Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines.

AIMS: To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with &supl;³N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m² at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m² (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (-0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = -0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = -0.31, P = 0.250). CONCLUSIONS: Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.

Application of a roughness-length representation to parameterize energy loss in 3-D numerical simulations of large rivers

Recent technological advances in remote sensing have enabled investigation of the morphodynamics and hydrodynamics of large rivers. However, measuring topography and flow in these very large rivers is time consuming and thus often constrains the spatial resolution and reach-length scales that can be monitored. Similar constraints exist for computational fluid dynamics (CFD) studies of large rivers, requiring maximization of mesh-or grid-cell dimensions and implying a reduction in the representation of bedform-roughness elements that are of the order of a model grid cell or less, even if they are represented in available topographic data. These ``subgrid'' elements must be parameterized, and this paper applies and considers the impact of roughness-length treatments that include the effect of bed roughness due to ``unmeasured'' topography. CFD predictions were found to be sensitive to the roughness-length specification. Model optimization was based on acoustic Doppler current profiler measurements and estimates of the water surface slope for a variety of roughness lengths. This proved difficult as the metrics used to assess optimal model performance diverged due to the effects of large bedforms that are not well parameterized in roughness-length treatments. However, the general spatial flow patterns are effectively predicted by the model. Changes in roughness length were shown to have a major impact upon flow routing at the channel scale. The results also indicate an absence of secondary flow circulation cells in the reached studied, and suggest simpler two-dimensional models may have great utility in the investigation of flow within large rivers. Citation: Sandbach, S. D. et al. (2012), Application of a roughness-length representation to parameterize energy loss in 3-D numerical simulations of large rivers, Water Resour. Res., 48, W12501, doi: 10.1029/2011WR011284.

Gastric bypass in morbid obese patients is associated with reduction in adipose tissue inflammation via N-oleoylethanolamide (OEA)-mediated pathways.

Paradoxically, morbid obesity was suggested to protect from cardiovascular co-morbidities as compared to overweight/obese patients. We hypothesise that this paradox could be inferred to modulation of the "endocannabinoid" system on systemic and subcutaneous adipose tissue (SAT) inflammation. We designed a translational project including clinical and in vitro studies at Geneva University Hospital. Morbid obese subjects (n=11) were submitted to gastric bypass surgery (GBS) and followed up for one year (post-GBS). Insulin resistance and circulating and SAT levels of endocannabinoids, adipocytokines and CC chemokines were assessed pre- and post-GBS and compared to a control group of normal and overweight subjects (CTL) (n=20). In vitro cultures with 3T3-L1 adipocytes were used to validate findings from clinical results. Morbid obese subjects had baseline lower insulin sensitivity and higher hs-CRP, leptin, CCL5 and anandamide (AEA) levels as compared to CTL. GBS induced a massive weight and fat mass loss, improved insulin sensitivity and lipid profile, decreased C-reactive protein, leptin, and CCL2 levels. In SAT, increased expression of resistin, CCL2, CCL5 and tumour necrosis factor and reduced MGLL were shown in morbid obese patients pre-GBS when compared to CTL. GBS increased all endocannabinoids and reduced adipocytokines and CC chemokines. In morbid obese SAT, inverse correlations independent of body mass index were shown between palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) levels and inflammatory molecules. In vitro, OEA inhibited CCL2 secretion from adipocytes via ERK1/2 activation. In conclusion, GBS was associated with relevant clinical, metabolic and inflammatory improvements, increasing endocannabinoid levels in SAT. OEA directly reduced CCL2 secretion via ERK1/2 activation in adipocytes.

ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm.

The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems.

Energy expenditure in obese women before and during weight loss, after refeeding, and in the weight-relapse period.

In 10 moderately obese women, 24-h energy expenditure (24EE) was measured in a respiration chamber under four conditions: 1) before weight loss (body weight = 77.9 kg), 2) during weight loss (63.9 kg), 3) after realimentation (62.5 kg), and 4) 6-15 mo after the study diet with ad libitum diet (67.7 kg). The 14 +/- 8 kg (mean +/- SD) weight loss produced a decrease in 24EE of 1498 +/- 1138 kJ/d (P < 0.001), ie, a decrease of weight of 107 kJ.kg body wt-1.d-1. The subsequent 24EE (conditions 3 and 4) remained lower than the value before weight loss. A significant correlation was found between changes before and after weight regain in basal respiratory quotient (RQ) and the spontaneous rate of body-weight gain after cessation of the period of low energy intake (r = 0.89, P < 0.01); this suggests that the value of the postabsorptive RQ may be a predictor of relapse of weight gain. After discontinuation of the low energy diet, an elevated postabsorptive RQ shows that the endogenous lipid oxidation is low, a condition favoring weight gain.

Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytosolic platelet calcium.

Although platelet cytosolic calcium has been shown to decrease during pharmacological treatment of hypertension, there is no evidence that cytosolic calcium also falls during a nonpharmacological reduction in blood pressure. To provide such evidence, we examined prospectively the relation between platelet cytosolic calcium and ambulatory blood pressure during weight reduction in moderately overweight (body mass index [BMI] greater than 25), mildly hypertensive individuals. The experimental group (responders: BMI reduction greater than 5%) consisted of 19 patients who lost 8.5 +/- 2.9 kg (mean +/- SD, p less than 0.05) during a 10-week hypocaloric diet, whereas the control group (nonresponders: BMI reduction less than 5%) consisted of 12 patients who showed no relevant change in body weight (-2.0 +/- 1.3 kg) during the same period of time. The moderate weight loss of the responders decreased blood pressure by 14/5 mm Hg (p less than 0.05), as measured by ambulatory monitoring, which renders a placebo effect unlikely. This nonpharmacological reduction in blood pressure was accompanied by a proportional 11% decrease (p less than 0.05) in platelet cytosolic calcium and also by significant (p less than 0.05) decreases in plasma catecholamines and serum cholesterol. These findings establish the concept of a nonpharmacological reduction in free cytosolic platelet calcium in humans and add further evidence suggesting a link between intracellular calcium homeostasis and blood pressure regulation.

Reduction of Helicobacter infection in IL-10-/- mice is dependent on CD4+ T cells but not on mast cells.

BACKGROUND: In contrast to wild type, interleukin-10-deficient (IL-10(-/-)) mice are able to clear Helicobacter infection. In this study, we investigated the immune response of IL-10(-/-) mice leading to the reduction of Helicobacter infection. MATERIALS AND METHODS: We characterized the immune responses of Helicobacter felis-infected IL-10(-/-) mice by studying the systemic antibody and cellular responses toward Helicobacter. We investigated the role of CD4(+) T cells in the Helicobacter clearance by injecting H. felis-infected IL-10(-/-) mice with anti-CD4 depleting antibodies. To examine the role of mast cells in Helicobacter clearance, we constructed and infected mast cells and IL-10 double-deficient mice. RESULTS: Reduction of Helicobacter infection in IL-10(-/-) mice is associated with strong humoral (fivefold higher serum antiurease antibody titers were measured in IL-10(-/-) in comparison to wild-type mice, p < .008) and cellular (urease-stimulated splenic CD4(+) T cells isolated from infected IL-10(-/-) mice produce 150-fold more interferon-gamma in comparison to wild-type counterparts, p < .008) immune responses directed toward Helicobacter. Depletion of CD4(+) cells from Helicobacter-infected IL-10(-/-) mice lead to the loss of bacterial clearance (rapid urease tests are threefold higher in CD4(+) depleted IL-10(-/-) in comparison to nondepleted IL-10(-/-) mice, p < .02). Mast cell IL-10(-/-) double-deficient mice clear H. felis infection, indicating that mast cells are unnecessary for the bacterial eradication in IL-10(-/-) mice. CONCLUSION: Taken together, these results suggest that CD4(+) cells are required for Helicobacter clearance in IL-10(-/-) mice. This reduction of Helicobacter infection is, however, not dependent on the mast cell population.

Postprandial thermogenesis in obese children before and after weight reduction.

The thermic effect of a meal (TEM) was measured in a group of 10 prepubertal obese children before (OB) and after (OA) weight reduction, and in a group of 10 age-matched control children (C) of normal body weight. Following a hypocaloric balanced diet for 6 +/- 1 months, the obese children lost 5.2 +/- 1.3 kg i.e. 11% of their initial body weight. The thermic response to the mixed liquid meal - fed at an energy level corresponding to 30% of the 24 h premeal resting metabolic rate - was found to be significantly lower in OB than in C children (61 +/- 25 kJ.3h-1 vs 79 +/- 21 kJ.3h-1, P less than 0.05), despite their higher test meal energy. After slimming, the TEM of obese children increased towards the controls' values (73 +/- 30 kJ.3h-1). These results support the hypothesis of the existence of a moderate thermogenic defect in some obese children which represents a consequence rather than an aetiological factor of obesity.

Effect of weight loss on resting energy expenditure in obese prepubertal children.

To assess the effect of weight loss on resting metabolic rate (RMR), the energy expenditure of eight obese prepubertal children (age 9 +/- 1 years; weight 48.7 +/- 9.1 kg; BMI 25.3 +/- 3.9) and of 14 age-matched children of normal body weight (age 9 +/- 1 years; weight 28.8 +/- 5.6 kg; BMI 16.5 +/- 1.7) was measured by indirect calorimetry. The obese children were reinvestigated after a mean weight loss of 5.4 +/- 1.2 kg induced by a six-months mixed hypocaloric diet. Before slimming, the obese group showed a higher daily energy intake than the control group (10.40 +/- 3.45 MJ/day vs 7.97 +/- 2.02 MJ/day respectively; P less than 0.05) but a similar value was observed per unit fat-free mass (FFM) (0.315 +/- 0.032 MJ/kgFFM/day vs 0.329 +/- 0.041 MJ/kgFFM/day respectively). The average RMR of the obese children was greater than that of the control group (5217 +/- 531 kJ/day vs 4477 +/- 506 kJ/day) but similar after adjusting for FFM (4728 +/- 3102 kJ/day vs 4899 +/- 3102 kJ/day). Weight loss resulted in a reduction in RMR (5217 +/- 531 kJ/day vs 4874 +/- 820 kJ/day), each kg of weight loss being accompanied by a decrease of RMR of 64 kJ (15.3 kcal) per day. The changes in RMR induced by weight loss paralleled the changes in FFM. No difference was found in average RQ in obese children vs controls (0.85 +/- 0.03 vs 0.87 +/- 0.03 respectively) and in the obese children before and after weight loss (0.87 +/- 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in range of cervical motion on serial long-term follow-up in patients undergoing oblique corpectomy for cervical spondylotic myelopathy.

PURPOSE: To determine whether motion preservation following oblique cervical corpectomy (OCC) for cervical spondylotic myelopathy (CSM) persists with serial follow-up. METHODS: We included 28 patients with preoperative and at least two serial follow-up neutral and dynamic cervical spine radiographs who underwent OCC for CSM. Patients with an ossified posterior longitudinal ligament (OPLL) were excluded. Changes in sagittal curvature, segmental and whole spine range of motion (ROM) were measured. Nathan's system graded anterior osteophyte formation. Neurological function was measured by Nurick's grade and modified Japanese Orthopedic Association (JOA) scores. RESULTS: The majority (23 patients) had a single or 2-level corpectomy. The average duration of follow-up was 45 months. The Nurick's grade and the JOA scores showed statistically significant improvements after surgery (p < 0.001). 17% of patients with preoperative lordotic spines had a loss of lordosis at last follow-up, but with no clinical worsening. 77% of the whole spine ROM and 62% of segmental ROM was preserved at last follow-up. The whole spine and segmental ROM decreased by 11.2° and 10.9°, respectively (p ≤ 0.001). Patients with a greater range of segmental movement preoperatively had a statistically greater range of movement at follow-up. The analysis of serial radiographs indicated that the range of movement of the whole spine and the range of movement at the segmental spine levels significantly reduced during the follow-up period. Nathan's grade showed increase in osteophytosis in more than two-thirds of the patients (p ≤ 0.01). The whole spine range of movement at follow-up significantly correlated with Nathan's grade. CONCLUSIONS: Although the OCC preserves segmental and whole spine ROM, serial measurements show a progressive decrease in ROM albeit without clinical worsening. The reduction in this ROM is probably related to degenerative ossification of spinal ligaments.

Sweet taste loss in myasthenia gravis: more than a coincidence?

Sweet dysgeusia, a rare taste disorder, may be encountered in severe anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG). A 42 year-old man reported progressive loss of sweet taste evolving for almost 10 weeks, revealing an AChRAb-positive MG with thymoma. Improvement of sweet perception paralleled reduction of the MG composite score during the 15 months follow up period, with immunosuppressive and surgical treatments. We suggest that sweet dysgeusia is a non-motor manifestation of MG that may result from a thymoma-dependent autoimmune mechanism targeting gustducin-positive G-protein-coupled taste receptor cells, in line with recent data from MRL/MpJ-Fas lpr/ (MRL/lpr) transgenic mice with autoimmune disease.

Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease.

The mechanisms underlying preferential atrophy of the striatum in Huntington's disease (HD) are unknown. One hypothesis is that a set of gene products preferentially expressed in the striatum could determine the particular vulnerability of this brain region to mutant huntingtin (mHtt). Here, we studied the striatal protein µ-crystallin (Crym). Crym is the NADPH-dependent p38 cytosolic T3-binding protein (p38CTBP), a key regulator of thyroid hormone (TH) T3 (3,5,3'-triiodo-l-thyronine) transportation. It has been also recently identified as the enzyme that reduces the sulfur-containing cyclic ketimines, which are potential neurotransmitters. Here, we confirm the preferential expression of the Crym protein in the rodent and macaque striatum. Crym expression was found to be higher in the macaque caudate than in the putamen. Expression of Crym was reduced in the BACHD and Knock-in 140CAG mouse models of HD before onset of striatal atrophy. We show that overexpression of Crym in striatal medium-size spiny neurons using a lentiviral-based strategy in mice is neuroprotective against the neurotoxicity of an N-terminal fragment of mHtt in vivo. Thus, reduction of Crym expression in HD could render striatal neurons more susceptible to mHtt suggesting that Crym may be a key determinant of the vulnerability of the striatum. In addition our work points to Crym as a potential molecular link between striatal degeneration and the THs deregulation reported in HD patients.

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.

New approach for weight reduction by a combination of diet, light resistance exercise and the timing of ingesting a protein supplement.

We have reported that ingesting a meal immediately after exercise increased skeletal muscle accretion and less adipose tissue accumulation in rats employed in a 10 week resistance exercise program. We hypothesized that a possible increase in the resting metabolic rate (RMR) as a result of the larger skeletal muscle mass might be responsible for the less adipose deposition. Therefore, the effect of the timing of a protein supplement after resistance exercise on body composition and the RMR was investigated in 17 slightly overweight men. The subjects participated in a 12-week weight reduction program consisting of mild energy restriction (17% energy intake reduction) and a light resistance exercise using a pair of dumbbells (3-5 kg). The subjects were assigned to two groups. Group S ingested a protein supplement (10 g protein, 7 g carbohydrate, 3.3 g fat and one-third of recommended daily allowance (RDA) of vitamins and minerals) immediately after exercise. Group C did not ingest the supplement. Daily intake of both energy and protein was equal between the two groups and the protein intake met the RDA. After 12 weeks, the bodyweight, skinfold thickness, girth of waist and hip and percentage bodyfat significantly decreased in the both groups, however, no significant differences were observed between the groups. The fat-free mass significantly decreased in C, whereas its decrease in S was not significant. The RMR and post-meal total energy output significantly increased in S, while these variables did not change in C. In addition, the urinary nitrogen excretion tended to increase in C but not in S. These results suggest that the RMR increase observed in S might be associated with an increase in body protein synthesis.