Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.

Objectives: Dehydration in older adults contributes to increased morbidity and mortality during hospitalization. As such, early diagnosis of dehydration may improve patient outcome and reduce the burden on healthcare. This prospective study investigated the diagnostic accuracy of routinely used physical signs, and non-invasive markers of hydration in urine and saliva. Design: Prospective diagnostic accuracy study. Setting: Hospital acute medical care unit and emergency department. Participants: One hundred and thirty older adults (59 males, 71 females, mean (SD) age = 78 (9) y). Measurements: Participants with any primary diagnosis underwent a hydration assessment within 30min of admittance to hospital. Hydration assessment comprised seven physical signs of dehydration (tachycardia (>100bpm), low systolic blood pressure (<100mmHg), dry mucous membrane, dry axilla, poor skin turgor, sunken eyes, and long capillary refill time (>2s)), urine color, urine specific gravity (USG), saliva flow rate (SFR) and saliva osmolality. Plasma osmolality (Posm) and the blood urea nitrogen to creatinine ratio (BUN:Cr) were assessed as reference standards of hydration, with 21% of participants classified with water-loss dehydration (Posm >295mOsm/kg), 19% classified with water-and-solute-loss dehydration (BUN:Cr >20) and 60% classified as euhydrated. Results: All physical signs showed poor sensitivity (0-44%) for detecting either form of dehydration, with only low systolic blood pressure demonstrating potential utility for aiding the diagnosis of water-and-solute-loss dehydration (diagnostic OR = 14.7). Neither urine color, USG, nor SFR could discriminate hydration status (area under the receiver operating characteristic curve, AUCROC = 0.49-0.57, P>0.05). In contrast, saliva osmolality demonstrated moderate diagnostic accuracy (AUCROC = 0.76, P<0.001) to distinguish both dehydration types (70% sensitivity, 68% specificity, OR =5.0 (95%CI 1.7-15.1) for water-loss dehydration, and 78% sensitivity, 72% specificity, OR =8.9 (95%CI 2.5-30.7) for water-and-solute-loss dehydration). Conclusions: With the exception of low systolic blood pressure, which could aid in the specific diagnosis of water-and-solute-loss dehydration, physical signs and urine markers show little utility to determine if an elderly patient is dehydrated. Saliva osmolality demonstrated superior diagnostic accuracy compared with physical signs and urine markers, and may have utility for the assessment of both water-loss and water-andsolute-loss dehydration in older individuals. It is particularly noteworthy that saliva osmolality was able to detect water-and-solute-loss dehydration, for which a measurement of plasma osmolality would have no diagnostic utility. Thankyou for allowing us to resubmit the above manuscript to your journal. We have responded to the reviewers comments (see below), with changes in the manuscript highlighted in red text. We hope you feel that these changes have improved the manuscript.Please don't hesitate to contact me if you require...

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor β (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13 C/ 31 P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor α sensitivity to elevated thyroid hormone levels.

BackgroundThe study aimed to i) assess nutritional knowledge in female athletes susceptible to the Female Athlete Triad (FAT) syndrome and to compare with controls; and ii) to compare nutritional knowledge of those who were classified as being 'at risk' for developing FAT syndrome and those who are 'not at risk'.MethodsIn this study, participants completed General Nutritional Knowledge Questionnaire (GNKQ), the Eating Attitude Test (EAT-26) and survey measures of training/physical activity, menstrual and skeletal injury history. The sample consisted of 48 regional endurance athletes, 11 trampoline gymnasts and 32 untrained controls. Based on proxy measures for the FAT components, participants were classified being 'at risk' or 'not at risk' and nutrition knowledge scores were compared for the two groups. Formal education related to nutrition was considered.ResultsA considerably higher percentage of athletes were classified 'at risk' of menstrual dysfunction than controls (28.8% and 9.4%, respectively) and a higher percentage scored at or above the cutoff value of 20 on the EAT-26 test among athletes than controls (10.2% and 3.1%, respectively). 8.5% of athletes were classified 'at risk' for bone mineral density in contrast to none from the control group. Nutrition knowledge and eating attitude appeared to be independent for both athletes and controls. GNKQ scores of athletes were higher than controls but the differences between the knowledge of 'at risk' and 'not at risk' athletes and controls were inconsequential. Formal education in nutrition or closely related subjects does not have an influence on nutrition knowledge or on being classified as 'at risk' or 'not at risk'.ConclusionThe lack of difference in nutrition knowledge between 'at risk' and 'not at risk' athletes suggests that lack of information is not accountable for restricted eating associated with the Female Athlete Triad.

Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.

These are the first published data to show that individuals classified as DE have higher Posm, indicating suboptimal hydration, compared with non-DE. These findings indicate that whole-body hydration is an important consideration in DE.

Background/objectives:The objective of this study was to develop approaches to expressing resting energy expenditure (REE) and lean body mass (LM) phenotypes of metabolic disorders in terms of Z-scores relative to their predicted healthy values.Subjects/methods:Body composition and REE were measured in 135 healthy participants. Prediction equations for LM and REE were obtained from linear regression and the range of normality by the standard deviation of residuals. Application is demonstrated in patients from three metabolic disorder groups (lipodystrophy, n=7; thyrotoxicosis, n=16; and resistance to thyroid hormone (RTH), n=46) in which altered REE and/or LM were characterised by departure from the predicted healthy values, expressed as a Z-score.Results:REE (kJ/min)=−0.010 × age (years)+0.016 × FM (kg)+0.054 × fat-free mass (kg)+1.736 (R2=0.732, RSD=0.36 kJ/min).LM (kg)=5.30 × bone mineral content (kg)+10.66 × height2 (m)+6.40 (male).LM (kg)=0.20 × fat (kg)+14.08 × height2 (m)−2.93 (female).(male R2=0.55, RSD=3.90 kg; female R2=0.59, RSD=3.85 kg).We found average Z-scores for REE and LM of 1.77 kJ/min and −0.17 kg in the RTH group, 5.82 kJ/min and −1.23 kg in the thyrotoxic group and 2.97 kJ/min and 4.20 kg in the LD group.Conclusion:This approach enables comparison of data from individuals with metabolic disorders with those of healthy individuals, describing their departure from the healthy mean by a Z-score.