Acute effects of exercise on appetite, ad libitum energy intake and appetite-regulatory hormones in lean and overweight/obese men and women.

BACKGROUND: Acute exercise does not elicit compensatory changes in appetite parameters in lean individuals; however, less is known about responses in overweight individuals. This study compared the acute effects of moderate-intensity exercise on appetite, energy intake and appetite-regulatory hormones in lean and overweight/obese individuals. METHODS: Forty-seven healthy lean (n=22, 11 females; mean (s.d.) 37.5 (15.2) years; 22.4 (1.5) kg m-2) and overweight/obese (n=25, 11 females; 45.0 (12.4) years, 29.2 (2.9) kg m-2) individuals completed two, 8 h trials (exercise and control). In the exercise trial, participants completed 60 min treadmill exercise (59 (4)% peak oxygen uptake) at 0-1 h and rested thereafter while participants rested throughout the control trial. Appetite ratings and concentrations of acylated ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured at predetermined intervals. Standardised meals were consumed at 1.5 and 4 h and an ad libitum buffet meal was provided at 7 h. RESULTS: Exercise suppressed appetite (95% confidence interval (CI) -3.1 to -0.5 mm, P=0.01), and elevated delta PYY (95% CI 10 to 17 pg ml-1, P<0.001) and GLP-1 (95% CI 7 to 10 pmol l-1, P<0.001) concentrations. Delta acylated ghrelin concentrations (95% CI -5 to 3 pg ml-1, P=0.76) and ad libitum energy intake (95% CI -391 to 346 kJ, P=0.90) were similar between trials. Subjective and hormonal appetite parameters and ad libitum energy intake were similar between lean and overweight/obese individuals (P⩾0.27). The exercise-induced elevation in delta GLP-1 was greater in overweight/obese individuals (trial-by-group interaction P=0.01), whereas lean individuals exhibited a greater exercise-induced increase in delta PYY (trial-by-group interaction P<0.001). CONCLUSIONS: Acute moderate-intensity exercise transiently suppressed appetite and increased PYY and GLP-1 in the hours after exercise without stimulating compensatory changes in appetite in lean or overweight/obese individuals. These findings underscore the ability of exercise to induce a short-term energy deficit without any compensatory effects on appetite regardless of weight status.

The effect of prone positioning with surgical bolsters on liver blood flow in healthy volunteers.

This study sought to identify changes in hepatic flood flow and cardiac output during prone positioning on surgical bolsters in awake volunteers, and was prompted by a local incident of significant hepatic dysfunction following surgery in the prone position. Cardiac output was determined using the non-invasive Peñáz technique, and plasma disappearance rate of indocyanine green (ICG-PDR) was measured as a surrogate maker for hepatic blood flow along with serum hepatic enzyme assays. Measurements were made after one hour in supine, prone and returned supine positions. Ten volunteers completed the study. There were significant changes in the disappearance rate of indocyanine green, which decreased this from mean (SD) 31.1 (9.70) supine to 19.6 (4.37)%.min prone, respectively (p = 0.02), increasing on return to the supine position to 24.6 (5.54)%.min (p = 0.019). Cardiac output was also significantly reduced when changing from the supine to the prone position, from mean (SD) 4.7 (1.0 to 3.5 (1.1) (l.min(-1) ), respectively (p = 0.002). We demonstrated an acute and reversible change in both hepatocellular function and cardiac output associated with the prone position.

Molecular gas clumps from the destruction of icy bodies in the ß Pictoris debris disk.

Many stars are surrounded by disks of dusty debris formed in the collisions of asteroids, comets, and dwarf planets, but is gas also released in such events? Observations at submillimeter wavelengths of the archetypal debris disk around ß Pictoris show that 0.3% of a Moon mass of carbon monoxide orbits in its debris belt. The gas distribution is highly asymmetric, with 30% found in a single clump 85 astronomical units from the star, in a plane closely aligned with the orbit of the inner planet, ß Pictoris b. This gas clump delineates a region of enhanced collisions, either from a mean motion resonance with an unseen giant planet or from the remnants of a collision of Mars-mass planets.

Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties.

AIM: In contrast to extensive reports on the roles of Na(v)1.5 alpha-subunits, there have been few studies associating the beta-subunits with cardiac arrhythmogenesis. We investigated the sino-atrial and conduction properties in the hearts of Scn3b(-/-) mice. METHODS: The following properties were compared in the hearts of wild-type (WT) and Scn3b(-/-) mice: (1) mRNA expression levels of Scn3b, Scn1b and Scn5a in atrial tissue. (2) Expression of the beta(3) protein in isolated cardiac myocytes. (3) Electrocardiographic recordings in intact anaesthetized preparations. (4) Bipolar electrogram recordings from the atria of spontaneously beating and electrically stimulated Langendorff-perfused hearts. RESULTS: Scn3b mRNA was expressed in the atria of WT but not Scn3b(-/-) hearts. This was in contrast to similar expression levels of Scn1b and Scn5a mRNA. Immunofluorescence experiments confirmed that the beta(3) protein was expressed in WT and absent in Scn3b(-/-) cardiac myocytes. Lead I electrocardiograms from Scn3b(-/-) mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts. Spontaneously beating Langendorff-perfused Scn3b(-/-) hearts demonstrated both abnormal atrial electrophysiological properties and evidence of partial or complete dissociation of atrial and ventricular activity. Atrial burst pacing protocols induced atrial tachycardia and fibrillation in all Scn3b(-/-) but hardly any WT hearts. Scn3b(-/-) hearts also demonstrated significantly longer sinus node recovery times than WT hearts. CONCLUSION: These findings demonstrate, for the first time, that a deficiency in Scn3b results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular electrophysiology reported on an earlier occasion.

Contribution of calcium-containing crystals to cartilage degradation and synovial inflammation in osteoarthritis.

OBJECTIVES: The role of calcium phosphate and pyrophosphate crystals in osteoarthritis (OA) is unclear: are they a symptom of the damage that occurs to the joint or a key intermediate in the progression of inflammation and joint damage that occurs in OA? The proinflammatory and catabolic response of synthetic calcium phosphate and pyrophosphate crystals and crystals extracted from human osteoarthritic knee cartilage has been investigated. The crystal forms eliciting a response have been characterised allowing a comparison of the biological effects of synthetic and native calcium crystals on human osteoarthritic chondrocytes and synoviocytes to be carried out. METHODS: Calcium phosphate and pyrophosphate crystals were synthesised in vitro and their crystal forms characterised by X-ray powder diffraction (XRPD). The inorganic crystalline material present in human osteoarthritic cartilage was extracted and its structural composition elucidated by XRPD. These crystals were applied to human primary osteoarthritic chondrocytes and synoviocytes and the production of proinflammatory and catabolic mediators measured. RESULTS: The crystals extracted from human osteoarthritic knee cartilage were identified as consisting of a mixture of monoclinic and triclinic calcium pyrophosphate dihydrate (m-CPPD and t-CPPD). These crystals elicited an inflammatory and catabolic response in human primary osteoarthritic chondrocytes and synoviocytes as measured by an increase in nitric oxide (NO), matrix metalloproteinase 13 (MMP-13) and prostaglandin E2 (PGE(2)) production. NO, MMP-13 and PGE(2) production was also increased when the synthetic calcium hydrogen phosphate dihydrate (DCPD) and calcium pyrophosphate hydrates were applied to the cells. CONCLUSIONS: Crystals extracted from human osteoarthritic knee cartilage induce the production of proinflammatory and catabolic mediators (NO, MMP-13 and PGE(2)) in human primary chondrocytes and synoviocytes. Synthetic calcium phosphate and pyrophosphate crystals elicit a similar response in those cells. Our findings suggest that these crystals could contribute to cartilage degradation and synovitis in OA.

17q21.31 microdeletion syndrome: further expanding the clinical phenotype.

Microdeletions of the 17q21.31 region are associated with hypotonia, oromotor dyspraxia, an apparently characteristic face, moderate learning disability and have an estimated prevalence of approximately 1 in 16,000. Here we report 3 individuals who extend further the phenotypic spectrum observed with microdeletions of the 17q21.31 region. They all have learning disability, hypotonia, and craniofacial dysmorphism in keeping with previous reported cases. One case has iris-choroid coloboma and partial situs inversus, 2 features that are newly recorded phenotype abnormalities. These deletions were detected from a cohort of 600 individuals with learning disability and congenital anomalies, reflecting that 17q21.31 microdeletions are a common finding in such cases. FISH analysis demonstrated that each of the deletions occurred as de novo events. The deleted region in our cases encompasses the previously defined critical region for 17q21.31, and includes CRHR1 and MAPT, putative candidate genes for the 17q21.31 phenotype. The 17q21.31 microdeletion phenotype is perhaps more variable than previously described despite haploinsufficiency for the same genes in many cases.

The genome of the simian and human malaria parasite Plasmodium knowlesi.

Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

A second locus for Aicardi-Goutieres syndrome at chromosome 13q14-21.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon alpha metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). METHODS: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. RESULTS: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. CONCLUSIONS: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.

Comparative study of the efficacy of eprinomectin versus ivermectin, and field efficacy of eprinomectin only, for the treatment of chorioptic mange in alpacas.

The efficacy of eprinomectin versus ivermectin (Study 1: a single-centre, randomised, treatment-controlled, blinded field trial), and the field efficacy of eprinomectin (Study 2: a single-centre, open, un-controlled field trial) for the treatment of chorioptic infestation in naturally infested alpacas were assessed in two studies. Thirty alpacas, all positive for Chorioptes sp. mite, were randomly allocated to two treatment groups in Study 1. Group A received a single topical administration of a 0.5% formulation of eprinomectin at the dose rate of 500mug/kg. Group B received three subcutaneous administrations at 14 days interval of a 1% formulation of ivermectin at the dose rate of 400mug/kg. Response to treatment was assessed by periodic mite count, and skin lesions scored. In Study 2, one group of 19 alpacas received four administrations at weekly interval of topical eprinomectin at the dose rate of 500mug/kg, and response to treatment was monitored by mite counts. No localised or systemic side effects were observed in either trial. There was a statistically significant decrease in mite counts on day 7 (P<0.001) within treatment Groups A and B of Study 1, but mite counts increased again on day 14 and remained high for the duration of the trial in both treatment groups. On day 14 of Study 2, there was a statistically significant reduction in mite counts (P<0.008) and the mite counts remained very low throughout the remainder of the study. The eprinomectin protocol employed in Study 2, consisting of four weekly topical administrations at the dose rate of 500mug/kg of body weight, proved highly effective at reducing the Chorioptes mite burden in alpacas.

Replication of cranial gunshot wounds.

It is possible to differentiate between entrance and exit wounds in bone by examining the specimen concerned. Because of the evidential usefulness of providing jurists or members of a jury with such specimens, we describe an easy and reliable method for replicating gunshot wounds in the human skull utilizing dental materials and methods.

An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13.

A new variant of congenital exfoliative ichthyosis in two related Bedouin families is reported. The ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the palms and soles. The prominent well-demarcated areas of denuded skin in moist and traumatized regions resembled the 'mauserung' phenomenon of ichthyosis bullosa of Siemens (IBS). Unlike in IBS, epidermolysis is absent on histological examination. Electron microscopy revealed a prominent intercellular oedema and numerous aggregates of keratin filaments in basal keratinocytes. Abnormal keratin (K) 1 expression was seen in the affected epidermis; however, all other keratins, including K2e, had a distribution comparable to that seen in normal controls. A maximum two-point LOD score of 2.53 and multipoint LOD score of 3.76 were obtained for marker D12S390, suggesting linkage to the type II keratin cluster on chromosome 12q13. Sequencing of both the K1 gene, the promotor and the 3' calcium regulatory region did not reveal a mutation. K2e and K5 genes, as well as the genes harboured within the minimal region, such as retinoic acid receptor gamma, sterol O-acyltransferase 2, integrin beta7 and insulin-like growth factor binding protein-6, were also excluded. This combination of clinical, histological, ultrastructural and genetic features has not been previously reported in other congenital exfoliative ichthyoses. We therefore suggest that it represents a new form of exfoliative ichthyosis.

Analysis of differential gene expression supports a role for amyloid precursor protein and a protein kinase C substrate (MARCKS) in long-term memory.

Previous work has identified the intermediate and medial part of the hyperstriatum ventrale (IMHV) as a region of the chick brain storing information acquired through the learning process of imprinting. We have examined in this brain region changes in expression of candidate genes involved in memory. Chicks were exposed to a rotating red box and the strength of their preference for it, a measure of learning, determined. Brain samples were removed approximately 24 h after training. Candidate genes whose expressions were different in IMHV samples derived from strongly imprinted chicks relative to those from chicks showing little or no learning were identified using subtractive hybridization. The translation products of two candidate genes were investigated further in samples from the left and right IMHV and from two other brain regions not previously implicated in imprinting, the left and right posterior neostriatum. One of the proteins was the amyloid precursor protein (APP), the other was myristoylated alanine rich C kinase substrate (MARCKS). In the left IMHV the levels of the two proteins increased with the strength of learning. The effects in the right IMHV were not significantly different from those in the left. There were no effects of learning in the posterior neostriatum. This is the first study to relate changes in the amounts of MARCKS and APP proteins to the strength of learning in a brain region known to be a memory store and demonstrates that the systematic identification of protein molecules involved in memory formation is possible.

Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism.

Aicardi-Goutiéres syndrome (AGS) is an early onset, progressive encephalopathy characterised by calcification of the basal ganglia, white matter abnormalities, and a chronic cerebrospinal fluid (CSF) lymphocytosis. Cree encephalitis shows phenotypic overlap with AGS although the conditions have been considered distinct because of immunological abnormalities observed in Cree encephalitis. We report that levels of interferon alpha (IFN-alpha), a marker of AGS, are raised in Cree encephalitis. Moreover, linkage analysis indicates that the disorders are allelic and refines the AGS1 locus to a 3.47 cM critical interval. Our data show that a CSF lymphocytosis is not necessary for the diagnosis of AGS and strongly suggest that AGS and pseudo-TORCH syndrome are the same disorder. Recognition of immunological dysfunction as part of the AGS phenotype provides further evidence of a primary pathogenic role for abnormal IFN-alpha production in AGS.

The sodium channel beta-subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart.

1. Cardiac sodium channels are composed of a pore-forming alpha-subunit, SCN5a, and one or more auxiliary beta-subunits. The aim of this study was to investigate the role of the recently discovered member of the beta-subunit family, SCN3b, in the heart. 2. Northern blot and Western blot studies show that SCN3b is highly expressed in the ventricles and Purkinje fibres but not in atrial tissue. This is in contrast to the uniform expression of SCN1b throughout the heart. 3. Co-expression of SCN3b with the cardiac-specific alpha-subunit SCN5a in Xenopus oocytes resulted in a threefold increase in the level of functional sodium channel expression, similar to that observed when SCN1b was co-expressed with SCN5a. These results suggest that both SCN1b and SCN3b improve the efficiency with which the mature channel is targeted to the plasma membrane. 4. When measured in cell-attached oocyte macropatches, SCN3b caused a significant depolarising shift in the half-voltage of steady-state inactivation compared to SCN5a alone or SCN5a + SCN1b. The half-voltage of steady-state activation was not significantly different between SCN5a alone and SCN5a + SCN3b or SCN5a + SCN1b. 5. The rates of inactivation for SCN5a co-expressed with either subunit were not significantly different from that for SCN5a alone. However, recovery from inactivation at -90 mV was significantly faster for SCN5a + SCN1b compared to SCN5a + SCN3b, and both were significantly faster than SCN5a alone. 6. Thus, SCN1b and SCN3b have distinctive effects on the kinetics of activation and inactivation, which, in combination with the different patterns of expression of SCN3b and SCN1b, could have important consequences for the integrated electrical activity of the intact heart.

Amphiphysin is necessary for organization of the excitation-contraction coupling machinery of muscles, but not for synaptic vesicle endocytosis in Drosophila.

Amphiphysins 1 and 2 are enriched in the mammalian brain and are proposed to recruit dynamin to sites of endocytosis. Shorter amphiphysin 2 splice variants are also found ubiquitously, with an enrichment in skeletal muscle. At the Drosophila larval neuromuscular junction, amphiphysin is localized postsynaptically and amphiphysin mutants have no major defects in neurotransmission; they are also viable, but flightless. Like mammalian amphiphysin 2 in muscles, Drosophila amphiphysin does not bind clathrin, but can tubulate lipids and is localized on T-tubules. Amphiphysin mutants have a novel phenotype, a severely disorganized T-tubule/sarcoplasmic reticulum system. We therefore propose that muscle amphiphysin is not involved in clathrin-mediated endocytosis, but in the structural organization of the membrane-bound compartments of the excitation-contraction coupling machinery of muscles.

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease.

We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.

Associations between employment and financial and parental stress in low-income single black mothers.

Using a sample of 188 low-income single black mothers (93 employed and 95 nonemployed), this study investigated financial strain, maternal depressive affect, and parenting stress among former welfare recipients who are now working, and current welfare recipients who are not employed. The findings suggested that being employed did not reduce financial strain, as the two groups reported similar levels of strain. However, regression analyses indicated that not being employed was associated with reporting higher levels of stress. Parenting stress was also associated with attaining less education, having boys, reporting more financial strain and depressive affect. Correlates of maternal depressive affect were mother's education and financial strain. Interaction effects were found for employment by financial strain, indicating that higher levels of depressive affect were related to more financial strain among nonemployed mothers. The findings suggest that although employment is associated with better mental health for poor mothers, entry into the workforce is associated with stronger links between financial strain, parenting stress and depressive affect for mothers leaving welfare.