Swelling of Thermo-Responsive Gels in Aqueous Solutions of Salts: A Predictive Model.

The equilibrium degree of swelling of thermo-responsive (TR) gels is strongly affected by the presence of ions in an aqueous solution. This phenomenon plays an important role in (i) the synthesis of multi-stimuli-responsive gels for soft robotics, where extraordinary strength and toughness are reached by soaking of a gel in solutions of multivalent ions, and (ii) the preparation of hybrid gels with interpenetrating networks formed by covalently cross-linked synthetic chains and ionically cross-linked biopolymer chains. A model is developed for equilibrium swelling of a TR gel in aqueous solutions of salts at various temperatures T below and above the critical temperature at which collapse of the gel occurs. An advantage of the model is that it involves a a small (compared with conventional relations) number of material constants and allows the critical temperature to be determined explicitly. Its ability (i) to describe equilibrium swelling diagrams on poly(N-isopropylacrylamide) gels in aqueous solutions of mono- and multivalent salts and (ii) to predict the influence of volume fraction of salt on the critical temperature is confirmed by comparison of observations with results of numerical simulation.

Fungal quinones: diversity, producers, and applications of quinones from Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium.

Quinones represent an important group of highly structurally diverse, mainly polyketide-derived secondary metabolites widely distributed among filamentous fungi. Many quinones have been reported to have important biological functions such as inhibition of bacteria or repression of the immune response in insects. Other quinones, such as ubiquinones are known to be essential molecules in cellular respiration, and many quinones are known to protect their producing organisms from exposure to sunlight. Most recently, quinones have also attracted a lot of industrial interest since their electron-donating and -accepting properties make them good candidates as electrolytes in redox flow batteries, like their often highly conjugated double bond systems make them attractive as pigments. On an industrial level, quinones are mainly synthesized from raw components in coal tar. However, the possibility of producing quinones by fungal cultivation has great prospects since fungi can often be grown in industrially scaled bioreactors, producing valuable metabolites on cheap substrates. In order to give a better overview of the secondary metabolite quinones produced by and shared between various fungi, mainly belonging to the genera Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium, this review categorizes quinones into families such as emodins, fumigatins, sorbicillinoids, yanuthones, and xanthomegnins, depending on structural similarities and information about the biosynthetic pathway from which they are derived, whenever applicable. The production of these quinone families is compared between the different genera, based on recently revised taxonomy. KEY POINTS: • Quinones represent an important group of secondary metabolites widely distributed in important fungal genera such as Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium. • Quinones are of industrial interest and can be used in pharmacology, as colorants and pigments, and as electrolytes in redox flow batteries. • Quinones are grouped into families and compared between genera according to the revised taxonomy.

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected.

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes.

AIMS: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. METHODS: A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). RESULTS: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. CONCLUSIONS: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia.

What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).

BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion. PATIENTS AND METHODS: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions. RESULTS: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays. CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).

Twice-daily insulin degludec/insulin aspart provides superior fasting plasma glucose control and a reduced rate of hypoglycaemia compared with biphasic insulin aspart 30 in insulin-naïve adults with Type 2 diabetes.

AIM: To evaluate the efficacy and safety of twice-daily insulin degludec/insulin aspart vs. twice-daily biphasic insulin aspart 30 in people with Type 2 diabetes mellitus who were naïve to insulin. METHODS: In this 26-week, multinational, open-label, controlled, two-arm, parallel-group, treat-to-target trial, participants [mean (± sd) age 58.9 (±8.9) years, duration of diabetes 9.5 (±5.9) years, HbA1c 68 (±8.7) mmol/mol or 8.4 (±0.8)% and BMI 31.2 (±4.2) kg/m(2) ) were randomized (1:1) to insulin degludec/insulin aspart (n = 197) or biphasic insulin aspart 30 (n = 197), administered with breakfast and the main evening meal, titrated to a self-monitored plasma glucose target > 3.9 and ≤ 5.0 mmol/l. RESULTS: The mean HbA1c was reduced to 49 mmol/mol (6.6%) with insulin degludec/insulin aspart and 48 mmol/mol (6.5%) with biphasic insulin aspart 30. Insulin degludec/insulin aspart achieved the prespecified non-inferiority margin (estimated treatment difference 0.02%; 95% CI -0.12, 0.17). Insulin degludec/insulin aspart was superior in lowering fasting plasma glucose (estimated treatment difference -1.00 mmol/l; 95% CI -1.4, -0.6; P < 0.001) and reducing overall and nocturnal confirmed hypoglycaemia at a similar overall insulin dose compared with biphasic insulin aspart 30. Similar proportions of participants in each arm experienced severe hypoglycaemia. Adverse events were equally distributed. CONCLUSIONS: Consistent with previous findings, insulin degludec/insulin aspart twice daily effectively improved long-term glycaemic control, with superior reductions in FPG, and significantly less overall and nocturnal confirmed hypoglycaemia compared with biphasic insulin aspart 30 in people with Type 2 diabetes who were insulin-naïve.

Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial.

AIMS: To investigate the effects of a single dose of 1.2 mg liraglutide, a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist, on key renal variables in patients with type 2 diabetes. METHODS: The study was a placebo-controlled, double-blind, crossover trial in 11 male patients with type 2 diabetes. Measurements included (51) Cr-EDTA plasma clearance estimated glomerular filtration rate (GFR) and MRI-based renal blood flow (RBF), tissue perfusion and oxygenation. RESULTS: Liraglutide had no effect on GFR [95% confidence interval (CI) -6.8 to 3.6 ml/min/1.73 m(2) ] or on RBF (95% CI -39 to 30 ml/min) and did not change local renal blood perfusion or oxygenation. The fractional excretion of lithium increased by 14% (p = 0.01) and sodium clearance tended to increase (p = 0.06). Liraglutide increased diastolic and systolic blood pressure (3 and 6 mm Hg) and heart rate (2 beats per min; all p < 0.05). Angiotensin II (ANG II) concentration decreased by 21% (p = 0.02), but there were no effects on other renin-angiotensin system components, atrial natriuretic peptides (ANPs), methanephrines or excretion of catecholamines. CONCLUSIONS: Short-term liraglutide treatment did not affect renal haemodynamics but decreased the proximal tubular sodium reabsorption. Blood pressure increased with short-term as opposed to long-term treatment. Catecholamine levels were unchanged and the results did not support a GLP-1-ANP axis. ANG II levels decreased, which may contribute to renal protection by GLP-1 receptor agonists.

Clinical use of the co-formulation of insulin degludec and insulin aspart.

AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Prescribing practices and clinical predictors of glucose-lowering therapy within the first year in people with newly diagnosed Type 2 diabetes.

AIM: To examine prescribing practices and predictors of glucose-lowering therapy within the first year following diagnosis of Type 2 diabetes mellitus in a clinical care setting. METHODS: We followed people enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort from outpatient hospital clinics and general practices throughout Denmark in 2010-2013. We used Poisson regression to compute age- and gender-adjusted risk ratios (RRs). RESULTS: Among 1158 new Type 2 diabetes mellitus patients, 302 (26%) did not receive glucose-lowering therapy within the first year, 723 (62%) received monotherapy [685 (95%) with metformin], and 133 (12%) received more than one drug. Predictors of receiving any vs. no therapy and combination vs. monotherapy were: age < 40 years [RR: 1.29 (95% CI: 1.16-1.44) and 3.60 (95% CI: 2.36-5.50)]; high Charlson Comorbidity Index [RRs: 1.20 (95% CI: 1.05-1.38) and 2.08 (95% CI: 1.16-3.72)]; central obesity [RRs: 1.23 (95% CI: 1.04-1.44) and 1.93 (95% CI: 0.76-4.94)]; fasting blood glucose of ≥ 7.5 mmol/l [RRs: 1.25 (95% CI: 1.10-1.42) and 1.94 (95% CI: 1.02-3.71)]; and HbA1c ≥ 59 mmol/mol (≥ 7.5%) [RR: 1.26 (95% CI: 1.20-1.32) and 2.86 (95% CI: 1.97-4.14)]. Weight gain ≥ 30 kg since age 20, lack of physical exercise and C-peptide of < 300 pmol/l also predicted therapy. CONCLUSIONS: Comorbidity, young age, central obesity and poor baseline glycaemic control are important predictors of therapy one year after Type 2 diabetes mellitus debut.

Modeling the effects of pH and ionic strength on swelling of polyelectrolyte gels.

A model is developed for the elastic response of a polyelectrolyte gel under unconstrained and constrained swelling in a water bath with an arbitrary pH, where a monovalent salt is dissolved. A gel is treated as a three-phase medium consisting of an equivalent polymer network, solvent (water), and solute (mobile ions). Transport of solvent and solute is thought of as their diffusion through the network accelerated by an electric field formed by mobile and fixed ions and accompanied by chemical reactions (self-ionization of water molecules, dissociation of functional groups attached to polymer chains, and formation of ion pairs between bound charges and mobile counter-ions). Constitutive equations are derived by means of the free energy imbalance inequality for an arbitrary three-dimensional deformation with finite strains. Adjustable parameters in the governing relations are found by fitting equilibrium swelling diagrams on several hydrogels. The effects of pH, ionic strength of solution, and constraints on equilibrium water uptake are studied numerically.

Arctic skate Amblyraja hyperborea preys on remarkably large glacial eelpouts Lycodes frigidus.

During scientific surveys on the continental slopes north-west of Spitsbergen and off north-east Greenland (c. 600 and 1000 m depths), two female Arctic skates Amblyraja hyperborea were caught while swallowing extraordinary large individuals of glacial eelpout Lycodes frigidus. The total length (LT) of the prey constituted 50 and 80% of the LT of the skates, which reveal that A. hyperborea are capable predators of fishes of surprisingly large relative size.

Variation in prescribing of lipid-lowering medication in primary care is associated with incidence of cardiovascular disease and all-cause mortality in people with screen-detected diabetes: findings from the ADDITION-Denmark trial.

AIMS: To examine variation between general practices in the prescription of lipid-lowering treatment to people with screen-detected Type 2 diabetes, and associations with practice and participant characteristics and risk of cardiovascular events and all-cause mortality. METHODS: Observational cohort analysis of data from 1533 people with screen-detected Type 2 diabetes aged 40-69 years from the ADDITION-Denmark study. One hundred and seventy-four general practices were cluster randomized to receive: (1) routine diabetes care according to national guidelines (623 individuals), or (2) intensive multifactorial target-driven management (910 individuals). Multivariable logistic regression was used to quantify the association between the proportion of individuals in each practice who redeemed prescriptions for lipid-lowering medication in the two years following diabetes diagnosis and a composite cardiovascular disease (CVD) outcome, adjusting for age, sex, prevalent chronic disease, baseline CVD risk factors, smoking and lipid-lowering medication, and follow-up time. RESULTS: The proportion of individuals treated with lipid-lowering medication varied widely between practices (0-100%). There were 118 CVD events over 9431 person-years of follow-up. For the whole trial cohort, the risk of CVD was significantly higher in practices in the lowest compared with the highest quartile for prescribing lipid-lowering medication [adjusted odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6-7.3]. Similar trends were found for all-cause mortality. CONCLUSIONS: More frequent prescription of lipid-lowering treatment was associated with a lower incidence of CVD and all-cause mortality. Improved understanding of factors underlying practice variation in prescribing may enable more frequent use of lipid-lowering treatment. The results highlight the benefits of intensive treatment of people with screen-detected diabetes (Clinical Trials Registry No; NCT 00237549).

Objective measurements of activity patterns in people with newly diagnosed Type 2 diabetes demonstrate a sedentary lifestyle.

AIMS: To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. METHODS: We analysed data from a study aimed at assessing carotid femoral pulse wave velocity in which a piezoelectric accelerometer was worn by 100 people with newly diagnosed Type 2 diabetes and by 100 age- and sex-matched control subjects. Differences in physical activity patterns were investigated. RESULTS: Compared with the control group, the people with Type 2 diabetes spent significantly more time engaged in sedentary or lower level activities during the day, with a mean (sd) time of 926 (44) vs 898 (70) min, P < 0.001). This difference remained significant after correction for differences in BMI between the two groups. CONCLUSIONS: Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

The efficacy and safety of long-term Norditropin® treatment in children with Prader-Willi syndrome.

Prader-Willi syndrome is a genetic disorder that is associated with short stature, partial growth hormone deficiency, small hands and feet, learning and behavioural problems, and hyperphagia leading to severe, often morbid, obesity. Growth hormone therapy is associated with an improvement in height and body composition. We evaluated the efficacy and safety of long-term growth hormone treatment in a retrospective observational multinational study of 41 prepubertal children (mean age 3.8±3.0 years) with genetically diagnosed Prader-Willi syndrome treated with growth hormone (0.03-0.06 mg/kg/day) for >12 months [mean duration 4.1 (range 0.9-9.5) years]. Height, weight, and body composition measurements were recorded at baseline and at 6 month intervals until last observation. Mean (SD) gain in height at 12 months was 0.9 (0.2) SD score (p<0.0001). At last observation (after approximately 6 years) mean gain in height was 1.3 (0.3) (p=0.0001) with 85% of children achieving height>- 2 SD score. Body composition improved during treatment with an estimated 9.1% increase in lean body mass and 9.1% decrease in fat mass at last observation (p=0.019). Scoliosis was reported in 3 patients at baseline and 8 patients at last observation. Sleep apnoea was recorded in 3 (7.3%) patients. There were no other severe adverse events reported. Long-term growth hormone treatment of prepubertal children with Prader-Willi syndrome was associated with significant improvements in height and body composition. Treatment was well tolerated. The development of scoliosis warrants monitoring by an orthopaedic specialist.

The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos.

Mutations in the human SRY-related gene, SOX9, located on chromosome 17, have recently been associated with the sex reversal and skeletal dysmorphology syndrome, campomelic dysplasia. In order to clarify the role of this gene in skeletal development, we have studied the expression of mouse Sox9 during embryogenesis. Sox9 is expressed predominantly in mesenchymal condensations throughout the embryo before and during the deposition of cartilage, consistent with a primary role in skeletal formation. Interspecific backcross mapping has localized mouse Sox9 to distal chromosome 11. The expression pattern and chromosomal location of Sox9 suggest that it may be the gene defective in the mouse skeletal mutant Tail-short, a potential animal model for campomelic dysplasia.

Lifetime Predictions for High-Density Polyethylene under Creep: Experiments and Modeling.

Observations are reported in uniaxial tensile tests with various strain rates, tensile relaxation tests with various strains, and tensile creep tests with various stresses on high-density polyethylene (HDPE) at room temperature. Constitutive equations are developed for the viscoelastoplastic response of semicrystalline polymers. The model involves seven material parameters. Four of them are found by fitting observations in relaxation tests, while the others are determined by matching experimental creep curves. The predictive ability of the model is confirmed by comparing observations in independent short- and medium-term creep tests (with the duration up to several days) with the results of numerical analysis. The governing relations are applied to evaluate the lifetime of HDPE under creep conditions. An advantage of the proposed approach is that it predicts the stress-time-to-failure diagrams with account for the creep endurance limit.

Postprandial VLDL-triacylglycerol secretion is not suppressed in obese type 2 diabetic men.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by insulin resistance and increased post-absorptive secretion of VLDL-triacylglycerol (VLDL-TAG). Whether postprandial suppression of endogenous VLDL-TAG secretion is abnormal--a finding that would link hyperlipidaemia and type 2 diabetes--remains unclear. METHODS: Eight type 2 diabetic men and eight healthy men were studied before and after a fat-free test meal (40% of resting energy expenditure). VLDL-TAG kinetics were assessed using a primed-constant infusion of ex vivo labelled [1-(14)C]triolein VLDL-TAG using non-steady-state calculations. RESULTS: Type 2 diabetic men had a higher basal VLDL-TAG secretion rate and concentration than healthy men (mean ± SD secretion rate 137 ± 61 vs 78 ± 30 µmol/min, respectively [p = 0.03]; median concentration 1.03 [range 0.58-1.75] vs 0.33 [0.13-1.14] mmol/l, respectively [p < 0.01]). Postprandially, the VLDL-TAG secretion rate decreased in healthy men (p < 0.01), but remained unchanged in diabetic men (p = 0.47). The VLDL-TAG concentration increased in diabetic men and decreased in healthy men postprandially (p < 0.05). The difference in VLDL-TAG secretion rate between the two groups approached significance (p = 0.06) and the relative change in VLDL-TAG secretion rate was significantly different (p = 0.01) between the two groups. Basal VLDL-TAG clearance was significantly lower in diabetic men (diabetic men 133 [49-390] ml/min; healthy controls 215 [137-933] ml/min [p < 0.05]). After meal ingestion, clearance decreased in healthy men (p = 0.03), but was unchanged in diabetic men (p = 0.58). CONCLUSIONS/INTERPRETATION: Obese type 2 diabetic men have impaired postprandial suppression of VLDL-TAG secretion compared with lean healthy men, contributing to their postprandial lipaemia and hypertriacylglycerolaemia.

The effect of weight loss on serum mannose-binding lectin levels.

BACKGROUND: Serum levels of the mannose-binding lectin (MBL), which is an activator of the complement system, have been considered as a pathogenic factor in a broad range of diseases, and means of modulating MBL are therefore being evaluated. In this study we examine the effects of weight loss on MBL levels, and in continuation of this if MBL is synthesized in human adipose tissue. METHODS: 36 nondiabetic obese subjects received a very low-calorie diet (VLCD) of 800 kcal/day for 8 weeks. Blood samples were collected at baseline and after VLCD. Furthermore, we measured MBL mRNA levels by the real-time RT-PCR on human adipose tissue compared to liver tissue. RESULTS: The mean body weight was reduced from 106.3 ± 2.6 kg to 92.8 ± 2.4 kg, P < 0.0001. Median MBL at baseline was 746 µg/L (IQR 316-1190) versus 892 µg/L (IQR 336-1511) after 8 weeks, P = 0.23. No correlations were found between weight loss and changes in MBL (r = -0.098, P = 0.57). MBL real-time RT-PCR showed no expression of mRNA in adipose tissue, but as expected a good expression in liver tissue was seen. CONCLUSIONS: MBL levels are not affected by weight loss and MBL is not synthesized in human adipose tissue.

Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone.

SUMMARY: Klinefelter syndrome (KS) patients have lower bone mineral density (BMD) at the spine, hip and forearm compared to healthy subjects, but frank osteoporosis is not common. Muscle strength and bone markers predicted BMD but KS itself and serum testosterone did not. Low vitamin D and high PTH were frequent among KS. INTRODUCTION: The long-term consequence of KS on bone health is not well described. The objective of this study is to investigate the regional BMD and its determinants in KS. METHODS: This is a cross-sectional study. BMD at the spine, hip and forearm are measured by DXA and correlated to biochemical markers of bone turnover, vitamin D metabolites, PTH, sex hormones, growth factors as well as muscle strength and anthropometric measures. The setting is at a university clinical research centre. The study involves 70 adult KS patients and 71 age-matched healthy subjects. RESULTS: In KS, BMD was universally lowered in all regions. Markers of bone formation or bone resorption were not altered in KS, but 25-OH-Dvitamin was lower (55 vs. 82 nmol/L, p < 0.0001) than in healthy subjects. Significantly more KS patients had low BMD (Z-scores below -2) at the forearm (15 KS vs. two healthy subjects, p = 0.001) but not at the spine or hip. Muscle strength (bicep and quadriceps) was lower among KS patients. Multivariate analysis revealed that muscle strength, treatment with testosterone (ever/never), age at diagnosis, SHBG, bone-specific alkaline phosphatase and 1CTP were all independent predictors of BMD, but androgens was not. CONCLUSIONS: KS patients had lower BMD at the spine, hip and forearm compared to age-matched healthy subjects, but frank osteoporosis was not common. Muscle strength, previous history of testosterone treatment, age at diagnosis and bone markers were predictors of BMD, but testosterone was not. Signs of secondary hyperparathyroidism were present among KS. Dietary intake of vitamin D or sun exposure may be lower in KS patients.

Molecular control of neural crest formation, migration and differentiation.

Induction, migration and differentiation of the neural crest are crucial for the development of the vertebrate embryo, and elucidation of the underlying mechanisms remains an important challenge. In the past year, a novel signal regulating the formation of neural crest cells has been identified, and advances have been made in uncovering roles for bone morphogenetic protein signals and for a transcription factor in the onset of neural crest migration. There have been new insights into the migration and plasticity of branchial neural crest cells. Important progress has been made in dissecting the roles of bone morphogenetic protein, Wnt and Notch signalling systems and their associated downstream transcription factors in the control of neural crest cell differentiation.