REM. Normalizaçäo dos índices de saturaçäo arterial de oxigênio (SaO2) foi constatada em três dos 4 casos. Esses dados sugerem que a gastroplastia pode ser utilizada como forma alternativa para reduçäo de peso em casos selecionados de ASO complementando outros procedimentos cirúrgicos como a traqueostomia