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- Familial Risks of Kidney Failure in Sweden: A Nationwide Family Study.Akrawi DS, Li X, Sundquist J, Sundquist K, Zöller BPLoS One
- Coping with having a depressed mother: The role of stress and coping in hypothalamic-pituitary-adrenal axis dysfunction in girls at familial risk for major depression.Foland-Ross LC, Kircanski K, Gotlib IHDev Psychopathol
- Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.Roh JH, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DMJ Exp Med
- Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation.Tan SH, Senarath-Yapa K, Chung MT, Longaker MT, Wu JY, Nusse RProc Natl Acad Sci U S A
- Going viral and the fatal vulnerability of neurons from immunity, not from infection.Steinman LProc Natl Acad Sci U S A
- Amazonian landscapes and the bias in field studies of forest structure and biomass.Marvin DC, Asner GP, Knapp DE, Anderson CB, Martin RE, Sinca F, Tupayachi RProc Natl Acad Sci U S A
- Molecular architecture of the αβ T cell receptor-CD3 complex.Birnbaum ME, Berry R, Hsiao YS, Chen Z, Shingu-Vazquez MA, Yu X, Waghray D, Fischer S, McCluskey J, Rossjohn J, Walz T, Garcia KCProc Natl Acad Sci U S A
- Pilot Cluster Randomized Controlled Trials to Evaluate Adoption of Water, Sanitation, and Hygiene Interventions and Their Combination in Rural Western Kenya.Christensen G, Dentz HN, Pickering AJ, Bourdier T, Arnold BF, Colford JM, Null CAm J Trop Med Hyg
- Alternative pathways of osteoclastogenesis in inflammatory arthritis.Adamopoulos IE, Mellins EDNat Rev Rheumatol
- EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Whelan JS, Bielack SS, Marina N, Smeland S, Jovic G, Hook JM, Krailo M, Anninga J, Butterfass-Bahloul T, Böhling T, Calaminus G, Capra M, Deffenbaugh C, Dhooge C, Eriksson M, Flanagan AM, Gelderblom H, Goorin A, Gorlick R, Gosheger G, Grimer RJ, Hall KS, Helmke K, Hogendoorn PC, Jundt G, Kager L, Kuehne T, Lau C, Letson GD, Meyer J, Meyers P, Morris C, Mottl H, Nadel H, Nagarajan R, Randall RL, Schomberg P, Schwarz R, Teot LA, Sydes MR, Bernstein M, on behalf of the EURAMOS collaboratorsAnn Oncol
- Estimating the Efficacy of Alcoholics Anonymous without Self-Selection Bias: An Instrumental Variables Re-Analysis of Randomized Clinical Trials.Humphreys K, Blodgett JC, Wagner THAlcohol Clin Exp Res
- Computational modeling of chemo-bio-mechanical coupling: a systems-biology approach toward wound healing.Buganza Tepole A, Kuhl EComput Methods Biomech Biomed Engin
- The Impact of Drug Resistance Associated Amino Acid Changes on HIV-1 Subtype C on Susceptibility to Newer NNRTIs.Basson AE, Rhee SY, Parry CM, El-Khatib Z, Charalambous S, De Oliveira T, Pillay D, Hoffmann C, Katzenstein D, Shafer RW, Morris LAntimicrob Agents Chemother
Familial Risks of Kidney Failure in Sweden: A Nationwide Family Study.
PLoS One. 2014;9(11):e113353
Authors: Akrawi DS, Li X, Sundquist J, Sundquist K, Zöller B
BACKGROUND: The value of family history as a risk factor for kidney failure has not been determined in a nationwide setting.
AIM: This nationwide family study aimed to determine familial risks for kidney failure in Sweden.
METHODS: The Swedish multi-generation register on 0-78-year-old subjects were linked to the Swedish patient register and the Cause of death register for 1987-2010. Individuals diagnosed with acute kidney failure (n = 10063), chronic kidney failure (n = 18668), or unspecified kidney failure (n = 3731) were included. Kidney failure patients with cystic kidney disease, congenital kidney and urinary tract malformations, urolithiasis, and rare inherited kidney syndromes, and hyperoxaluria were excluded. Standardized incidence ratios (SIRs) were calculated for individuals whose parents/siblings were diagnosed with kidney failure compared to those whose parents or siblings were not.
RESULTS: The concordant (same disease) familial risks (sibling/parent history) were increased for chronic kidney failure SIR = 2.02 (95% confidence interval, CI 1.90-2.14) but not for acute kidney failure SIR = 1.08 (95% CI 0.94-1.22) and for unspecified kidney failure SIR = 1.25 (95% CI 0.94-1.63). However, the discordant (different disease) familial risk for acute kidney failure SIR = 1.19 (95% CI 1.06-1.32) and unspecified kidney failure SIR = 1.63 (95% CI 1.40-1.90) was significantly increased in individuals with a family history of chronic kidney failure. The familial risk for chronic kidney failure was similar for males SIR = 2.04 (95% CI 1.90-2.20) and females SIR = 1.97 (95% CI 1.78-2.17). Familial risks for chronic kidney failure were highest at age of 10-19 years SIR = 6.33 (95% CI 4.16-9.22).
CONCLUSIONS: The present study shows that family history is an important risk factor for chronic kidney failure but to a lower degree for acute kidney failure and unspecified kidney failure.
PMID: 25423475 [PubMed - as supplied by publisher]
Coping with having a depressed mother: The role of stress and coping in hypothalamic-pituitary-adrenal axis dysfunction in girls at familial risk for major depression.
Dev Psychopathol. 2014 Nov;26(4pt2):1401-1409
Authors: Foland-Ross LC, Kircanski K, Gotlib IH
Having a depressed mother is one of the strongest predictors of depression in adolescence. We investigated whether the stress of having a mother with recurrent depression is associated with dysfunction in adolescents in the HPA axis and whether the tendency to use involuntary coping strategies in dealing with this stress is associated with exacerbation of dysfunction in this system. Sixty-four never-disordered daughters of mothers with recurrent depression (high risk) and 64 never-disordered daughters of never-disordered mothers (low risk) completed diurnal cortisol and stress assessments. High-risk girls secreted more diurnal cortisol than did low-risk girls. Whereas low-risk girls secreted higher levels of cortisol with increasing stress associated with having a depressed mother, no such relation was present in high-risk girls. Finally, in contrast to low-risk girls, girls at familial risk for depression who more frequently used involuntary versus voluntary coping exhibited the greatest elevations in diurnal cortisol. These findings indicate that a tendency to utilize involuntary, as opposed to voluntary, coping strategies in dealing with stress involving maternal depression exacerbates already high levels of cortisol in youth at risk for depression. Future research that examines whether interventions aimed at increasing the use of voluntary coping strategies normalizes HPA axis dysfunction is of interest.
PMID: 25422969 [PubMed - as supplied by publisher]
Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.
J Exp Med. 2014 Nov 24;
Authors: Roh JH, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DM
Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.
PMID: 25422493 [PubMed - as supplied by publisher]
Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation.
Proc Natl Acad Sci U S A. 2014 Nov 24;
Authors: Tan SH, Senarath-Yapa K, Chung MT, Longaker MT, Wu JY, Nusse R
Wnt signaling is a critical regulator of bone development, but the identity and role of the Wnt-producing cells are still unclear. We addressed these questions through in situ hybridization, lineage tracing, and genetic experiments. First, we surveyed the expression of all 19 Wnt genes and Wnt target gene Axin2 in the neonatal mouse bone by in situ hybridization, and demonstrated-to our knowledge for the first time-that Osterix-expressing cells coexpress Wnt and Axin2. To track the behavior and cell fate of Axin2-expressing osteolineage cells, we performed lineage tracing and showed that they sustain bone formation over the long term. Finally, to examine the role of Wnts produced by Osterix-expressing cells, we inhibited Wnt secretion in vivo, and observed inappropriate differentiation, impaired proliferation, and diminished Wnt signaling response. Therefore, Osterix-expressing cells produce their own Wnts that in turn induce Wnt signaling response, thereby regulating their proliferation and differentiation.
PMID: 25422448 [PubMed - as supplied by publisher]
Going viral and the fatal vulnerability of neurons from immunity, not from infection.
Proc Natl Acad Sci U S A. 2014 Nov 24;
Authors: Steinman L
PMID: 25422437 [PubMed - as supplied by publisher]
Amazonian landscapes and the bias in field studies of forest structure and biomass.
Proc Natl Acad Sci U S A. 2014 Nov 24;
Authors: Marvin DC, Asner GP, Knapp DE, Anderson CB, Martin RE, Sinca F, Tupayachi R
Tropical forests convert more atmospheric carbon into biomass each year than any terrestrial ecosystem on Earth, underscoring the importance of accurate tropical forest structure and biomass maps for the understanding and management of the global carbon cycle. Ecologists have long used field inventory plots as the main tool for understanding forest structure and biomass at landscape-to-regional scales, under the implicit assumption that these plots accurately represent their surrounding landscape. However, no study has used continuous, high-spatial-resolution data to test whether field plots meet this assumption in tropical forests. Using airborne LiDAR (light detection and ranging) acquired over three regions in Peru, we assessed how representative a typical set of field plots are relative to their surrounding host landscapes. We uncovered substantial mean biases (9-98%) in forest canopy structure (height, gaps, and layers) and aboveground biomass in both lowland Amazonian and montane Andean landscapes. Moreover, simulations reveal that an impractical number of 1-ha field plots (from 10 to more than 100 per landscape) are needed to develop accurate estimates of aboveground biomass at landscape scales. These biases should temper the use of plots for extrapolations of forest dynamics to larger scales, and they demonstrate the need for a fundamental shift to high-resolution active remote sensing techniques as a primary sampling tool in tropical forest biomass studies. The potential decrease in the bias and uncertainty of remotely sensed estimates of forest structure and biomass is a vital step toward successful tropical forest conservation and climate-change mitigation policy.
PMID: 25422434 [PubMed - as supplied by publisher]
Molecular architecture of the αβ T cell receptor-CD3 complex.
Proc Natl Acad Sci U S A. 2014 Nov 24;
Authors: Birnbaum ME, Berry R, Hsiao YS, Chen Z, Shingu-Vazquez MA, Yu X, Waghray D, Fischer S, McCluskey J, Rossjohn J, Walz T, Garcia KC
αβ T-cell receptor (TCR) activation plays a crucial role for T-cell function. However, the TCR itself does not possess signaling domains. Instead, the TCR is noncovalently coupled to a conserved multisubunit signaling apparatus, the CD3 complex, that comprises the CD3εγ, CD3εδ, and CD3ζζ dimers. How antigen ligation by the TCR triggers CD3 activation and what structural role the CD3 extracellular domains (ECDs) play in the assembled TCR-CD3 complex remain unclear. Here, we use two complementary structural approaches to gain insight into the overall organization of the TCR-CD3 complex. Small-angle X-ray scattering of the soluble TCR-CD3εδ complex reveals the CD3εδ ECDs to sit underneath the TCR α-chain. The observed arrangement is consistent with EM images of the entire TCR-CD3 integral membrane complex, in which the CD3εδ and CD3εγ subunits were situated underneath the TCR α-chain and TCR β-chain, respectively. Interestingly, the TCR-CD3 transmembrane complex bound to peptide-MHC is a dimer in which two TCRs project outward from a central core composed of the CD3 ECDs and the TCR and CD3 transmembrane domains. This arrangement suggests a potential ligand-dependent dimerization mechanism for TCR signaling. Collectively, our data advance our understanding of the molecular organization of the TCR-CD3 complex, and provides a conceptual framework for the TCR activation mechanism.
PMID: 25422432 [PubMed - as supplied by publisher]
Pilot Cluster Randomized Controlled Trials to Evaluate Adoption of Water, Sanitation, and Hygiene Interventions and Their Combination in Rural Western Kenya.
Am J Trop Med Hyg. 2014 Nov 24;
Authors: Christensen G, Dentz HN, Pickering AJ, Bourdier T, Arnold BF, Colford JM, Null C
In preparation for a larger trial, the Water, Sanitation, and Hygiene (WASH) Benefits pilot study enrolled 72 villages and 499 subjects in two closely related randomized trials of WASH interventions in rural western Kenya. Intervention households received hardware and promotion for one of the following: water treatment, sanitation and latrine improvements, handwashing with soap, or the combination of all three. Interventions were clustered by village. A follow-up survey was conducted 4 months after intervention delivery to assess uptake. Intervention households were significantly more likely than controls to have chlorinated stored water (36-60% point increases), covers over latrine drop holes (55-75% point increases), less stool visible on latrine floors (16-47% point reductions), and a place for handwashing (71-85% point increases) with soap available (49-66% point increases). The high uptake in all arms shows that combined interventions can achieve high short-term adoption rates if well-designed.
PMID: 25422394 [PubMed - as supplied by publisher]
Alternative pathways of osteoclastogenesis in inflammatory arthritis.
Nat Rev Rheumatol. 2014 Nov 25;
Authors: Adamopoulos IE, Mellins ED
Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. Under physiological conditions, the osteoclastogenesis pathway depends on macrophage colony-stimulating factor 1 (CSF-1, also known as M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). However, an emerging hypothesis is that alternative pathways of osteoclast generation might be active during inflammatory arthritis. In this Perspectives article, we summarize the physiological pathway of osteoclastogenesis and then focus on experimental findings that support the hypothesis that infiltrating inflammatory cells and the cytokine milieu provide multiple routes to bone destruction. The precise identity of osteoclast precursor(s) is not yet known. We propose that myeloid cell differentiation during inflammation could be an important contributor to the differentiation of osteoclast populations and their associated pathologies. Understanding the dynamics of osteoclast differentiation in inflammatory arthritis is crucial for the development of therapeutic strategies for inflammatory joint disease in children and adults.
PMID: 25422000 [PubMed - as supplied by publisher]
EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.
Ann Oncol. 2014 Nov 24;
Authors: Whelan JS, Bielack SS, Marina N, Smeland S, Jovic G, Hook JM, Krailo M, Anninga J, Butterfass-Bahloul T, Böhling T, Calaminus G, Capra M, Deffenbaugh C, Dhooge C, Eriksson M, Flanagan AM, Gelderblom H, Goorin A, Gorlick R, Gosheger G, Grimer RJ, Hall KS, Helmke K, Hogendoorn PC, Jundt G, Kager L, Kuehne T, Lau C, Letson GD, Meyer J, Meyers P, Morris C, Mottl H, Nadel H, Nagarajan R, Randall RL, Schomberg P, Schwarz R, Teot LA, Sydes MR, Bernstein M, on behalf of the EURAMOS collaborators
BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response.
PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) x 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality-of-life was undertaken.
RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were 3 (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen.
CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future.
PMID: 25421877 [PubMed - as supplied by publisher]
Estimating the Efficacy of Alcoholics Anonymous without Self-Selection Bias: An Instrumental Variables Re-Analysis of Randomized Clinical Trials.
Alcohol Clin Exp Res. 2014 Nov;38(11):2688-94
Authors: Humphreys K, Blodgett JC, Wagner TH
BACKGROUND: Observational studies of Alcoholics Anonymous' (AA) effectiveness are vulnerable to self-selection bias because individuals choose whether or not to attend AA. The present study, therefore, employed an innovative statistical technique to derive a selection bias-free estimate of AA's impact.
METHODS: Six data sets from 5 National Institutes of Health-funded randomized trials (1 with 2 independent parallel arms) of AA facilitation interventions were analyzed using instrumental variables models. Alcohol-dependent individuals in one of the data sets (n = 774) were analyzed separately from the rest of sample (n = 1,582 individuals pooled from 5 data sets) because of heterogeneity in sample parameters. Randomization itself was used as the instrumental variable.
RESULTS: Randomization was a good instrument in both samples, effectively predicting increased AA attendance that could not be attributed to self-selection. In 5 of the 6 data sets, which were pooled for analysis, increased AA attendance that was attributable to randomization (i.e., free of self-selection bias) was effective at increasing days of abstinence at 3-month (B = 0.38, p = 0.001) and 15-month (B = 0.42, p = 0.04) follow-up. However, in the remaining data set, in which preexisting AA attendance was much higher, further increases in AA involvement caused by the randomly assigned facilitation intervention did not affect drinking outcome.
CONCLUSIONS: For most individuals seeking help for alcohol problems, increasing AA attendance leads to short- and long-term decreases in alcohol consumption that cannot be attributed to self-selection. However, for populations with high preexisting AA involvement, further increases in AA attendance may have little impact.
PMID: 25421504 [PubMed - in process]
Computational modeling of chemo-bio-mechanical coupling: a systems-biology approach toward wound healing.
Comput Methods Biomech Biomed Engin. 2014 Nov 24;:1-18
Authors: Buganza Tepole A, Kuhl E
Wound healing is a synchronized cascade of chemical, biological, and mechanical phenomena, which act in concert to restore the damaged tissue. An imbalance between these events can induce painful scarring. Despite intense efforts to decipher the mechanisms of wound healing, the role of mechanics remains poorly understood. Here, we establish a computational systems biology model to identify the chemical, biological, and mechanical mechanisms of scar formation. First, we introduce the generic problem of coupled chemo-bio-mechanics. Then, we introduce the model problem of wound healing in terms of a particular chemical signal, inflammation, a particular biological cell type, fibroblasts, and a particular mechanical model, isotropic hyperelasticity. We explore the cross-talk between chemical, biological, and mechanical signals and show that all three fields have a significant impact on scar formation. Our model is the first step toward rigorous multiscale, multifield modeling in wound healing. Our formulation has the potential to improve effective wound management and optimize treatment on an individualized patient-specific basis.
PMID: 25421487 [PubMed - as supplied by publisher]
The Impact of Drug Resistance Associated Amino Acid Changes on HIV-1 Subtype C on Susceptibility to Newer NNRTIs.
Antimicrob Agents Chemother. 2014 Nov 24;
Authors: Basson AE, Rhee SY, Parry CM, El-Khatib Z, Charalambous S, De Oliveira T, Pillay D, Hoffmann C, Katzenstein D, Shafer RW, Morris L
OBJECTIVE: To assess the phenotypic susceptibility of NNRTI resistance associated amino acid changes to newer NNRTIs in HIV-1 subtype C.
METHODS: A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones were created and assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV) and nevirapine (NVP) in an in vitro single-cycle phenotypic assay.
RESULTS: Amino acid substitutions E138Q/R, Y181I/V and M230L conferred high-level resistance to ETR while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution caused decreased susceptibility to ETR and to a lesser extent RPV when combined with other mutations. This included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was in most cases <1%. The more common EFV/NVP resistance substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. Low-level resistance to RPV and ETR conferred by the RPV-specific amino acid substitution E138K was not significantly enhanced in the presence of the common NRTI substitution M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP while only 24% and 16% were resistant to ETR and RPV, respectively.
CONCLUSION: Only a few, relatively rare, NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background suggesting that these newer NNRTI would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.
PMID: 25421485 [PubMed - as supplied by publisher]
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