Social jetlag, obesity and metabolic disorder: investigation in a cohort study.

BACKGROUND: Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction. METHODS: We studied participants from the population-representative Dunedin Longitudinal Study (N=1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes. RESULTS: Our analysis was restricted to N=815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation. CONCLUSIONS: The findings are consistent with the possibility that 'living against our internal clock' may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time.

Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and post-traumatic stress disorder.

There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective longitudinal Dunedin Study (n=1037). Analyses showed that the persistence of internalizing disorders across repeated assessments from ages 11 to 38 years predicted shorter LTL at age 38 years in a dose-response manner, specifically in men (ß=-0.137, 95% confidence interval (CI): -0.232, -0.042, P=0.005). This association was not accounted for by alternative explanatory factors, including childhood maltreatment, tobacco smoking, substance dependence, psychiatric medication use, poor physical health or low socioeconomic status. Additional analyses using DNA from blood collected at two time points (ages 26 and 38 years) showed that LTL erosion was accelerated among men who were diagnosed with internalizing disorder in the interim (ß=-0.111, 95% CI: -0.184, -0.037, P=0.003). No significant associations were found among women in any analysis, highlighting potential sex differences in internalizing-related telomere biology. These findings point to a potential mechanism linking internalizing disorders to accelerated biological aging in the first half of the life course, particularly in men. Because internalizing disorders are treatable, the findings suggest the hypothesis that treating psychiatric disorders in the first half of the life course may reduce the population burden of age-related disease and extend health expectancy.

Pseudotumoral presentation of fungating mycetoma caused by Phaeoacremonium fuscum in a renal transplant patient.

Eumycetoma is an unusual infection in immunocompromised patients outside the tropics, caused by a variety of fungal pathogens. We describe the case of a 51-year-old renal transplant recipient who presented with a large pseudotumoral foot lesion necessitating complete surgical excision of the lesion. Cultures and molecular diagnosis confirmed Phaeoacremonium fuscum. This is the first case, to our knowledge, of fungating mycetoma caused by this fungal species in a solid organ transplant recipient.

Assessing the accuracy and certainty in interpreting chest X-rays in the medical division.

The chest X-ray (CXR) is an important diagnostic tool in diagnosing and monitoring a spectrum of diseases. Despite our universal reliance on the CXR, our ability to confidently diagnose and accurately document our findings can be unreliable. We sought to assess the diagnostic accuracy and certainty of making a diagnosis based on 10 short clinical histories with one CXR each. We conclude from our study that specialist registrars (StRs) and consultants scored the highest marks with the highest average certainty levels. Junior trainees felt least certain about making their diagnosis and were less likely to be correct. We recommend that StRs and consultants review all the CXRs requested to ensure accuracy of diagnosis. There also needs to be discussion with the Joint Royal Colleges of Physicians Training Board (JRCPTB) about the need of including a separate CXR competency as part of a trainee's generic curriculum on the e-portfolio, something which is currently lacking.

Anti-tuberculosis prophylaxis following renal transplantation: acceptable variations?

BACKGROUND: Guidelines suggest tuberculosis (TB) prophylaxis in renal transplant recipients originating in endemic areas or in those at risk from non-endemic countries. Concern remains that these guidelines may fail to provide adequate prophylaxis for a cohort of patients who remain at potential risk. We aimed to determine variation patterns among different transplant units within the United Kingdom (UK) with regard to TB prophylaxis policy. METHODS: The renal pharmacist at each of the 25 UK renal transplant centers was contacted. Specific information was obtained relating to drug prophylaxis given, duration of treatment, as well as which transplant recipients were eligible for treatment. RESULTS: A 96% response rate (24/25 centers) was achieved. Prophylaxis regimens varied from no prophylaxis to isoniazid 300 mg given life-long. The most common duration of treatment was 6 months post transplantation (at 7 centers). Variations existed in the concurrent use of pyridoxine. A wide discrepancy was seen in the determination of who should receive prophylaxis, with no clear association with frequency of TB incidence in the region. CONCLUSIONS: A marked discrepancy exists among national renal transplant units in pharmacologic prophylaxis for TB, as well in the selection of individuals for this treatment.

Hormonal evidence supports the theory of selection in utero.

OBJECTIVES: Antagonists in the debate over whether the maternal stress response during pregnancy damages or culls fetuses have invoked the theory of selection in utero to support opposing positions. We describe how these opposing arguments arise from the same theory and offer a novel test to discriminate between them. Our test, rooted in reports from population endocrinology that human chorionic gonadotropin (hCG) signals fetal fitness, contributes not only to the debate over the fetal origins of illness, but also to the more basic literature concerned with whether and how natural selection in utero affects contemporary human populations. METHODS: We linked maternal serum hCG measurements from prenatal screening tests with data from the California Department of Public Health birth registry for the years 2001-2007. We used time series analysis to test the association between the number of live-born male singletons and median hCG concentration among males in monthly gestational cohorts. RESULTS: Among the 1.56 million gestations in our analysis, we find that median hCG levels among male survivors of monthly conception cohorts rise as the number of male survivors falls. RESULTS: Elevated median hCG among relatively small male birth cohorts supports the theory of selection in utero and suggests that the maternal stress response culls cohorts in gestation by raising the fitness criterion for survival to birth.

An exploration of secondary sex ratios among women diagnosed with anxiety disorders.

BACKGROUND: Theory suggests that natural selection conserved reactivity in part because highly reactive women spontaneously abort less fit conceptuses, particularly small males. Other literature argues that high reactivity manifests clinically as anxiety disorders. If true, births to women diagnosed with anxiety disorders should exhibit a low secondary sex ratio (i.e. ratio of male to female births). We explored whether births to women diagnosed with anxiety disorders exhibit a lower sex ratio than births to women diagnosed with other psychiatric disorders, or to women without mental health diagnoses. METHODS: We performed a case-control comparison of the secondary sex ratios among groups of women categorized by mental health diagnosis using birth records linked to data from California County Mental Health system records. We compared sex ratios among 5994 deliveries to mothers diagnosed with anxiety disorders, 23 443 deliveries to mothers diagnosed with other psychiatric disorders and 1 099 198 'comparison' births. RESULTS: Although comparison births exhibited a higher sex ratio than births to women diagnosed with anxiety disorders or with other diagnoses, differences were not statistically significant. Births to African American women diagnosed with anxiety disorders, however, exhibited sex ratios significantly lower than comparison births among African Americans (OR = 0.89, P = 0.038) or births to African American women with other mental health diagnoses (OR = 0.88, P = 0.042). CONCLUSIONS: We found that infants born to African American women diagnosed with anxiety disorders exhibited a significantly lower secondary sex ratio than reference groups. We urge confirmatory tests of our findings and discuss implications of the reactivity/anxiety hypothesis for psychiatry, obstetrics and public health.

Psychological distress and circulating inflammatory markers in healthy young adults.

BACKGROUND: Although a substantial body of research points to a link between psychological distress and inflammatory responses in middle-aged and older adults, particularly those with cardiovascular disease, the relationship between inflammation and distress in young, healthy individuals has not been established. This study was designed to investigate the cross-sectional association between psychological distress and inflammatory proteins in a young, healthy representative population of English adults. METHOD: Participants were 1338 individuals aged 16-34 years from the 2006 Health Survey for England (HSE). Blood samples to measure plasma fibrinogen and high sensitivity C-reactive protein (hsCRP), as well as measures of psychological distress (using the General Health Questionnaire 12-item scale, GHQ-12) and covariates, were collected during home visits. Linear regression was used to assess the relationship between psychological distress and fibrinogen and hsCRP. RESULTS: Higher self-rated distress was positively associated with fibrinogen level in this young population, independently of age, sex, ethnicity, body mass index (BMI), high density lipoprotein (HDL) cholesterol, smoking, and alcohol and medication use (ß=0.024, p<0.01). Psychological distress was not related to hsCRP. CONCLUSIONS: Psychological distress may negatively impact inflammatory processes in young adulthood before the onset of chronic health problems such as hypertension and cardiovascular disease. Longitudinal research is needed to elucidate the relationship between distress and inflammation in young adults and its significance for later disease states.

Breathing exercises for asthma: a randomised controlled trial.

BACKGROUND: The effect of breathing modification techniques on asthma symptoms and objective disease control is uncertain. METHODS: A prospective, parallel group, single-blind, randomised controlled trial comparing breathing training with asthma education (to control for non-specific effects of clinician attention) was performed. Subjects with asthma with impaired health status managed in primary care were randomised to receive three sessions of either physiotherapist-supervised breathing training (n = 94) or asthma nurse-delivered asthma education (n = 89). The main outcome was Asthma Quality of Life Questionnaire (AQLQ) score, with secondary outcomes including spirometry, bronchial hyper-responsiveness, exhaled nitric oxide, induced sputum eosinophil count and Asthma Control Questionnaire (ACQ), Hospital Anxiety and Depression (HAD) and hyperventilation (Nijmegen) questionnaire scores. RESULTS: One month after the intervention there were similar improvements in AQLQ scores from baseline in both groups but at 6 months there was a significant between-group difference favouring breathing training (0.38 units, 95% CI 0.08 to 0.68). At the 6-month assessment there were significant between-group differences favouring breathing training in HAD anxiety (1.1, 95% CI 0.2 to 1.9), HAD depression (0.8, 95% CI 0.1 to 1.4) and Nijmegen (3.2, 95% CI 1.0 to 5.4) scores, with trends to improved ACQ (0.2, 95% CI 0.0 to 0.4). No significant between-group differences were seen at 1 month. Breathing training was not associated with significant changes in airways physiology, inflammation or hyper-responsiveness. CONCLUSION: Breathing training resulted in improvements in asthma-specific health status and other patient-centred measures but not in asthma pathophysiology. Such exercises may help patients whose quality of life is impaired by asthma, but they are unlikely to reduce the need for anti-inflammatory medication.

Hodgkin's disease of appendix: report of a case.

BACKGROUND: A number of cases of non Hodgkin's lymphoma of the appendix have been described, but Hodgkin's lymphoma is extremely rare. To our knowledge there are only two reports up to 1966 and none since then. METHOD: We report a case of a 65-year-old gentleman who was treated for suspected Crohn's disease. He failed to respond to medical treatment and underwent right haemicolectomy. The resected segment of bowel demonstrated classical Hodgkin's disease originating in the appendix. He recovered well from the operation and responded well to postoperative chemotherapy. CONCLUSION: Hodgkin's lymphoma of appendix is extremely rare. This case demonstrates the significance of repeated clinical evaluation of patients particularly in the absence of expected response to therapy.

Targeted lung cancer screening selects individuals at high risk of cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention. METHODS: The Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55-74 and 6-year risk ≥1.51%, using PLCOM2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score. RESULTS: Seventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCOM2012) scores were correlated (r = 0.26, p < 0.001). Median QRISK2 score was 21.1% (IQR 14.9-29.6) in those without established CVD (77.6%, n = 714/920), double that of HSE controls (10.3%, IQR 6.6-16.2; n = 714) (p < 0.001). QRISK2 score was significantly higher in those with CAC (p < 0.001). Screening attendees were 10-fold more likely to be classified high risk (OR 10.2 [95% CI 7.3-14.0]). One third (33.7%, n = 310/920) of all study participants were high risk but not receiving statin therapy for primary CVD prevention. DISCUSSION: Opportunistic CVD risk assessment within a targeted lung cancer screening programme is feasible and is likely to identify a very large number of individuals suitable for primary prevention.

Military surgery in the 21st century.

The battlefield has changed. UK and US Forces in Iraq and Afghanistan are engaged in asymmetric, three bloc warfare. Three bloc warfare indicates that what is effectively war-fighting occurs in parallel with peace-keeping and humanitarian operations. Casualties are numerically lower than in previous conflicts but many survivors are horrifically mutilated as body armour prevents the fatal injury in this severely injured group. Rapid evacuation of severely injured from the point of injury, usually by helicopter, provides extreme challenges for surgical teams. Damage control surgery requires support in the form of environmental control, adequate diagnostics (including computerised tomography) and effective intensive care facilities if the patient is to survive. Teams need to be highly trained and to have experience of complex surgery and trauma. They must be adequately resourced if lives are to be saved.

betaA- and betaC-activin, follistatin, activin receptor mRNA and betaC-activin peptide expression during rat liver regeneration.

The mRNA expression of two activin growth factor subunits (betaA- and betaC-activin), activin receptor subunits (ActRIIA, ActRIIB) and the activin-binding protein follistatin, and peptide expression of betaA-activin and betaC-activin subunits, were examined in regenerating rat liver after partial hepatectomy (PHx). Liver samples were collected from adult, male Sprague-Dawley rats, 12-240 h (n=3-5 rats per time point) after PHx or from sham-operated controls at the same time points. Hepatocyte mitosis and apoptosis were assessed histologically and by in situ cell death detection. RT and PCR were used to assess relative gene expression. betaA- and betaC-activin peptide immunoreactivity was assessed in liver and serum samples by western blotting, whereas cellular expression was investigated by immunohistochemistry, using specific monoclonal antibodies. betaA- and betaC-activin mRNA dropped to < 50% of sham control values 12 h after PHx and remained at this level until 168 h post-PHx, when betaA-activin expression increased to three times sham control values and betaC-activin mRNA returned to pre-PHx levels. A peak in follistatin expression was observed 24-48 h post-PHx, coincident with an increase in hepatocyte mitosis. No changes were observed in ActRIIA mRNA, whereas ActRIIB expression paralleled that of betaA-activin mRNA. betaC-activin immunoreactive homo- and heterodimers were observed in regenerating liver and serum. Mitotic hepatocytes frequently contained betaC-activin immunoreactivity, whereas apoptotic hepatocytes were often immunoreactive for betaA-activin. We conclude that betaA- and betaC-activin subunit proteins are autocrine growth regulators in regenerating liver and when expressed independently lead to hepatocyte apoptosis or mitosis in a subset of hepatocytes.

Evolution of Renal Transplant Practice Over the Past Decade: A U.K. Center Experience.

OBJECTIVE: As renal transplantation continues to evolve, there appears to be a change in both donor and recipient populations. Traditional markers of high-risk donor (e.g. donation after cardiac death [DCD]/expanded criteria donor [ECD]) and recipient (e.g. obese, highly sensitized) operations appear to be more common without any noticeable worsening of patient outcome. The present study aimed to compare outcome and define the change in donor and recipient populations for cadaveric transplants over a 10-year period at a large U.K. center. METHODS: Single-center analysis of all adult patients undergoing cadaveric renal transplantation between January 2004 and January 2014 (n = 754). Transplants were divided into 3 groups (early, middle, and late) depending on the era, with donor, recipient and outcomes compared. RESULTS: There were considerable changes in both donor and recipient factors between the 3 eras, with a greater proportion of high-risk operations performed, as reflected by significant increases in Donor Risk Index (median: 1.11-1.16, P = .022), and the proportions of ECD (22.2%-33.9%, P = .003) and DCD kidneys (10.8%-19.4% P = .011). However, 1-year graft survival was comparable between the eras, with a decrease in the average 1-year serum creatinine between the early and late cohort (median: 161 µmol/L vs 132 µmol/L, P < .001). There was no significant increase in body mass index (BMI) in either the donor or recipient population across the eras. CONCLUSION: Improvement in transplant outcome continues despite a greater proportion of transplants previously considered as high risk being performed. This is likely to reflect a considerable improvement in pre- and postoperative management. BMI remains a major continuing block to transplantation.

Expression of activin A and follistatin core proteins by human prostate tumor cell lines.

Activin and follistatin (FS) messenger RNA and protein are expressed and localized to human prostate tissue from men with high grade cancer and to human prostate tumor cell lines LNCaP, DU145, and PC3. Although activin A induces apoptosis and inhibits cell proliferation in LNCaP cells, PC3 cells are insensitive to the effect of exogenous addition of activin A. The results of this study show that activin A and FS are produced and can be measured by specific enzyme-linked immunosorbent assays in PC3 cells and media but are not detectable in LNCaP cells. Over 10 days in culture, the production of activin A by PC3 cells declines and is inversely correlated (r = -0.779) to FS288 production, which steadily increases and is significantly elevated compared with Day 1 of culture. The presence of FS288 and FS315 proteins was confirmed by immunocytochemistry and showed that only PC3 cells produced the FS288 isoform. Western blotting of PC3 cell media confirmed the presence of the FS288 isoform. Blockade of FS288 activity with a neutralizing antibody rendered PC3 cells responsive to activin A, as measured by inhibition of proliferation. Collectively, these results suggest that PC3 tumor cells are insensitive to activin A because they produce measurable amounts of activin ligand and FS288 protein, which is capable of blocking the autocrine response of these cells to activin A.

Loss of the expression and localization of inhibin alpha-subunit in high grade prostate cancer.

Serum inhibin levels are elevated in postmenopausal women with granulosa and mucinous epithelial tumors of the ovary. In contrast, functional deletion of the inhibin alpha gene in male and female mice results in the development of primary gonadal granulosa/Sertoli cell tumors. The aim of this study was to determine whether inhibin alpha-subunit gene and protein expression are altered in prostate cancer. Messenger ribonucleic acid expression was studied by in situ hybridization, and protein localization was studied by immunohistochemistry. Inhibin alpha-subunit messenger ribonucleic acid expression and protein localization were observed in the epithelium of tissues from men with benign prostatic hyperplasia, in regions of basal cell hyperplasia, and in nonmalignant regions of tissue from men with high grade prostate cancer. In the malignant regions of tissue from men with high grade prostate cancer, the expression of the inhibin alpha-subunit gene was suppressed and was not detectable in poorly differentiated tumor cells. These results demonstrate that in contrast to ovarian granulosa cell tumors, inhibin alpha gene expression is down-regulated in poorly differentiated prostate cancer.

Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit.

Activin ligands are formed by dimerization of activin ss(A)- and/or ss(B)-subunits to produce activins A, AB, or B. These ligands are members of the transforming growth factor-ss superfamily and act as growth and differentiation factors in many cells and tissues. New additions to this family include activin ss(C)-, ss(D)-, and ss(E)-subunits. The aim of this investigation was to examine the localization of and dimerization among activin subunits; the results demonstrate that activin ss(C) can form dimers with activin ss(A) and ss(B) in vitro, but not with the inhibin alpha-subunit. Using a specific antibody, activin ss(C) protein was localized to human liver and prostate and colocalized with ss(A)- and ss(B)-subunits to specific cell types in benign and malignant prostate tissues. Activin C did not alter DNA synthesis of the prostate tumor cell line, LNCaP, or the liver tumor cell line, HepG2, in vitro when added alone or with activin A. Therefore, the capacity to form novel activin heterodimers (but not inhibin C) resides in the human liver and prostate. Activin A, AB, and B have diverse actions in many tissues, including liver and prostate, but there is no known biological activity for activin C. Thus, the evidence of formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biological activity of other activins in these tissues.

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers.

Activins are cytokines of the transforming growth factor beta family, which plays a central role in the determination of cell fate and the regulation of tissue balance. Family members are composed of two subunits and this dimerization is critical for liganding their cognate receptors and execution of proper functions. In the current study we focused on the localization of activin betaA, betaB, betaC and betaE subunits in the adult rat and analyzed the composition of putative activin beta dimers. By dissecting tissue distribution of various activins, we found that the liver, in particular the hepatocytes, is the major source for activin betaC and betaE transcripts, since other tissues almost failed to express these isoforms. In sharp contrast, the emergence of activin betaA and betaB appeared ubiquitous. Using a highly selective proteome approach, we were able to identify homo- as well as heterodimers of individual activin subunits, indicating a high redundancy of ligand composition. Certainly, this broad potential to homo- and heterodimerize has to be considered in future studies on activin function.

Antinociceptive effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone in the land snail, Cepaea nemoralis.

Results of investigations with vertebrates have implicated neuroactive steroids and in particular 5alpha-reduced metabolites of progesterone such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/3A5P and originally allopregnanolone) in the rapid modulation of diverse functions including that of nociceptive sensitivity. These effects have been indicated to involve modulation of GABA receptors. Results of recent phylogenetic studies have revealed the presence of GABA receptors in invertebrates that may also be subject to modulation by steroids and neuroactive steroids. The present study examined the effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one, as well as progesterone on aversive thermal (nociceptive) responses in a mollusc, the land snail, Cepaea nemoralis. 3alpha-Hydroxy-5alpha-pregnan-20-one had significant dose-related (0.01-1.0 microg) antinociceptive effects in Cepaea increasing the latency of response to a 40 degrees C surface, with maximum effects being evident 15-30 min after administration. These effects of 3alpha-hydroxy-5alpha-pregnan-20-one were stereospecific, with the stereoisomer 3beta-hydroxy-5alpha-pregnan-20-one (3B5P) failing to affect nociceptive responses. Progesterone also had significant dose-related (0.10-10 microg) antinociceptive effects that, however, were delayed in onset and relatively prolonged (60-120 min), suggestive of the formation of active metabolites. The presence of endogenous progesterone (12.36+/-0.17 ng/g tissue) was ascertained by a radioimmunoassay further supporting a functional role for steroids in Cepaea. The antinociceptive effects of 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone were blocked by the GABA antagonists, bicuculline and picrotoxin, while being relatively insensitive to opioid and N-methyl-D-aspartate antagonists. These results suggest an early evolutionary development and phylogenetic continuity of neuroactive steroid and GABA involvement in the mediation of nociception.