One size does not fit all - Application of accelerometer thresholds in chronic disease

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record National Institute for Health Research (NIHR

Thirst Perception And Drinking In Euhydrate And Dehydrate Human Subjects

Summary: Studies on how the body senses the need to correct extracellular and intracellular volumes and ionic concentration changes is relatively scanty. The present studies were designed to determine the effect of oral distilled water (DW) and saline loads, gargling with DW and DW preload on thirst perception (TP) and drinking in euhydrate and dehydrated subjects. The subjects were healthy male volunteers between the ages of 17 and 35 years. Group A subjects were given DW or various concentrations of sodium chloride (NaCl) orally. Subjects in groups B, C and D were dehydrated for 18 hours before the experiment. Group B gargled 500ml of DW in divided volume of 50ml at five minutes interval over a period of 50 minutes. Group C gargled with DW and different concentrations of NaCl. Group D were preloaded with four volumes of DW before ad libitum DW intake. TP was rated using the Visual Analogue Scale. Results showed that in Group A, drinking DW reduced TP, suggesting that baseline TP in normal euhydrate subjects is slightly elevated. Drinking DW reduced TP more than drinking NaCl solutions. Gargling resulted in a gradual fall in TP. The decrease in TP was statistically significant after 30 minutes of gargling. Gargling with different concentrations of NaCl solutions resulted in significant reductions in TP in all the groups. There was a significant decrease in TP in the group preloaded with 1000ml of distilled water at 5 minutes of rehydration. At 20 minutes TP was abolished suggesting that approximately 1000ml of water was needed for the rehydration. These results show that baseline TP in euhydrates is elevated and that TP increases in dehydrated subjects. Gargling reduces TP, but did not abolish thirst. It is suggested that a fall in plasma osmolality due to drinking may be responsible for abolishing thirst

Comparison of Load-Bearing Capacities of 3-Unit Fiber-Reinforced Composite Adhesive Bridges with Different Framework Designs

Background: The aim of this study was to investigate and compare the load-bearing capacities of three-unit direct resin-bonded fiber-reinforced composite fixed dental prosthesis with different framework designs.Material/Methods: Sixty mandibular premolar and molar teeth without caries were collected and direct glass fiber-resin fixed FDPs were divided into 6 groups (n=10). Each group was restored via direct technique with different designs. In Group 1, the inlay-retained bridges formed 2 unidirectional FRC frameworks and pontic-reinforced transversal FRC. In Group 2, the inlay-retained bridges were supported by unidirectional lingual and occlusal FRC frameworks. Group 3, had buccal and lingual unidirectional FRC frameworks without the inlay cavities. Group 4 had reinforced inlay cavities and buccal-lingual FRC with unidirectional FRC frameworks. Group 5, had a circular form of fiber reinforcement around cusps in addition to buccal-lingual FRC frameworks. Group 6 had a circular form of fiber reinforcement around cusps with 2 bidirectional FRC frameworks into inlay cavities. All groups were loaded until final fracture using a universal testing machine at a crosshead speed of 1 mm/min.Results: Mean values of the groups were determined with ANOVA and Tukey HSD. When all data were evaluated, Group 6 had the highest load-bearing capacities and revealed significant differences from Group 3 and Group 4. Group 6 had the highest strain (p>0.05). When the fracture patterns were investigated, Group 6 had the durability to sustain fracture propagation within the restoration.Conclusions: The efficiency of fiber reinforcement of the restorations alters not only the amount of fiber, but also the design of the restoration with fibers

Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers

The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions

Pancytopenia due to iron deficiency worsened by iron infusion: a case report

<p>Abstract</p> <p>Introduction</p> <p>Iron deficiency anemia is commonly associated with thrombocytosis, although thrombocytopenia has been reported in occasional patients with iron-deficiency anemia. Much less common is the development of thrombocytopenia following replenishment of iron stores.</p> <p>Case Presentation</p> <p>We present the unusual case of a 39 year old African American female Jehovah's Witness who presented with a 10 month history of menorrhagia and pancytopenia. Laboratory investigations confirmed a severe iron deficiency. Since blood transfusion was unacceptable to her, she was started on intravenous iron replacement therapy. This precipitated a sudden drop in both her platelet and white blood cell counts. Histopathological examination of the bone marrow revealed a hypercellular marrow with orderly trilineage hematopoiesis, iron deficiency anemia, granulocytic hyperplasia, and mild megakaryocytic hypoplasia. Both her white blood cell and platelet counts recovered uneventfully with continuing iron supplementation. The possible mechanism for this phenomenon is discussed in this report.</p> <p>Conclusion</p> <p>This case illustrates two rather uncommon associations of a very common problem. Severe iron deficiency anemia may be associated with pancytopenia and iron replacement may cause a transient decline in megakaryopoiesis and leukopoiesis. Severe iron deficiency should be added to the list of conditions leading to thrombocytopenia.</p

Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events

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Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.Portuguese Fundacao para Ciencia e Tecnologia (FCT) [PTDC/EXPL/MARBIO/0430/2013]; CCMAR FCT Plurianual financing [UID/Multi/04326/2013]; FCT [SFRH/BD/111226/2015, SFRH/BD/108842/2015, SFRH/BPD/89889/2012]; FCT-IF Starting Grant [IF/01274/2014]info:eu-repo/semantics/publishedVersio

Sub-Optimal Vitamin B-12 Levels among ART-Naïve HIV-Positive Individuals in an Urban Cohort in Uganda

Malnutrition is common among HIV-infected individuals and is often accompanied by low serum levels of micronutrients. Vitamin B-12 deficiency has been associated with various factors including faster HIV disease progression and CD4 depletion in resource-rich settings. To describe prevalence and factors associated with sub-optimal vitamin B-12 levels among HIV-infected antiretroviral therapy (ART) naïve adults in a resource-poor setting, we performed a cross-sectional study with a retrospective chart review among individuals attending either the Mulago-Mbarara teaching hospitals’ Joint AIDS Program (MJAP) or the Infectious Diseases Institute (IDI) clinics, in Kampala, Uganda. Logistic regression was used to determine factors associated with sub-optimal vitamin B-12. The mean vitamin B-12 level was 384 pg/ml, normal range (200–900). Sub-optimal vitamin B-12 levels (<300 pg/ml) were found in 75/204 (36.8%). Twenty-one of 204 (10.3%) had vitamin B-12 deficiency (<200 pg/ml) while 54/204 (26.5%) had marginal depletion (200–300 pg/ml). Irritable mood was observed more among individuals with sub-optimal vitamin B-12 levels (OR 2.5, 95% CI; 1.1–5.6, P = 0.03). Increasing MCV was associated with decreasing serum B-12 category; 86.9 fl (±5.1) vs. 83 fl (±8.4) vs. 82 fl (±8.4) for B-12 deficiency, marginal and normal B-12 categories respectively (test for trend, P = 0.017). Compared to normal B-12, individuals with vitamin B-12 deficiency had a longer known duration of HIV infection: 42.2 months (±27.1) vs. 29.4 months (±23.8; P = 0.02). Participants eligible for ART (CD4<350 cells/µl) with sub-optimal B-12 had a higher mean rate of CD4 decline compared to counterparts with normal B-12; 118 (±145) vs. 22 (±115) cells/µl/year, P = 0.01 respectively. The prevalence of a sub-optimal vitamin B-12 was high in this HIV-infected, ART-naïve adult clinic population in urban Uganda. We recommend prospective studies to further clarify the causal relationships of sub-optimal vitamin B-12, and explore the role of vitamin B-12 supplementation in immune recovery