No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis

BACKGROUND: Mitochondrial dysfunction is an established feature of multiple sclerosis (MS). We recently described high levels of mitochondrial DNA (mtDNA) deletions within respiratory enzyme-deficient (lacking mitochondrial respiratory chain complex IV with intact complex II) neurons and choroid plexus epithelial cells in progressive MS. OBJECTIVES: The objective of this paper is to determine whether respiratory enzyme deficiency and mtDNA deletions in MS were in excess of age-related changes within muscle, which, like neurons, are post-mitotic cells that frequently harbour mtDNA deletions with ageing and in disease. METHODS: In progressive MS cases (n=17), known to harbour an excess of mtDNA deletions in the central nervous system (CNS), and controls (n=15), we studied muscle (paraspinal) and explored mitochondria in single fibres. Histochemistry, immunohistochemistry, laser microdissection, real-time polymerase chain reaction (PCR), long-range PCR and sequencing were used to resolve the single muscle fibres. RESULTS: The percentage of respiratory enzyme-deficient muscle fibres, mtDNA deletion level and percentage of muscle fibres harbouring high levels of mtDNA deletions were not significantly different in MS compared with controls. CONCLUSION: Our findings do not provide support to the existence of a diffuse mitochondrial abnormality involving multiple systems in MS. Understanding the cause(s) of the CNS mitochondrial dysfunction in progressive MS remains a research priority

Transcriptional regulation of the IGF signaling pathway by amino acids and insulin-like growth factors during myogenesis in Atlantic salmon

The insulin-like growth factor signalling pathway is an important regulator of skeletal muscle growth. We examined the mRNA expression of components of the insulin-like growth factor (IGF) signalling pathway as well as Fibroblast Growth Factor 2 (FGF2) during maturation of myotubes in primary cell cultures isolated from fast myotomal muscle of Atlantic salmon (Salmo salar). The transcriptional regulation of IGFs and IGFBP expression by amino acids and insulin-like growth factors was also investigated. Proliferation of cells was 15% d(-1) at days 2 and 3 of the culture, increasing to 66% d(-1) at day 6. Three clusters of elevated gene expression were observed during the maturation of the culture associated with mono-nucleic cells (IGFBP5.1 and 5.2, IGFBP-6, IGFBP-rP1, IGFBP-2.2 and IGF-II), the initial proliferation phase (IGF-I, IGFBP-4, FGF2 and IGF-IRb) and terminal differentiation and myotube production (IGF2R, IGF-IRa). In cells starved of amino acids and serum for 72 h, IGF-I mRNA decreased 10-fold which was reversed by amino acid replacement. Addition of IGF-I and amino acids to starved cells resulted in an 18-fold increase in IGF-I mRNA indicating synergistic effects and the activation of additional pathway(s) leading to IGF-I production via a positive feedback mechanism. IGF-II, IGFBP-5.1 and IGFBP-5.2 expression was unchanged in starved cells, but increased with amino acid replacement. Synergistic increases in expression of IGFBP5.2 and IGFBP-4, but not IGFBP5.1 were observed with addition of IGF-I, IGF-II or insulin and amino acids to the medium. IGF-I and IGF-II directly stimulated IGFBP-6 expression, but not when amino acids were present. These findings indicate that amino acids alone are sufficient to stimulate myogenesis in myoblasts and that IGF-I production is controlled by both endocrine and paracrine pathways. A model depicting the transcriptional regulation of the IGF pathway in Atlantic salmon muscle following feeding is proposed.Publisher PDFPeer reviewe

Low coverage of intermittent preventive treatment for malaria in pregnancy in Nigeria: demand-side influences

BACKGROUND: Nigeria instituted intermittent preventive treatment for malaria (IPTp) using sulphadoxine-pyrimethamine (SP) for pregnant women in 2001, but coverage remains low. This study examined the influence of demand side factors on IPTp coverage. METHODS: Data were collected using a household survey from 1307 women who were delivered of a live baby within the one-year period preceding the study and through an exit poll from 146 women attending antenatal clinics (ANC). Data analysis examined coverage based on the national and WHO guidelines for IPTp delivery which differ with regards to use of IPTp in the last month of pregnancy. Focus group discussions (FGDs) were undertaken to further explain demand side constraints to coverage. RESULTS: From the household survey, 96.1% of respondents attended ANC, with most having five or more visits. Overall IPTp coverage for the first and second doses was 13.7% and 7.3% respectively. The coverage was higher in the urban areas compared to rural areas (p < 0.01). Amongst women who could have received IPTp based on the timing of their attendance, only 14.1% and 14.3% were offered the first dose based on national and WHO guidelines, while 7.7% and 7.5% were offered the second dose respectively giving significant missed opportunities. Amongst ANC attendees offered first and second doses, 98.9% and 96.9% respectively took the medicine. Only 13.6% and 21.5% of these clients reported taking the drug under direct observation. The low level of coverage was confirmed by exit survey data, which found coverage of 11.6% and 3.0% for the first and second doses. The FGDs revealed that women do not have many concerns about side effects, but they take drugs providers give them because they believe such drugs must be safe. CONCLUSION: This study found low coverage of IPTp and high levels of missed opportunities supporting findings that high ANC attendance does not guarantee high IPTp coverage. Demand side factors such as ANC attendance, appropriate timing of attendance, and perceptions about side effects were not constraining factors to increased coverage, raising the need to examine supply side factors

Malaria associated symptoms in pregnant women followed-up in Benin

<p>Abstract</p> <p>Background</p> <p>It is generally agreed that in high transmission areas, pregnant women have acquired a partial immunity to malaria and when infected they present few or no symptoms. However, longitudinal cohort studies investigating the clinical presentation of malaria infection in pregnant women in stable endemic areas are lacking, and the few studies exploring this issue are unconclusive.</p> <p>Methods</p> <p>A prospective cohort of women followed monthly during pregnancy was conducted in three rural dispensaries in Benin from August 2008 to September 2010. The presence of symptoms suggestive of malaria infection in 982 women during antenatal visits (ANV), unscheduled visits and delivery were analysed. A multivariate logistic regression was used to determine the association between symptoms and a positive thick blood smear (TBS).</p> <p>Results</p> <p>During routine ANVs, headache was the only symptom associated with a higher risk of positive TBS (aOR = 1.9; p < 0.001). On the occasion of unscheduled visits, fever (aOR = 5.2; p < 0.001), headache (aOR = 2.1; p = 0.004) and shivering (aOR = 3.1; p < 0.001) were significantly associated with a malaria infection and almost 90% of infected women presented at least one of these symptoms. Two thirds of symptomatic malaria infections during unscheduled visits occurred in late pregnancy and long after the last intermittent preventive treatment dose (IPTp).</p> <p>Conclusion</p> <p>The majority of pregnant women were symptomless during routine visits when infected with malaria in an endemic stable area. The only suggestive sign of malaria (fever) was associated with malaria only on the occasion of unscheduled visits. The prevention of malaria in pregnancy could be improved by reassessing the design of IPTp, i.e. by determining an optimal number of doses and time of administration of anti-malarial drugs.</p

The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on pcr-diagnosed malaria at delivery: A randomized controlled trial

10.1371/journal.pone.0041123PLoS ONE77

Specifying the design for customer learning in the mixed reality experience

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A Randomized Placebo-Controlled Trial of Intermittent Preventive Treatment in Pregnant Women in the Context of Insecticide Treated Nets Delivered through the Antenatal Clinic

Background:Current recommendations to prevent malaria in African pregnant women rely on insecticide treated nets(ITNs) and intermittent preventive treatment (IPTp). However, there is no information on the safety and efficacy of theircombined use.Methods:1030 pregnant Mozambican women of all gravidities received a long-lasting ITN during antenatal clinic (ANC)visits and, irrespective of HIV status, were enrolled in a randomised, double blind, placebo-controlled trial, to assess thesafety and efficacy of 2-dose sulphadoxine-pyrimethamine (SP). The main outcome was the reduction in low birth weight.Findings:Two-dose SP was safe and well tolerated, but was not associated with reductions in anaemia prevalence atdelivery (RR, 0.92 [95% CI, 0.79-1.08]), low birth weight (RR, 0.99 [95% CI, 0.70-1.39]), or overall placental infection(p = 0.964). However, the SP group showed a 40% reduction (95% CI, 7.40-61.20]; p = 0.020) in the incidence of clinicalmalaria during pregnancy, and reductions in the prevalence of peripheral parasitaemia (7.10% vs 15.15%) (p,0.001), and ofactively infected placentas (7.04% vs 13.60%) (p = 0.002). There was a reduction in severe anaemia at delivery of borderlinestatistical significance (p = 0.055). These effects were not modified by gravidity or HIV status. Reported ITN's use was morethan 90% in both groups.Conclusions:Two-dose SP was associated with a reduction in some indicators, but these were not translated to significantimprovement in other maternal or birth outcomes. The use of ITNs during pregnancy may reduce the need to administerIPTp. ITNs should be part of the ANC package in sub-Saharan Afric

Distinct distribution and prognostic significance of molecular subtypes of breast cancer in Chinese women: a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Molecular classification of breast cancer is an important prognostic factor. The distribution of molecular subtypes of breast cancer and their prognostic value has not been well documented in Asians.</p> <p>Methods</p> <p>A total of 2,791 breast cancer patients recruited for a population-based cohort study were evaluated for molecular subtypes of breast cancer by immunohistochemical assays. Data on clinicopathological characteristics were confirmed by centralized pathology review. The average follow-up of the patients was 53.4 months. Overall and disease-free survival by molecular subtypes of breast cancer were evaluated.</p> <p>Results</p> <p>The prevalence of the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and triple-negative subtypes were 48.6%, 16.7%, 13.7%, and 12.9%, respectively. The luminal A subtype was more likely to be diagnosed in older women (P = 0.03) and had a stronger correlation with favorable clinicopathological factors (smaller tumor size, lower histologic grade, and earlier TNM stage) than the triple-negative or HER2 subtypes. Women with triple-negative breast cancer had a higher frequency of family history of breast cancer than women with other subtypes (P = 0.048). The 5-year overall/disease-free survival percentages for the luminal A, luminal B, HER2, and triple-negative subtypes were 92.9%/88.6%, 88.6%/85.1%, 83.2%/79.1%, and 80.7%/76.0%, respectively. A similar pattern was observed in multivariate analyses. Immunotherapy was associated with improved overall and disease-free survival for luminal A breast cancer, but reduced disease-free survival (HR = 2.21, 95% CI, 1.09-4.48) for the HER2 subtype of breast cancer.</p> <p>Conclusions</p> <p>The triple-negative and HER2 subtypes were associated with poorer outcomes compared with the luminal A subtype among these Chinese women. The HER2 subtype was more prevalent in this Chinese population compared with Western populations, suggesting the importance of standardized HER2 detection and anti-HER2 therapy to potentially benefit a high proportion of breast cancer patients in China.</p

Omnichannel Value Chain: Mapping Digital Technologies for Channel Integration Activities

In order to provide a seamless customer experience, researchers and practitioners have proposed creation of an omnichannel retailing environment by integrating online and offline channels. Channel integration necessitates use of digital technologies and there are myriads of technological solutions available. However, retailers are struggling with selection and implementation of suitable technologies to add value through channel integration. Despite the strong practical need, this issue has not been effectively addressed in the academic literature. This paper presents an omnichannel value chain underpinned by Porter’s value chain model. We identify ten channel integration activities for value creation by carrying out a synthesis of current research on omnichannel retailing. Enabling digital technologies are then mapped to these activities using technology implementation examples and provide a guideline for retailers to select appropriate technologies for the identified value creation activities

Aberrant Mitochondrial Homeostasis in the Skeletal Muscle of Sedentary Older Adults

The role of mitochondrial dysfunction and oxidative stress has been extensively characterized in the aetiology of sarcopenia (aging-associated loss of muscle mass) and muscle wasting as a result of muscle disuse. What remains less clear is whether the decline in skeletal muscle mitochondrial oxidative capacity is purely a function of the aging process or if the sedentary lifestyle of older adult subjects has confounded previous reports. The objective of the present study was to investigate if a recreationally active lifestyle in older adults can conserve skeletal muscle strength and functionality, chronic systemic inflammation, mitochondrial biogenesis and oxidative capacity, and cellular antioxidant capacity. To that end, muscle biopsies were taken from the vastus lateralis of young and age-matched recreationally active older and sedentary older men and women (N = 10/group; ♀  =  ♂). We show that a physically active lifestyle is associated with the partial compensatory preservation of mitochondrial biogenesis, and cellular oxidative and antioxidant capacity in skeletal muscle of older adults. Conversely a sedentary lifestyle, associated with osteoarthritis-mediated physical inactivity, is associated with reduced mitochondrial function, dysregulation of cellular redox status and chronic systemic inflammation that renders the skeletal muscle intracellular environment prone to reactive oxygen species-mediated toxicity. We propose that an active lifestyle is an important determinant of quality of life and molecular progression of aging in skeletal muscle of the elderly, and is a viable therapy for attenuating and/or reversing skeletal muscle strength declines and mitochondrial abnormalities associated with aging