Novel Approaches to Investigate One-Carbon Metabolism and Related B-Vitamins in Blood Pressure.

Hypertension, a major risk factor for heart disease and stroke, is the world's leading cause of preventable, premature death. A common polymorphism (677C→T) in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with increased blood pressure, and there is accumulating evidence demonstrating that this phenotype can be modulated, specifically in individuals with the MTHFR 677TT genotype, by the B-vitamin riboflavin, an essential co-factor for MTHFR. The underlying mechanism that links this polymorphism, and the related gene-nutrient interaction, with hypertension is currently unknown. Previous research has shown that 5-methyltetrahydrofolate, the product of the reaction catalysed by MTHFR, appears to be a positive allosteric modulator of endothelial nitric oxide synthase (eNOS) and may thus increase the production of nitric oxide, a potent vasodilator. Blood pressure follows a circadian pattern, peaking shortly after wakening and falling during the night, a phenomenon known as 'dipping'. Any deviation from this pattern, which can only be identified using ambulatory blood pressure monitoring (ABPM), has been associated with increased cardiovascular disease (CVD) risk. This review will consider the evidence linking this polymorphism and novel gene-nutrient interaction with hypertension and the potential mechanisms that might be involved. The role of ABPM in B-vitamin research and in nutrition research generally will also be reviewed.The PhD studentship of A.M. was funded by the Northern Ireland Department for Employment and Learning. DSM Nutritional Products Ltd. partly supported project costs associated with this work. The funders had no role in the design, analysis or writing of this paper

Novel O-palmitolylated beta-E1 subunit of pyruvate dehydrogenase is phosphorylated during ischemia/reperfusion injury

<p>Abstract</p> <p>Background</p> <p>During and following myocardial ischemia, glucose oxidation rates are low and fatty acids dominate as a source of oxidative metabolism. This metabolic phenotype is associated with contractile dysfunction during reperfusion. To determine the mechanism of this reliance on fatty acid oxidation as a source of ATP generation, a functional proteomics approach was utilized.</p> <p>Results</p> <p>2-D gel electrophoresis of mitochondria from working rat hearts subjected to 25 minutes of global no flow ischemia followed by 40 minutes of aerobic reperfusion identified 32 changes in protein abundance compared to aerobic controls. Of the five proteins with the greatest change in abundance, two were increased (long chain acyl-coenzyme A dehydrogenase (48 ± 1 versus 39 ± 3 arbitrary units, n = 3, P < 0.05) and α subunit of ATP synthase (189 ± 15 versus 113 ± 23 arbitrary units, n = 3, P < 0.05)), while two were decreased (24 kDa subunit of NADH-ubiquinone oxidoreductase (94 ± 7 versus 127 ± 9 arbitrary units, n = 3, P < 0.05) and D subunit of ATP synthase (230 ± 11 versus 368 ± 47 arbitrary units, n = 3, P < 05)). Two forms of pyruvate dehydrogenase βE1 subunit, the rate-limiting enzyme for glucose oxidation, were also identified. The protein level of the more acidic form of pyruvate dehydrogenase was reduced during reperfusion (37 ± 4 versus 56 ± 7 arbitrary units, n = 3, P < 05), while the more basic form remained unchanged. The more acidic isoform was found to be O-palmitoylated, while both isoforms exhibited ischemia/reperfusion-induced phosphorylation. <it>In silico </it>analysis identified the putative kinases as the insulin receptor kinase for the more basic form and protein kinase Cζ or protein kinase A for the more acidic form. These modifications of pyruvate dehydrogenase are associated with a 35% decrease in glucose oxidation during reperfusion.</p> <p>Conclusions</p> <p>Cardiac ischemia/reperfusion induces significant changes to a number of metabolic proteins of the mitochondrial proteome. In particular, ischemia/reperfusion induced the post-translational modification of pyruvate dehydrogenase, the rate-limiting step of glucose oxidation, which is associated with a 35% decrease in glucose oxidation during reperfusion. Therefore these post-translational modifications may have important implications in the regulation of myocardial energy metabolism.</p

Effects of Cognitive Behavioral Therapy on Daily Living Skills in Children with High-Functioning Autism and Concurrent Anxiety Disorders

CBT is a promising treatment for children with autism spectrum disorders (ASD) and focuses, in part, on children’s independence and self-help skills. In a trial of CBT for anxiety in ASD (Wood et al. in J Child Psychol Psychiatry 50:224–234, 2009), children’s daily living skills and related parental intrusiveness were assessed. Forty children with ASD (7–11 years) and their primary caregiver were randomly assigned to an immediate treatment (IT; n = 17) or 3-month waitlist (WL; n = 23) condition. In comparison to WL, IT parents reported increases in children’s total and personal daily living skills, and reduced involvement in their children’s private daily routines. Reductions correlated with reduced anxiety severity. These results provide preliminary evidence that CBT may yield increased independence and daily living skills among children with ASD

Locomotor adaptability in persons with unilateral transtibial amputation

Background Locomotor adaptation enables walkers to modify strategies when faced with challenging walking conditions. While a variety of neurological injuries can impair locomotor adaptability, the effect of a lower extremity amputation on adaptability is poorly understood. Objective Determine if locomotor adaptability is impaired in persons with unilateral transtibial amputation (TTA). Methods The locomotor adaptability of 10 persons with a TTA and 8 persons without an amputation was tested while walking on a split-belt treadmill with the parallel belts running at the same (tied) or different (split) speeds. In the split condition, participants walked for 15 minutes with the respective belts moving at 0.5 m/s and 1.5 m/s. Temporal spatial symmetry measures were used to evaluate reactive accommodations to the perturbation, and the adaptive/de-adaptive response. Results Persons with TTA and the reference group of persons without amputation both demonstrated highly symmetric walking at baseline. During the split adaptation and tied post-adaptation walking both groups responded with the expected reactive accommodations. Likewise, adaptive and de-adaptive responses were observed. The magnitude and rate of change in the adaptive and de-adaptive responses were similar for persons with TTA and those without an amputation. Furthermore, adaptability was no different based on belt assignment for the prosthetic limb during split adaptation walking. Conclusions Reactive changes and locomotor adaptation in response to a challenging and novel walking condition were similar in persons with TTA to those without an amputation. Results suggest persons with TTA have the capacity to modify locomotor strategies to meet the demands of most walking conditions despite challenges imposed by an amputation and use of a prosthetic limb

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1

Perforated Meckel's diverticulum presenting with combined bowel and urinary obstruction and mimicking Crohn's disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Meckel's diverticulum is a common congenital anomaly of the gastrointestinal tract, but is an uncommon cause of serious complications in adults. Although cases of patients with hemorrhage, bowel obstruction or perforation associated with Meckel's diverticulum have been reported, there have been no prior reports of patients with combined urinary and bowel obstruction due to abscess formation.</p> <p>Case presentation</p> <p>We describe the case of a 21-year-old man with a history of recurrent papillary thyroid cancer, but no prior abdominal surgeries, who presented with a one-month history of rectal pain and new-onset obstipation with urinary retention. He reported night sweats and weight loss, and had a second-degree relative with known Crohn's disease. A digital rectal examination was notable and revealed marked tenderness with proximal induration. A computed tomography scan of the patient's abdomen revealed a large, complex, circumferential perirectal abscess compressing the rectal lumen and base of the urinary bladder, associated with terminal ileal thickening and an ileocecal fistula. A flexible sigmoidoscopy with an endorectal ultrasound scan displayed a complex abscess with extensive mucosal and surrounding inflammation. An exploratory laparotomy revealed a Meckel's diverticulum with a large perforation at its base, positioned near the ileocecal fistula and immediately superior to the perirectal abscess. The section of small bowel containing the Meckel's diverticulum, the terminal ileum, and the cecum, were all resected, and the abscess was debrided.</p> <p>Conclusions</p> <p>Pre-operative diagnosis of Meckel's diverticulum can be difficult. If the nature of the complication makes ultimate surgical management likely, an early laparoscopic or open exploration should be performed to prevent the morbidity and mortality associated with late complications.</p

Plantar fasciitis and calcaneal spur formation are associated with abductor digiti minimi atrophy on MRI of the foot

Objective To determine the association of atrophy of the abductor digiti minimi muscle (ADMA), an MRI manifestation of chronic compression of the inferior calcaneal nerve suggesting the clinical diagnosis of Baxter’s neuropathy, with MRI markers of potential etiologies, including calcaneal spur formation, plantar fasciitis, calcaneal edema, Achilles tendinosis and posterior tibial tendon dysfunction (PTTD). Materials and methods Prevalence of calcaneal spur formation, plantar fasciitis, calcaneal edema, Achilles tendinosis and PTTD was assessed retrospectively on 100 MRI studies with ADMA and 100 MRI studies without ADMA. Patients ranged in age from 10–92 years. Pearson chi-square analyses and Fisher’s exact test were used to compare prevalence of the above findings in patients with and without ADMA. Logistic regression was used to determine which variables were significantly associated with ADMA. Results Among patients with ADMA, there was significantly greater age (57.2 years vs 40.8 years, p \u3c 0.001), presence of Achilles tendinosis (22.0% vs 3.0%, P \u3c 0.001), calcaneal edema (15.0% vs 3.0%, P = 0.005), calcaneal spur (48.0% vs 7.0%, P \u3c 0.001), plantar fasciitis (52.5% vs 11.0%, P \u3c 0.001), and PTTD (32.0% vs 11.0%, P \u3c 0.001). After multivariate logistic regression analysis, only age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.03, 1.09], calcaneal spur (OR 3.60, 95% CI 1.28, 10.17), and plantar fasciitis (OR 3.35, 95% CI 1.31, 8.56) remained significant. Conclusion Advancing age, calcaneal spur, and plantar fasciitis are significantly associated with ADMA. Their high odds ratios support the notion of a possible etiologic role for calcaneal spur and plantar fasciitis in the progression to Baxter’s neuropathy

The impact of mental health recovery narratives on recipients experiencing mental health problems: Qualitative analysis and change model.

BACKGROUND: Mental health recovery narratives are stories of recovery from mental health problems. Narratives may impact in helpful and harmful ways on those who receive them. The objective of this paper is to develop a change model identifying the range of possible impacts and how they occur. METHOD: Semi-structured interviews were conducted with adults with experience of mental health problems and recovery (n = 77). Participants were asked to share a mental health recovery narrative and to describe the impact of other people's recovery narratives on their own recovery. A change model was generated through iterative thematic analysis of transcripts. RESULTS: Change is initiated when a recipient develops a connection to a narrator or to the events descripted in their narrative. Change is mediated by the recipient recognising experiences shared with the narrator, noticing the achievements or difficulties of the narrator, learning how recovery happens, or experiencing emotional release. Helpful outcomes of receiving recovery narratives are connectedness, validation, hope, empowerment, appreciation, reference shift and stigma reduction. Harmful outcomes are a sense of inadequacy, disconnection, pessimism and burden. Impact is positively moderated by the perceived authenticity of the narrative, and can be reduced if the recipient is experiencing a crisis. CONCLUSIONS: Interventions that incorporate the use of recovery narratives, such as peer support, anti-stigma campaigns and bibliotherapy, can use the change model to maximise benefit and minimise harms from narratives. Interventions should incorporate a diverse range of narratives available through different mediums to enable a range of recipients to connect with and benefit from this material. Service providers using recovery narratives should preserve authenticity so as to maximise impact, for example by avoiding excessive editing

What if we decided to take care of everyone who needed treatment? Workforce planning in Mozambique using simulation of demand for HIV/AIDS care

Background: The growing AIDS epidemic in southern Africa is placing an increased strain on health systems, which are experiencing steadily rising patient loads. Health care systems are tackling the barriers to serving large populations in scaled-up operations. One of the most significant challenges in this effort is securing the health care workforce to deliver care in settings where the manpower is already in short supply. Methods: We have produced a demand-driven staffing model using simple spreadsheet technology, based on treatment protocols for HIV-positive patients that adhere to Mozambican guidelines. The model can be adjusted for the volumes of patients at differing stages of their disease, varying provider productivity, proportion who are pregnant, attrition rates, and other variables. Results: Our model projects the need for health workers using three different kinds of goals: 1) the number of patients to be placed on anti-retroviral therapy (ART), 2) the number of HIV-positive patients to be enrolled for treatment, and 3) the number of patients to be enrolled in a treatment facility per month. Conclusion: We propose three scenarios, depending on numbers of patients enrolled. In the first scenario, we start with 8000 patients on ART and increase that number to 58 000 at the end of three years (those were the goals for the country of Mozambique). This would require thirteen clinicians and just over ten nurses by the end of the first year, and 67 clinicians and 47 nurses at the end of the third year. In a second scenario, we start with 34 000 patients enrolled for care (not all of them on ART), and increase to 94 000 by the end of the third year, requiring a growth in clinician staff from 18 to 28. In a third scenario, we start a new clinic and enrol 200 new patients per month for three years, requiring 1.2 clinicians in year 1 and 2.2 by the end of year 3. Other clinician types in the model include nurses, social workers, pharmacists, phlebotomists, and peer counsellors. This planning tool could lead to more realistic and appropriate estimates of workforce levels required to provide high-quality HIV care in a low-resource settings

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe