Distal posterior tibial artery perforator flaps for the management of calcaneal and Achilles tendon injuries in diabetic and non-diabetic patients

Management of Achilles tendon and heel area defects is a common challenge for the reconstructive surgeon due to the lack of soft tissue availability in that region. In this article, we present our experience in covering these defects by using the distal perforator propeller flaps based on the posterior tibial artery. Perforator flaps are based on cutaneous, small diameter vessels that originate from a main pedicle and perforate the fascia or muscle to reach the skin. Their development has followed the understanding of the blood supply from a source artery to the skin. Six patients (five males and one female) underwent reconstruction by using the posterior tibial artery distal perforator flap for covering defects in the distal Achilles tendon region in patients with and without diabetes mellitus. Postoperative complications included a hypertrophic scar formation in one patient, partial marginal flap necrosis in another patient, and a wound infection in a third patient. All wounds were eventually healed by the last postoperative visit. In conclusion, perforator flaps based on the distal posterior tibial artery may be a reliable option for the coverage of small to moderate size defects of the Achilles tendon and heel area regions

Family composition and age at menarche: findings from the international Health Behaviour in School-Aged Children Study

This research was funded by The University of St Andrews and NHS Health Scotland.Background Early menarche has been associated with father absence, stepfather presence and adverse health consequences in later life. This article assesses the association of different family compositions with the age at menarche. Pathways are explored which may explain any association between family characteristics and pubertal timing. Methods Cross-sectional, international data on the age at menarche, family structure and covariates (age, psychosomatic complaints, media consumption, physical activity) were collected from the 2009–2010 Health Behaviour in School-aged Children (HBSC) survey. The sample focuses on 15-year old girls comprising 36,175 individuals across 40 countries in Europe and North America (N = 21,075 for age at menarche). The study examined the association of different family characteristics with age at menarche. Regression and path analyses were applied incorporating multilevel techniques to adjust for the nested nature of data within countries. Results Living with mother (Cohen’s d = .12), father (d = .08), brothers (d = .04) and sisters (d = .06) are independently associated with later age at menarche. Living in a foster home (d = −.16), with ‘someone else’ (d = −.11), stepmother (d = −.10) or stepfather (d = −.06) was associated with earlier menarche. Path models show that up to 89% of these effects can be explained through lifestyle and psychological variables. Conclusions Earlier menarche is reported amongst those with living conditions other than a family consisting of two biological parents. This can partly be explained by girls’ higher Body Mass Index in these families which is a biological determinant of early menarche. Lower physical activity and elevated psychosomatic complaints were also more often found in girls in these family environments.Publisher PDFPeer reviewe

Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles

Developmental processes and their results, morphological characters, are inherited through transmission of genes regulating development. While there is ample evidence that cis-regulatory elements tend to be modular, with sequence segments dedicated to different roles, the situation for proteins is less clear, being particularly complex for transcription factors with multiple functions. Some motifs mediating protein-protein interactions may be exclusive to particular developmental roles, but it is also possible that motifs are mostly shared among different processes. Here we focus on HoxA13, a protein essential for limb development. We asked whether the HoxA13 amino acid sequence evolved similarly in three limbless clades: Gymnophiona, Amphisbaenia and Serpentes. We explored variation in ω (dN/dS) using a maximum-likelihood framework and HoxA13sequences from 47 species. Comparisons of evolutionary models provided low ω global values and no evidence that HoxA13 experienced relaxed selection in limbless clades. Branch-site models failed to detect evidence for positive selection acting on any site along branches of Amphisbaena and Gymnophiona, while three sites were identified in Serpentes. Examination of alignments did not reveal consistent sequence differences between limbed and limbless species. We conclude that HoxA13 has no modules exclusive to limb development, which may be explained by its involvement in multiple developmental processes

GAD1 mRNA Expression and DNA Methylation in Prefrontal Cortex of Subjects with Schizophrenia

Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia

Higher occurrence of nausea and vomiting after total hip arthroplasty using general versus spinal anesthesia: an observational study.

BACKGROUND: Under the assumption that postoperative nausea and vomiting (PONV) may occur after total hip arthroplasty (THA) regardless of the anesthetic technique used, it is not clear whether general (GA) or spinal (SA) anesthesia has higher causal effect on this occurrence. Conflicting results have been reported. METHODS: In this observational study, we selected all elective THA interventions performed in adults between 1999 and 2008 in a Swiss orthopedic clinic under general or spinal anesthesia. To assess the effect of anesthesia type on the occurrence of PONV, we used the propensity score and matching methods, which allowed us to emulate the design and results of an RCT. RESULTS: Among 3922 procedures, 1984 (51 %) patients underwent GA, of which 4.1 % experienced PONV, and 1938 underwent SA, of which 3.5 % experienced PONV. We found that the average treatment effect on the treated, i.e. the effect of anesthesia type for a sample of individuals that actually received spinal anesthesia compared to individuals who received GA, was ATET = 2.00 % [95 % CI, 0.78-3.19 %], which translated into an OR = 1.97 [95 % CI 1.35; 2.87]. CONCLUSION: This suggests that the type of anesthesia is not neutral regarding PONV, general anesthesia being more strongly associated with PONV than spinal anesthesia in orthopedic surgery

Solubility and Permeation of Hydrogen Sulfide in Lipid Membranes

Hydrogen sulfide (H2S) is mainly known for its toxicity but has recently been shown to be produced endogenously in mammalian tissues and to be associated with physiological regulatory functions. To better understand the role of biomembranes in modulating its biological distribution and effects; we measured the partition coefficient of H2S in models of biological membranes. The partition coefficients were found to be 2.1±0.2, 1.9±0.5 and 2.0±0.6 in n-octanol, hexane and dilauroylphosphatidylcholine liposome membranes relative to water, respectively (25°C). This two-fold higher concentration of H2S in the membrane translates into a rapid membrane permeability, Pm = 3 cm s−1. We used a mathematical model in three dimensions to gain insight into the diffusion of total sulfide in tissues. This model shows that the sphere of action of sulfide produced by a single cell expands to involve more than 200 neighboring cells, and that the resistance imposed by lipid membranes has a significant effect on the diffusional spread of sulfide at pH 7.4, increasing local concentrations. These results support the role of hydrogen sulfide as a paracrine signaling molecule and reveal advantageous pharmacokinetic properties for its therapeutic applications

Androgen Excess Produces Systemic Oxidative Stress and Predisposes to β-Cell Failure in Female Mice

In women, excess production of the male hormone, testosterone (T), is accompanied by insulin resistance. However, hyperandrogenemia is also associated with β-cell dysfunction and type 2 diabetes raising the possibility that androgen receptor (AR) activation predisposes to β-cell failure. Here, we tested the hypothesis that excess AR activation produces systemic oxidative stress thereby contributing to β-cell failure. We used normal female mice (CF) and mice with androgen resistance by testicular feminization (Tfm). These mice were exposed to androgen excess and a β-cell stress induced by streptozotocin (STZ). We find that following exposure to T, or the selective AR-agonist dehydrotestosterone (DHT), CF mice challenged with STZ, which are normally protected, are prone to β-cell failure and insulin-deficient diabetes. Conversely, T-induced predisposition to β-cell failure is abolished in Tfm mice. We do not observe any proapoptotic effect of DHT alone or in the presence of H2O2 in cultured mouse and human islets. However, we observe that exposure of CF mice to T or DHT provokes systemic oxidative stress, which is eliminated in Tfm mice. This work has significance for hyperandrogenic women; excess activation of AR by testosterone may provoke systemic oxidative stress. In the presence of a prior β-cell stress, this may predispose to β-cell failure

Defining the Earliest Transcriptional Steps of Chondrogenic Progenitor Specification during the Formation of the Digits in the Embryonic Limb

The characterization of genes involved in the formation of cartilage is of key importance to improve cell-based cartilage regenerative therapies. Here, we have developed a suitable experimental model to identify precocious chondrogenic events in vivo by inducing an ectopic digit in the developing embryo. In this model, only 12 hr after the implantation of a Tgfβ bead, in the absence of increased cell proliferation, cartilage forms in undifferentiated interdigital mesoderm and in the course of development, becomes a structurally and morphologically normal digit. Systematic quantitative PCR expression analysis, together with other experimental approaches allowed us to establish 3 successive periods preceding the formation of cartilage. The “pre-condensation stage”, occurring within the first 3 hr of treatment, is characterized by the activation of connective tissue identity transcriptional factors (such as Sox9 and Scleraxis) and secreted factors (such as Activin A and the matricellular proteins CCN-1 and CCN-2) and the downregulation of the galectin CG-8. Next, the “condensation stage” is characterized by intense activation of Smad 1/5/8 BMP-signaling and increased expression of extracellular matrix components. During this period, the CCN matricellular proteins promote the expression of extracellular matrix and cell adhesion components. The third period, designated the “pre-cartilage period”, precedes the formation of molecularly identifiable cartilage by 2–3 hr and is characterized by the intensification of Sox 9 gene expression, along with the stimulation of other pro-chondrogenic transcription factors, such as HifIa. In summary, this work establishes a temporal hierarchy in the regulation of pro-chondrogenic genes preceding cartilage differentiation and provides new insights into the relative roles of secreted factors and cytoskeletal regulators that direct the first steps of this process in vivo

Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy humans stratified for low and high gating levels

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D2-like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebo-controlled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D2-like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs