Cardiomyocyte substructure reverts to an immature phenotype during heart failure.

KEY POINTS: As reactivation of the fetal gene program has been implicated in pathological remodelling during heart failure (HF), we examined whether cardiomyocyte subcellular structure and function revert to an immature phenotype during this disease. Surface and internal membrane structures appeared gradually during development, and returned to a juvenile state during HF. Similarly, dyadic junctions between the cell membrane and sarcoplasmic reticulum were progressively 'packed' with L-type Ca2+ channels and ryanodine receptors during development, and 'unpacked' during HF. Despite similarities in subcellular structure, dyads were observed to be functional from early developmental stages, but exhibited an impaired ability to release Ca2+ in failing cardiomyocytes. Thus, while immature and failing cardiomyocytes share similarities in subcellular structure, these do not fully account for the marked impairment of Ca2+ homeostasis observed in HF. ABSTRACT: Reactivation of the fetal gene programme has been implicated as a driver of pathological cardiac remodelling. Here we examined whether pathological remodelling of cardiomyocyte substructure and function during heart failure (HF) reflects a reversion to an immature phenotype. Using scanning electron microscopy, we observed that Z-grooves and t-tubule openings at the cell surface appeared gradually during cardiac development, and disappeared during HF. Confocal and super-resolution imaging within the cell interior revealed similar structural parallels; disorganization of t-tubules in failing cells was strikingly reminiscent of the late stages of postnatal development, with fewer transverse elements and a high proportion of longitudinal tubules. Ryanodine receptors (RyRs) were observed to be laid down in advance of developing t-tubules and similarly 'orphaned' in HF, although RyR distribution along Z-lines was relatively sparse. Indeed, nanoscale imaging revealed coordinated packing of L-type Ca2+ channels and RyRs into dyadic junctions during development, and orderly unpacking during HF. These findings support a 'last in, first out' paradigm, as the latest stages of dyadic structural development are reversed during disease. Paired imaging of t-tubules and Ca2+ showed that the disorganized arrangement of dyads in immature and failing cells promoted desynchronized and slowed Ca2+ release in these two states. However, while developing cells exhibited efficient triggering of Ca2+ release at newly formed dyads, dyadic function was impaired in failing cells despite similar organization of Ca2+ handling proteins. Thus, pathologically deficient Ca2+ homeostasis during HF is only partly linked to the re-emergence of immature subcellular structure, and additionally reflects lost dyadic functionality.

Spatial patterns in markers of contaminant exposure, glucose and glycogen metabolism, and immunological response in juvenile winter flounder (Pseudoplueronectes americanus).

Inshore winter flounder (Pseudoplueronectes americanus) populations in NY, USA have reached record low numbers in recent years, and recruitment into the fishery appears to be limited by survival of post-settlement juvenile fish. In order to identify cellular pathways associated with site-specific variation in condition and mortality, we examined differential mRNA expression in juvenile winter flounder collected from six different bays across a gradient in human population density and sewage inputs. Illumina sequencing of pooled samples of flounder from contrasting degraded sites and less impacted sites was used to guide our choice of targets for qPCR analysis. 253 transcripts of >100bp were differentially expressed, with 60% showing strong homology to mostly teleost sequences within the NCBI database. Based on these data, transcripts representing nine genes of interest associated with contaminant exposure, immune response and glucose and glycogen metabolism were examined by qPCR in individual flounder from each site. Statistically significant site-specific differences were observed in expression of all but one gene, although patterns in expression were complex with only one (vitellogenin), demonstrating a west to east gradient consistent with known loadings of municipal sewage effluent. Principal components analysis (PCA) identified relationships among the genes evaluated. Our data indicate that juvenile winter flounder are responding to estrogenic chemicals in more urbanized coastal bays, and suggests potential mechanistic links between immune response, contaminant exposure and energy metabolism.

Genetic mixed-stock analysis of Atlantic sturgeon Acipenser oxyrinchus oxyrinchus in a heavily exploited marine habitat indicates the need for routine genetic monitoring.

Although a previous genetic mixed-stock analysis (gMSA) conducted in the early 1990s showed that marine-captured New York Bight Atlantic sturgeon Acipenser oxyrinchus oxyrinchus almost exclusively originated from the Hudson River, fish from southern U.S. rivers were well represented within this contemporary sample (n = 364 fish), at least during the autumn. Widely distributed spawning stocks are therefore exposed to heavy fishing activity and habitat degradation in this relatively small area, illustrating the need for spatial management across multiple management jurisdictions and routine gMSA to account for temporal change.

An investigation on the effect of photoperiod and temperature on vertebral band deposition in little skate Leucoraja erinacea.

An investigation was undertaken to determine whether photoperiod or temperature have an effect on the timing of vertebral opaque-transluscent band-pair deposition in captive young-of-the-year (YOY) little skate Leucoraja erinacea. The experimental design consisted of a randomized complete block split plot design with two factors: temperature and light. Temperature was nested within light and therefore four variables were tested: 1) constant light, 2) constant temperature, 3) seasonal light and 4) seasonal temperature. For 18 months, L. erinacea experienced accelerated seasonal conditions of temperature and light to mimic 3 years of growth. This study provides primary and supporting evidence that seasonal photoperiod and temperature, respectively, have no effect on timing of vertebral band-pair deposition in captive L. erinacea. Vertebral analysis of surviving L. erinacea (n = 6, time = 18 months) showed that all produced 1-1·5 band pairs, while centrum edge analysis (n = 56) showed timing of winter and summer band deposition were similar regardless of treatment. The winter band (translucent) appeared in February 2007 and January 2008 while the summer band (opaque) showed up in July for both 2007 and 2008 and mimicked patterns observed in the wild. While temperature and photoperiod appear to have no effect on timing of band-pair deposition in YOY L. erinacea, other mechanisms which may influence band deposition should be investigated including the effect of food ration and the presence of a circa-annual rhythm and hormone secretion.

Sudden unexpected death in a female fitness athlete, with a possible connection to the use of anabolic androgenic steroids (AAS) and ephedrine.

The use of anabolic androgenic steroids (AAS) has been associated with different adverse effects, some of which potentially lethal. Most users of AAS are male, but the prevalence of such use appears to be increasing in females. Here we present a sudden unexpected death in a female fitness athlete with a possible connection to use of doping agents.

New hypothesis helps explain elasmobranch "outburst" on Georges Bank in the 1980s.

Regime shifts are a feature of many ecosystems. During the last 40 years, intensive commercial exploitation and environmental changes have driven substantial shifts in ecosystem structure and function in the northwest Atlantic. In the Georges Bank-southern New England region, commercially important species have declined, and the ecosystem shifted to one dominated by economically undesirable species such as skates and dogfish. Aggregated abundance indices indicate a large increase of small and medium-sized elasmobranchs in the early 1980s following the decline of many commercial species. It has been hypothesized that ecological interactions such as competition and predation within the Georges Bank region were responsible for and are maintaining the "elasmobranch outburst" at the heart of the observed ecosystem shift. We offer an alternative hypothesis invoking population connectivity among winter skate populations such that the observed abundance increase is a result of migratory dynamics, perhaps with the Scotian Shelf (i.e., it is an open population). Here we critically evaluate the survey data for winter skate, the species principally responsible for the increase in total skate abundance during the 1980s on Georges Bank, to assess support for both hypotheses. We show that time series from different surveys within the Georges Bank region exhibit low coherence, indicating that a widespread population increase was not consistently shown by all surveys. Further, we argue that observed length-frequency data for Georges Bank indicate biologically unrealistic population fluctuations if the population is closed. Neither finding supports the elasmobranch outburst hypothesis. In contrast, survey time series for Georges Bank and the Scotian Shelf are negatively correlated, in support of the population connectivity hypothesis. Further, we argue that understanding the mechanisms of ecosystem state changes and population connectivity are needed to make inferences about both the causes and appropriate management responses to large-scale system change.

Environmental tobacco smoke exposure during childhood is associated with increased prevalence of asthma in adults.

OBJECTIVE: To examine if exposure to environmental tobacco smoke (ETS) during childhood has an impact on asthma prevalence in adults, and to identify the amount of nuisance from ETS and other lower airway irritants (LAWIs) in a city population. DESIGN: A postal survey. SETTING: The municipality of Orebro, Sweden. PARTICIPANTS: A total of 8,008 randomly selected inhabitants aged 15 to 69 years. MEASUREMENTS: Exposures, airway symptoms, and respiratory history were assessed using a questionnaire. RESULTS: The response rate was 84%. In never-smokers with childhood ETS exposure, the prevalence of physician-diagnosed asthma was 7.6% vs 5.9% in nonexposed subjects (p = 0.036). In never-smokers without a family history of asthma, the prevalence of physician-diagnosed asthma in subjects reporting childhood ETS exposure was 6.8% vs 3.8% in nonexposed subjects (p < 0.001). Subjects with childhood ETS exposure were more likely to start smoking in adulthood. The prevalence of ever-smokers was 54.5% vs 33.8% (p < 0.0001) in nonexposed subjects. ETS was the most commonly reported LAWI in the total sample (21%), followed by exercise in cold air (20%), dust (19%), exercise (16%), perfume (15%), cold air (12%), pollen (10%), and pets (8%). All LAWIs were more frequently reported by women. CONCLUSIONS: Childhood exposure to ETS is associated with an increased prevalence of asthma among adult never-smokers, especially in nonatopic subjects. Children exposed to ETS are also more likely to become smokers. ETS is as a major LAWI.

A complex background in children and adolescents with psychiatric disorders: developmental delay, dyslexia, heredity, slow cognitive processing and adverse social factors in a multifactorial entirety.

A consecutive cohort of 112 children, 42 girls and 70 boys, aged 5-17 years, receiving child psychiatric inpatient care, was investigated regarding the probability of a complex background of concomitant biological and social factors. Most of the subjects showed maladjustment and depressive states, school problems, problems with peers, psychosomatic complaints and anxiety. A very high rate of factors indicating neurodevelopmental dysfunctions was found particularly in boys, who exhibited developmental delay, dyslexia, heredity for dyslexia, and a slow complex reaction time (CRT) - suggesting slow cognitive processing - considered an impairment in itself. Further, many children obtained errors on the CRT task, indicating attention deficit and deterioration during the test, pointing toward exhaustion. The social background displayed frequent problems such as broken homes, care outside the biological home, and disordered and/or abusing parents. The biological and social factors created a complex web, predisposing the child to primary, secondary and/or comorbidity problems, and leading to an interactive process reducing the child's psychosocial capacity and competence. A pattern was developed of an impaired child, living in an inadequate/insufficient family milieu in a modern society, with increasing demands on children.

Social competence and emotional/behaviour problems in 6-16 year-old Swedish school children.

Social competence and emotional/behavioural problems as reported by parents on a Swedish version of the Child Behaviour Checklist (CBCL) were examined in 1308 Swedish school-aged children/adolescents recruited from a stratified, random sample of schools in urban, semirural, and rural areas in Uppsala County, Sweden, and from Stockholm, the capital city of Sweden. The overall response rate was 80.6%. Few gender differences were found, but adolescents received higher problem scores and higher social competence scores than the younger children. Children from the middle SES groups were regarded as having higher social competence levels, and children from the lower SES groups had higher emotional/behaviour problem scores. Children from the larger cities consistently obtained higher problem scores. Those who had received help during the previous year because of psychological problems (2%) had much higher problems scores than those who had not received help. The levels of emotional/behavioural problems in children and adolescents in the present sample seem to be comparable to those reported in similar Scandinavian studies where the CBCL has been used. However, they were considerably lower than those commonly reported in epidemiological studies of children/adolescents from other countries and cultures.

Mental and somatic health and social adjustment in ordinary school children during childhood and adolescence related to central nervous functions as expressed by a complex reaction time.

A cohort of ordinary Swedish children were followed up from school entry through childhood and adolescence and checked retrospectively from birth to the age of 6 years regarding psychiatric and physical health and contact with the social welfare authorities. The children were allocated to different risk groups at age 7 on the basis of their psycho-physical development expressed as complex reaction time (CRT). It was previously shown that many of the slow CRT children have problems in psychomotor and language development at school, and that many leave compulsory school with poor achievements in Swedish and gymnastics as continuing signs of their developmental delay. This study shows that slow CRT children have an increased prevalence of child psychiatric problems. At an early age there were symptoms of aggression, hyperactivity and withdrawal in conjunction with developmental delay. During adolescence, depression, maladjustment and psycho-somatic disorders were prominent features, often in association with developmental delay, dyslexia and poor motoric skill. These children could have a disadvantage at school and in society and they felt themselves "handicapped" and were stressed by feelings of limited future possibilities. In adolescence, many of them were in need of help, especially financial aid from the social welfare services. The findings stress that a slow cognitive processing ability seen as a slow CRT must be considered a handicap of importance and a risk-factor in the society of today, with primary or secondary psychic and social manifestations often in a multifactorial setting of biological co-morbidity and family problems. In contrast, an advanced CNS development with a fast CRT may be seen as a protective factor.

Effects of zolpidem on sleep architecture, night time ventilation, daytime vigilance and performance in heavy snorers.

1. In a double-blind, crossover, placebo controlled trial, zolpidem 10 mg, a new imidazopyridine hypnotic drug, was administered in a single dose to 10 healthy non-obese heavy snorers. 2. Nocturnal polysomnography showed that zolpidem increased total sleep time, sleep efficiency and the percentage of stage 2. 3. Respiratory monitoring showed that zolpidem did not modify the percentage of total sleep time spent snoring. The percentages of total sleep time with a SaO2 < 4% of the baseline value and with a SaO2 < 90% and the mean SaO2 were also unchanged with zolpidem. The respiratory disturbance index was modestly increased by zolpidem although in all but one subject it remained < 5 with both treatments. 4. Zolpidem intake did not impair daytime vigilance and performance evaluated the day after.

School achievement and school adaptation in children in relation to CNS development as assessed by a complex reaction time measured on school entry--a follow-up.

Schoolchildren aged seven years underwent a complex reaction time (CRT) measurement and were followed up regarding language achievements and performance in gymnastics during the nine years of compulsory school. An analysis was made of the correlation between school results and CRT findings. In grade 3, there were large differences in psychomotor development between children with fast and slow CRT in both sexes. Only minor differences in school achievement were seen between girls in different CRT groups. Among the boys, however, many with a slow CRT were considered handicapped in language development, with dyslexia as the most important problem in addition to poor motoricity. They left compulsory school with poor results in Swedish, their native language, and gymnastics, and with a certificate that may reduce their changes of future studies and employment. The boys in general were inferior to the girls. The slow CRT boys, who were mainly considered to be developmentally delayed, also carried a risk of social maladjustment. It would appear to be important that psychophysical maturity receives attention at school, in addition to emotional and social factors. The school health services have an important responsibility in this respect.

Chloroquine in malaria. Isn't it time for revision of prophylaxis schedules?

Two antimalarial prophylactic regimens were compared in healthy subjects belonging to the flying personnel of Scandinavian Airlines System. Regimen I: 310 mg chloroquine (CQ) base was given once weekly, starting the week prior to departure to the endemic area, then weekly during presence there and for four weeks after return. Regimen II: a loading dose of 620 mg chloroquine base was given at the latest 48 h prior to departure to the endemic area, followed by 310 mg base weekly throughout the visit. Blood samples were analysed by HPLC for CQ and its major metabolite desethylchloroquine (CQM). Regimen I gave suboptimal whole blood concentrations of CQ and CQM at the end of the first week of treatment. Regimen II gave prophylactic concentrations from the beginning of visit up to 6 weeks after departure from the endemic area. Both regimens were well tolerated, but Regimen II appeared better accepted by the volunteers due to its shorter duration.

Effect of zolpidem during sleep on ventilation and cardiovascular variables in normal subjects.

A double-blind study comparing the effect of zolpidem 10 mg, and placebo, on sleep architecture, nocturnal ventilation, cardiovascular parameters (heart rate, systolic, diastolic and mean blood pressures) was carried out. Ten healthy middle-aged males took part in the study. No significant differences were found between zolpidem and placebo in relation to sleep architecture. Mean respiratory disturbance index (RDI) and SaO2 values (mean SaO2, time spent with SaO2 < 90%) were similar under both conditions. The diastolic and mean blood pressure readings taken from REM periods which occurred during the first third of the night were significantly higher with zolpidem. No changes in systolic blood pressure or heart rate were found with zolpidem in comparison to placebo.