McLeod syndrome: Five new pedigrees with novel mutations.

OBJECTIVE: To present five new McLeod Syndrome (MLS) pedigrees with novel XK gene mutations, review the literature of this disorder, and discuss the typical and atypical clinical features noted with these new mutations. METHODS: This is a multi-center retrospective review of five MLS cases with novel gene mutations. Genotypic and phenotypic information has been obtained from each center. RESULTS: Five novel mutations are reported in this Case series. New clinical findings include prolonged asymptomatic elevated creatine kinase (CK) levels, vocal tics, presence of obstructive sleep apnea (OSA), and one patient of Vietnamese ethnicity. CONCLUSIONS: We expand on the clinical and genetic spectrum of MLS demonstrating the clinical variability of MLS.

The myokinetic control interface: tracking implanted magnets as a means for prosthetic control.

Upper limb amputation deprives individuals of their innate ability to manipulate objects. Such disability can be restored with a robotic prosthesis linked to the brain by a human-machine interface (HMI) capable of decoding voluntary intentions, and sending motor commands to the prosthesis. Clinical or research HMIs rely on the interpretation of electrophysiological signals recorded from the muscles. However, the quest for an HMI that allows for arbitrary and physiologically appropriate control of dexterous prostheses, is far from being completed. Here we propose a new HMI that aims to track the muscles contractions with implanted permanent magnets, by means of magnetic field sensors. We called this a myokinetic control interface. We present the concept, the features and a demonstration of a prototype which exploits six 3-axis sensors to localize four magnets implanted in a forearm mockup, for the control of a dexterous hand prosthesis. The system proved highly linear (R2 = 0.99) and precise (1% repeatability), yet exhibiting short computation delay (45 ms) and limited cross talk errors (10% the mean stroke of the magnets). Our results open up promising possibilities for amputees, demonstrating the viability of the myokinetic approach in implementing direct and simultaneous control over multiple digits of an artificial hand.

Roles of PPAR transcription factors in the energetic metabolic switch occurring during adult neurogenesis.

PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions.

Effect of thyroid state on enzymatic and non-enzymatic processes in H2O2 removal by liver mitochondria of male rats.

We investigated thyroid state effect on capacity of rat liver mitochondria to remove exogenously produced H2O2, determining their ability to decrease fluorescence generated by an H2O2 detector system. The rate of H2O2 removal by both non respiring and respiring mitochondria was increased by hyperthyroidism and decreased by hypothyroidism. However, the rate was higher in the presence of respiratory substrates, in particular pyruvate/malate, indicating a respiration-dependent process. Generally, the changes in H2O2 removal rates mirrored those in H2O2 release rates excluding the possibility that endogenous and exogenous H2O2 competed for the removing system. Pharmacological inhibition revealed thyroid state-linked differences in antioxidant enzyme contribution to H2O2 removal which were consistent with those in antioxidant system activities. The H2O2 removal was only in part due to enzymatic systems and that imputable to non-enzymatic processes was higher in hyperthyroid and lower in hypothyroid mitochondria. The levels of cytochrome c and the light emissions, due to luminol oxidation catalyzed by cytochrome/H2O2, exhibited similar changes with thyroid state supporting the idea that non-enzymatic scavenging was mainly due to hemoprotein action, which produces hydroxyl radicals. Further support was obtained showing that the whole antioxidant capacity, which provides an evaluation of capacity of the systems, different from cytochromes, assigned to H2O2 scavenging, was lower in hyperthyroid than in hypothyroid state. In conclusion, our results show that mitochondria from hyperthyroid liver have a high capacity for H2O2 removal, which, however, leading in great part to more reactive oxygen species, results harmful for such organelles.

Vitamin E supplementation modifies adaptive responses to training in rat skeletal muscle.

Aim of the present study was to test, by vitamin E treatment, the hypothesis that muscle adaptive responses to training are mediated by free radicals produced during the single exercise sessions. Therefore, we determined aerobic capacity of tissue homogenates and mitochondrial fractions, tissue content of mitochondrial proteins and expression of factors (PGC-1, NRF-1, and NRF-2) involved in mitochondrial biogenesis. Moreover, we determined the oxidative damage extent, antioxidant enzyme activities, and glutathione content in both tissue preparations, mitochondrial ROS production rate. Finally we tested mitochondrial ROS production rate and muscle susceptibility to oxidative stress. The metabolic adaptations to training, consisting in increased muscle oxidative capacity coupled with the proliferation of a mitochondrial population with decreased oxidative capacity, were generally prevented by antioxidant supplementation. Accordingly, the expression of the factors involved in mitochondrial biogenesis, which were increased by training, was restored to the control level by the antioxidant treatment. Even the training-induced increase in antioxidant enzyme activities, glutathione level and tissue capacity to oppose to an oxidative attach were prevented by vitamin E treatment. Our results support the idea that the stimulus for training-induced adaptive responses derives from the increased production, during the training sessions, of reactive oxygen species that stimulates the expression of PGC-1, which is involved in mitochondrial biogenesis and antioxidant enzymes expression. On the other hand, the observation that changes induced by training in some parameters are only attenuated by vitamin E treatment suggests that other signaling pathways, which are activated during exercise and impinge on PGC-1, can modify the response to the antioxidant integration.

Brain monitoring: do we need a hole? An update on invasive and noninvasive brain monitoring modalities.

The ability to measure reliably the changes in the physical and biochemical environment after a brain injury is of great value in the prevention, treatment, and understanding of the secondary injuries. Three categories of multimodal brain monitoring exist: direct signals which are monitored invasively; variables which may be monitored noninvasively; and variables describing brain pathophysiology which are not monitored directly but are calculated at the bedside by dedicated computer software. Intracranial pressure (ICP) monitoring, either as stand-alone value or study of a dynamic trend, has become an important diagnostic tool in the diagnosis and management of multiple neurological conditions. Attempts have been made to measure ICP non-invasively, but this is not a clinical reality yet. There is contrasting evidence that monitoring of ICP is associated with better outcome, and further RCTs based on management protocol are warranted. Computer bedside calculation of "secondary parameters" has shown to be potentially helpful, particularly in helping to optimize "CPP-guided therapy." In this paper we describe the most popular invasive and non invasive monitoring modalities, with great attention to their clinical interpretation based on the current published evidence.

Effect of training and vitamin E administration on rat liver oxidative metabolism.

We studied vitamin E effects on metabolic changes and oxidative damage elicited by swim training in rat liver. Training reduced mitochondrial aerobic capacity but increased liver content of mitochondrial proteins, so that tissue aerobic capacity was not different in trained and sedentary animals. Vitamin E supplementation prevented the training-induced mitochondrial changes. Training and vitamin E effects were consistent with the changes in tissue content of factors involved in mitochondrial biogenesis (peroxisomal proliferator-activated receptor-γ coactivator and nuclear respiratory factors 1 and 2). Tissue and mitochondrial oxidative damage was reduced by training decreasing the rate of mitochondrial reactive oxygen species (ROS) production and enhancing glutathione levels and glutathione peroxidase and glutathione reductase activities. The effects of vitamin E were different when it was administered to sedentary or trained rats. In the former, vitamin E reduced liver preparations oxidative damage decreasing ROS production rate and increasing GSH content without any effect on antioxidant enzyme activities. In the latter, vitamin E did not modify ROS production and oxidative damage but decreased antioxidant levels. This decrease was likely responsible for the enhanced susceptibility to in vitro oxidative attack of the hepatic tissue from trained rats following vitamin E supplementation. These results indicate that vitamin E integration, which can be healthy for animals subjected to acute exercise, is not advisable during training because it prevents or reduces the favourable effects of the physical activity. They also support the idea that the stimulus for training-induced adaptive responses can derive from the increased ROS production that accompanies the single sessions of the training program.

Osteoconductive and bioresorbable composites based on poly(L,L-lactide) and pseudowollastonite: from synthesis and interfacial compatibilization to in vitro bioactivity and in vivo osseointegration studies.

This contribution reports on the elaboration of novel bioresorbable composites consisting of pseudowollastonite (psW) (a silicate-based polycrystalline ceramic (α-CaSiO(3))) and poly(L,L-lactide) as a valuable polymeric candidate in bone-guided regeneration. These composites were prepared by direct melt-blending to avoid the use of organic solvents harmful for biomedical applications. Amphiphilic poly(ethylene oxide-b-L,L-lactide) diblock copolymers synthesized by ring-opening polymerization were added to psW-based composites to modulate the bioactivity of the composites. The bioactivity of the composites was first evaluated by monitoring the release of bioactive Ca(2+) and (SiO(4))(4-) ions as well as the concomitant formation of hydroxyapatite on the material surface after soaking them in physiological fluid. Subsequently, the composites were studied in vitro to evaluate their cytotoxicity in the presence of SaOS-2 osteoblastic cells and in vivo to assess their osteoconductivity in an orthotopic rat tibia model. This study provides a first insight into the use of direct melt-blended psW-poly(L,L-lactide) composites for bone-regeneration applications.

Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.

A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.

Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates.

The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.

Static and ELF magnetic fields enhance the in vivo anti-tumor efficacy of cis-platin against lewis lung carcinoma, but not of cyclophosphamide against B16 melanotic melanoma.

Previous works showed that exposure to static and extremely low frequency (ELF) magnetic fields (MF) over 3 mT slows down the growth kinetics of human tumors engrafted s.c. in immunodeficient mice, reducing their metastatizing power and prolonging mouse survival. In the experiments reported here, immunocompetent mice bearing murine Lewis Lung carcinomas (LLCs) or B16 melanotic melanomas were exposed to MF and treated respectively with two commonly used anti-cancer drugs: cis-diamminedichloroplatinum (cis-platin) and N,N-bis (2-chloroethyl)tetra-hydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (cyclophosphamide). The experiment endpoint was survival time. The survival time of mice treated with cis-platin (3mg/kg i.p.) and exposed to MF was significantly (P<0.01) longer than that of mice treated only with cis-platin or only exposed to MF, superimposing that of mice treated with 10mg/kg i.p. of the drug, showing that MF act synergically with the pharmacological treatment. On the contrary, when mice treated with cyclophosphamide (50mg/kg i.p.) were exposed to MF no synergic effects were observed, the survival curve being exactly the same as that of mice treated with the drug alone. No clinical signs or toxicity were seen in any of the mice exposed to MF alone or along with cis-platin or cyclophosphamide treatment, compared to mice given only the two known drugs.A possible explanation for the synergic effect of MF being found in mice treated with cis-platin could be that the platinum ion stimulates radical production and that MF enhance active oxygen production bringing about changes in tumor cell membrane permeability, influencing positively the drug uptake. Alternatively, or in addition to this, it has been demonstrated that the rate of conversion of cis-platin to reactive species able to bind to DNA, is increased by localized production of free radicals by MF.

Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors.

Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.

Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group.

The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.

A social cognitive perspective on religious beliefs: their functions and impact on coping and psychotherapy.

Religious beliefs are an important part of clients' culture, whether acknowledged or not. Psychological theories about social and cognitive processes can help mental-health professionals better understand the function of religious beliefs in coping and their role in therapy. Religious individuals are likely to use heuristics to form rapid judgments rather than engage in formal information-gathering processes. The confirmatory and in-group/out-group biases support such judgments and shield them from disconfirmatory evidence. Religious beliefs provide order and understanding to an otherwise chaotic and unpredictable world. Many religions advocate forgiveness, which is often helpful in resolving conflicts. Another beneficial religious belief is an ever-present spiritual attachment figure. Negative effects of religion include its exercising aversive control to maintain conformity and its promoting an external locus of control. In contrast, mental-health professionals belong to a tradition of free inquiry and self-development, and guide clients to acquire competencies necessary to change and direct their lives. Therapist attitudes are far less likely to include allegiance to religion than are those of the public and psychiatric patients. Rather than being biased against religion or trying to debate religion, therapists need to engage in problem solving with clients in the context of this example of sociocultural factors.

Static and ELF magnetic fields induce tumor growth inhibition and apoptosis.

The ability of static and extremely low frequency (ELF) Magnetic Fields (MF) to interfere with neoplastic cell function has been evaluated. In vitro experiments were carried out to study the role of MF characteristics (intensity, frequency, and modulation) on two transformed cell lines (WiDr human colon adenocarcinoma and MCF-7 human breast adenocarcinoma) and one nontransformed cell line (MRC-5 embryonal lung fibroblast). Increase in cell death morphologically consistent with apoptosis was reported exclusively in the two transformed cell lines. Cell-death induction was observed with MF of more than 1 mT. It was independent of the MF frequency and increased when modulated MF (static with a superimposition of ELF at 50 Hz) were used. Based on the in vitro results, four different MF exposure characteristics were selected and used to treat nude mice xenografted with WiDr cells. The treatment of nude mice bearing WiDr tumors subcutaneously. with daily exposure for 70 min to MF for 4 weeks caused significant tumor growth inhibition (up to 50%) by the end of the treatment when modulated MF were used for at least 60% of the whole treatment period and the time-averaged total MF intensity was higher than 3.59 mT. No toxic morphological changes induced by exposure were observed in renewing, slowly proliferating, or static normal cells. A discussion on the possible biophysical mechanism at the base of the observed biological results is also offered.

Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents.

In order to clarify the interaction of betahistine (BH) and its metabolites [aminoethylpyridine (AEP) and hydroxyethylpyridine (HEP)] for receptors that mediate the physio-pharmacological activities of histamine, we performed in vitro competition binding studies to obtain their binding affinity profile for H(1)-, H(2)- and H(3)-histamine receptors prepared from rodent brains. Crude synaptosomal membranes were incubated in the absence (total binding) or presence of the unlabelled ligands used to saturate the specific binding, or with different concentrations of BH, AEP or HEP. Receptor binding methods were validated by running known standard drugs together with the test compounds. Like histamine, only BH interacted with H(1)-histamine receptors with comparable affinity (around 10(-5)M). BH and its metabolite AEP both interacted with the H(3)-histamine receptors, with microM affinity. HEP still showed some affinity for the H(3)-receptors but with a K(i)only 1/50 that of the parent compound. Histamine showed 10(-8)M affinity for the H(3)-receptor sites and was the only ligand to interact with H(2)-histamine receptors, all the others giving affinities above the mM range. Hill coefficients (as slopes of the sigmoidal inhibition isotherms) were close to unity for BH against H(1)- and H(3)-binding sites and for AEP against H(3)-sites, indicating that these interactions take place in the absence of cooperativity. Histamine and HEP interacted with H(1)- and H(3)-receptors with a Hill coefficient less than unity for the former and higher than unity for the latter (presence of negative and positive cooperativity, respectively). The results suggest that BH and its metabolites may act as neurotransmitter modulators of the histaminergic system.

Binding of mepartricin to sex hormones, a key factor of its activity on benign prostatic hyperplasia.

Androgens and estrogens, mainly testosterone (TES) and dihydrotestosterone (DHT) and 17 beta-estradiol (EST), are widely recognized to regulate the prostate growth and their imbalance with aging, leading to reduction of androgens and relative increase of estrogens, may be responsible for the development of benign prostatic hyperplasia (BPH). Mepartricin (CAS 11121-32-7), a polyene drug for medical treatment of BPH, was assayed in vitro for its ability to bind with 14C-labelled sex hormones, by incubation in buffered saline, serum and bile, followed by centrifugation and dosing of the radioactivity in the supernatant. It proved effective in complexing up to 90% of TES and DHT in buffered saline and up to 80% of EST in bile. Due to minimal absorption of oral mepartricin and to much higher enterohepatic circulation for estrogens than for androgens, the binding effect of mepartricin on EST in the gut should be of particular pharmacological relevance to explain its mechanism of action on BPH.