Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres.

Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20-300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.

Nitrate-responsive oral microbiome modulates nitric oxide homeostasis and blood pressure in humans.

Imbalances in the oral microbial community have been associated with reduced cardiovascular and metabolic health. A possible mechanism linking the oral microbiota to health is the nitrate (NO3-)-nitrite (NO2-)-nitric oxide (NO) pathway, which relies on oral bacteria to reduce NO3- to NO2-. NO (generated from both NO2- and L-arginine) regulates vascular endothelial function and therefore blood pressure (BP). By sequencing bacterial 16S rRNA genes we examined the relationships between the oral microbiome and physiological indices of NO bioavailability and possible changes in these variables following 10 days of NO3- (12 mmol/d) and placebo supplementation in young (18-22 yrs) and old (70-79 yrs) normotensive humans (n = 18). NO3- supplementation altered the salivary microbiome compared to placebo by increasing the relative abundance of Proteobacteria (+225%) and decreasing the relative abundance of Bacteroidetes (-46%; P < 0.05). After NO3-supplementation the relative abundances of Rothia (+127%) and Neisseria (+351%) were greater, and Prevotella (-60%) and Veillonella (-65%) were lower than in the placebo condition (all P < 0.05). NO3- supplementation increased plasma concentration of NO2- and reduced systemic blood pressure in old (70-79 yrs), but not young (18-22 yrs), participants. High abundances of Rothia and Neisseria and low abundances of Prevotella and Veillonella were correlated with greater increases in plasma [NO2-] in response to NO3- supplementation. The current findings indicate that the oral microbiome is malleable to change with increased dietary intake of inorganic NO3-, and that diet-induced changes in the oral microbial community are related to indices of NO homeostasis and vascular health in vivo.

A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity.

Iron supplementation ameliorates the neurotoxicity of the environmental contaminant lead (Pb); however, the mechanism remains undefined. Iron is an essential nutrient but high levels are toxic due to the catalytic generation of destructive hydroxyl radicals. Using human neuroblastoma SH-SY5Y cells to model human neurons, we investigated the effect of Pb on proteins of iron homeostasis: the Alzheimer's amyloid precursor protein (APP), which stabilizes the iron exporter ferroportin 1; and, the heavy subunit of the iron-storage protein, ferritin (FTH). Lead (Pb(II) and Pb(IV) inhibited APP translation and raised cytosolic iron(II). Lead also increased iron regulatory protein-1 binding to the cognate 5'untranslated region-specific iron-responsive element (IRE) of APP and FTH mRNAs. Concurrent iron treatment rescued cells from Pb toxicity by specifically restoring APP synthesis, i.e. levels of the APP-related protein, APLP-2, were unchanged. Significantly, iron/IRE-independent over-expression of APP695  protected SH-SY5Y cells from Pb toxicity, demonstrating that APP plays a key role in maintaining safe levels of intracellular iron. Overall, our data support a model of neurotoxicity where Pb enhances iron regulatory protein/IRE-mediated repression of APP and FTH translation. We propose novel treatment options for Pb poisoning to include chelators and the use of small molecules to maintain APP and FTH translation. We propose the following cascade for Lead (Pb) toxicity to neurons; by targeting the interaction between Iron regulatory protein-1 and Iron-responsive elements, Pb caused translational repression of proteins that control intracellular iron homeostasis, including the Alzheimer's amyloid precursor protein (APP) that stabilizes the iron exporter ferroportin, and the ferroxidase heavy subunit of the iron-storage protein, ferritin. When unregulated, IRE-independent over-expression of APP695 protected SH-SY5Y neurons from Pb toxicity. There is a novel and key role for APP in maintaining safe levels of intracellular iron pertinent to lead toxicity.

Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders.

The goal here is to describe our current understanding of heme metabolism and the deleterious effects of "free" heme on immunological processes, endothelial function, systemic inflammation, and various end-organ tissues (e.g., kidney, lung, liver, etc.), with particular attention paid to the role of hemopexin (HPX). Because heme toxicity is the impetus for much of the pathology in sepsis, sickle cell disease (SCD), and other hemolytic conditions, the biological importance and clinical relevance of HPX, the predominant heme binding protein, is reinforced. A perspective on the function of HPX and haptoglobin (Hp) is presented, updating how these two proteins and their respective receptors act simultaneously to protect the body in clinical conditions that entail hemolysis and/or systemic intravascular (IVH) inflammation. Evidence from longitudinal studies in patients supports that HPX plays a Hp-independent role in genetic and non-genetic hemolytic diseases without the need for global Hp depletion. Evidence also supports that HPX has an important role in the prognosis of complex illnesses characterized predominantly by the presence of hemolysis, such as SCD, sepsis, hemolytic-uremic syndrome, and conditions involving IVH and extravascular hemolysis (EVH), such as that generated by extracorporeal circulation during cardiopulmonary bypass (CPB) and from blood transfusions. We propose that quantitating the amounts of plasma heme, HPX, Hb-Hp, heme-HPX, and heme-albumin levels in various disease states may aid in the diagnosis and treatment of the above-mentioned conditions, which is crucial to developing targeted plasma protein supplementation (i.e., "replenishment") therapies for patients with heme toxicity due to HPX depletion.

Health-related quality-of-life outcomes after open versus endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Endovascular repair (EVAR) of abdominal aortic aneurysms is a safe alternative to open aneurysm repair (OAR) in selected patients. The aim of this study was to compare the health-related quality-of-life (HR-QoL) outcomes of patients following EVAR and OAR. METHODS: A literature search of PubMed, EMBASE, and the Cochrane Library identified five randomized trials that reported on HR-QoL in EVAR and OAR for elective management of infrarenal abdominal aortic aneurysms. No consistent HR-QOL instrument was used among the studies. A meta-analysis was performed on the 36-Item Short Form (SF-36) and the EuroQol-5D (EQ-5D) HR-QoL results. RESULTS: SF-36 general health scores were higher for EVAR at 3, 6, and 12 months postoperatively. SF-36 physical functioning scores were higher for EVAR at 6 months but this advantage was lost at 12 months. In addition, SF-36 social functioning scores were higher for EVAR at 12 months. SF-36 component summary scores were not significantly different. EVAR was associated with a better EQ-5D score at 3, 6, and 12 months, but not at 24 months of follow-up. CONCLUSIONS: EVAR was associated with better HR-QoL in some domains up to 12 months postoperatively. There is insufficient data to demonstrate a HR-QoL advantage beyond 12 months. More studies are required to examine any long-term HR-QoL advantages for either intervention.

Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome.

PURPOSE: To describe an ophthalmic phenotype in children at relatively early stages of Wolfram syndrome. METHODS: Quantitative ophthalmic testing of visual acuity, color vision, automated visual field sensitivity, optic nerve pallor and cupping, and retinal nerve fiber layer (RNFL) thickness assessed by optical coherence tomography (OCT) was performed in 18 subjects 5-25 years of age. Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus. RESULTS: Subnormal visual acuity was detected in 89% of subjects, color vision deficits in 94%, visual field defects in 100%, optic disk pallor in 94%, abnormally large optic nerve cup:disk ratio in 33%, thinned RNFL in 100%, afferent pupillary defects in 61%, cataracts in 22%, nystagmus in 39%, and strabismus in 39% of subjects. RNFL thinning (P < 0.001), afferent pupillary defects (P = 0.01), strabismus (P = 0.04), and nystagmus (P = 0.04) were associated with more severe disease using the Wolfram United Rating Scale. CONCLUSIONS: Children and adolescents with Wolfram syndrome have multiple ophthalmic markers that correlate with overall disease severity. RNFL thickness measured by OCT may be the most reliable early marker.

The evaluation of mindfulness-based stress reduction for veterans with mental health conditions.

PURPOSE: To assess the feasibility of mindfulness-based stress reduction (MBSR) for veterans with mental health conditions and to evaluate its efficacy on psychological well-being and stress reduction. DESIGN: Single-group, pretest-posttest design. METHOD: 30 veterans within a mental health clinic of a VA (Veterans Administration) medical center were enrolled in an 8-week standard MBSR program. Perceived stress, sleep, mindfulness, and depression were measured via self-reports at baseline and study end. Feasibility was measured by compliance and satisfaction with the course. FINDINGS: Scores on the Perceived Stress Scale (p =.002) and Beck Depression Inventory-II (p = .005) were significantly reduced (p = .002). The global measure for sleep from the Pittsburgh Sleep Quality Index improved significantly (p = .035). Satisfaction and compliance were high. CONCLUSION: MBSR is a feasible intervention that has potential efficacy for veterans with mental health conditions. Future controlled trials are needed in this area.

Leading in practice: a case study of how health visitors share and develop good practice.

The aim of this study was to find out more about health visitors' current situated practice in the context of national policy drivers outlining a new lead role for them in delivering co-ordinated and integrated services for children and families, tailored to local needs. The study focused on health visitors within a recently merged primary care trust and a qualitative approach was adopted with use of focus groups to generate data. The transcripts were subsequently analysed for key themes and dimensions. These related to how health visitors defined their own role and the skills with which they carried it out, the development of their expertise, role tensions and factors affecting leadership development. By drawing together the grounded experience of health visitors, policy drivers and theoretical interpretations a rich picture of existing practices was established, with recommendations made to promote distributed leadership and change.

Sensory motor and functional skills of dizygotic twins: one with Smith-Magenis syndrome and a twin control.

Smith-Magenis syndrome (SMS), the result of an interstitial deletion within chromosome 17p11.2, is a disorder that may include minor dysmorphic features, brachydactyly, short stature, hypotonia, speech delays, cognitive deficits, signs of peripheral neuropathy, scoliosis, and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behaviors. Physical and occupational therapists provide services for children who have the syndrome, whose genetic disorder is frequently not identified or diagnosed before 1 year of age. A comprehensive physical and occupational therapy evaluation was completed in nonidentical twins with one having SMS, using the Sensory Profile; Brief Assessment of Motor Function (BAMF); Peabody Developmental Motor Scales, Second Edition (PDMS-2); and Pediatric Evaluation of Disability Inventory (PEDI). This provides a framework for conducting assessments to enhance early detection and interdisciplinary management with this specialized population.

Changes in the contents of oleoresin and pungent bioactive principles of Jamaican ginger (Zingiber officinale Roscoe.) during maturation.

Changes in the yields of the oleoresin and content of pungent bioactive principles: [6], [8], [10] gingerols and [6] shogaol of Jamaican ginger ( Zingiber officinale) were investigated during different stages of maturity (7-9 months). Ethanolic oleoresin extracts were prepared (95%, w/w) by cold maceration of dried ginger powder, and their percentage yields were calculated (w/w). The pungent bioactive principles in the ginger oleoresin were extracted with methanol and quantitatively analyzed by high performance liquid chromatography (HPLC). Ginger harvested at 8 months from Bourbon, Portland had the highest oleoresin yield (8.46 +/- 0.46%). [6] Gingerol was found to be the most abundant pungent bioactive principle in all the oleoresin samples investigated, with the 9 months sample from Bourbon, Portland containing the highest level (28.94 +/- 0.39%). The content of [6] gingerols was also found to be consistently high (7-9 months) in oleoresin samples from Johnson Mountain, St. Thomas (15.12 +/- 0.39 to 16.02 +/- 0.95%). The results suggest that Bourbon in Portland may be the most ideal location for cultivating ginger for high yields and quality, however, Johnson Mountain in St. Thomas could prove to be the least restrictive location, allowing for harvesting of good quality material throughout the maturity period (7-9 months).