tbuckley/cabot-search huggingface dataset:
Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy
Authors: John F. O’Toole, Yangjian Liu, Erica E. Davis, Christopher J. Westlake, Massimo Attanasio, Edgar A. Otto, Dominik Seelow, Gudrun Nurnberg, Christian Becker, Matti Nuutinen, Mikko Kärppä, Jaakko Ignatius, Johanna Uusimaa, Salla Pakanen, Elisa Jaakkola, Lambertus P. van den Heuvel, Henry Fehrenbach, Roger Wiggins, Meera Goyal, Weibin Zhou, Matthias T.F. Wolf, Eric Wise, Juliana Helou, Susan J. Allen, Carlos A. Murga-Zamalloa, Shazia Ashraf, Moumita Chaki, Saskia Heeringa, Gil Chernin, Bethan E. Hoskins, Hassan Chaib, Joseph Gleeson, Takehiro Kusakabe, Takako Suzuki, R. Elwyn Isaac, Lynne M. Quarmby, Bryan Tennant, Hisashi Fujioka, Hannu Tuominen, Ilmo Hassinen, Hellevi Lohi, Judith L. van Houten, Agnes Rotig, John A. Sayer, Boris Rolinski, Peter Freisinger, Sethu M. Madhavan, Martina Herzer, Florence Madignier, Holger Prokisch, Peter Nurnberg, Peter Jackson, Hemant Khanna, Nicholas Katsanis, Friedhelm Hildebrandt
Journal: Journal of Clinical Investigation (2010)

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients
Authors: Isa E.L.M. Kuppens, Els O. Witteveen, Roxanne C. Jewell, Sandra A. Radema, Elaine M. Paul, Steve G. Mangum, Jos H. Beijnen, Emile E. Voest, Jan H.M. Schellens
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein–mediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. Experimental Design: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m2 i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. Results: Complete apparent oral bioavailability of topotecan (102 ± 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level. Conclusion: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.
Allelic variation at the C-reactive protein gene associates to both hand osteoarthritis severity and serum high sensitive C-reactive protein levels in the GARP study
Authors: S D Bos, H E D Suchiman, M Kloppenburg, J J Houwing-Duistermaat, M P Hellio le Graverand, A B Seymour, H M Kroon, P E Slagboom, I Meulenbelt
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To gain more insight into the role of genetic variation of the C-reactive protein (CRP) gene in serum CRP levels and osteoarthritis (OA). <h3>Methods:</h3> Serum high sensitive CRP (S-HsCRP) levels were measured in the Genetics of osteoARthritis and Progression (GARP) study. Furthermore, to assess genetic variation of the CRP gene, genotypes of five tagging single nucleotide polymorphisms were assessed in the GARP study and a random control sample. <h3>Results:</h3> A significant and consistent relation between S-HsCRP levels and observed haplotypes was identified. Additionally, a CRP haplotype, which also associated to a significantly higher expected phenotypic mean S-HsCRP level, was associated to severe hand OA. This haplotype was tagged by a single nucleotide polymorphism (rs3091244). Carriers of this allele have an increased risk for the presence of severe hand OA with an OR of 2.3 (95% confidence interval 1.2 to 4.3, p = 0.009). <h3>Conclusions:</h3> A haplotype of the CRP gene, associated to high basal S-HsCRP level, is also associated to severity of hand OA, indicating that innate high basal S-HsCRP levels may influence OA onset.
Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a)
Authors: F Hartgens, G Rietjens, H A Keizer, H Kuipers, B H R Wolffenbuttel
Journal: British Journal of Sports Medicine (2004)

To investigate the effects of two different regimens of androgenic-anabolic steroid (AAS) administration on serum lipid and lipoproteins, and recovery of these variables after drug cessation, as indicators of the risk for cardiovascular disease in healthy male strength athletes.In a non-blinded study (study 1) serum lipoproteins and lipids were assessed in 19 subjects who self administered AASs for eight or 14 weeks, and in 16 non-using volunteers. In a randomised double blind, placebo controlled design, the effects of intramuscular administration of nandrolone decanoate (200 mg/week) for eight weeks on the same variables in 16 bodybuilders were studied (study 2). Fasting serum concentrations of total cholesterol, triglycerides, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C), HDL3-cholesterol (HDL3-C), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), and lipoprotein (a) (Lp(a)) were determined.In study 1 AAS administration led to decreases in serum concentrations of HDL-C (from 1.08 (0.30) to 0.43 (0.22) mmol/l), HDL2-C (from 0.21 (0.18) to 0.05 (0.03) mmol/l), HDL3-C (from 0.87 (0.24) to 0.40 (0.20) mmol/l, and Apo-A1 (from 1.41 (0.27) to 0.71 (0.34) g/l), whereas Apo-B increased from 0.96 (0.13) to 1.32 (0.28) g/l. Serum Lp(a) declined from 189 (315) to 32 (63) U/l. Total cholesterol and triglycerides did not change significantly. Alterations after eight and 14 weeks of AAS administration were comparable. No changes occurred in the controls. Six weeks after AAS cessation, serum HDL-C, HDL2-C, Apo-A1, Apo-B, and Lp(a) had still not returned to baseline concentrations. Administration of AAS for 14 weeks was associated with slower recovery to pretreatment concentrations than administration for eight weeks. In study 2, nandrolone decanoate did not influence serum triglycerides, total cholesterol, HDL-C, HDL2-C, HDL3-C, Apo-A1, and Apo-B concentrations after four and eight weeks of intervention, nor six weeks after withdrawal. However, Lp(a) concentrations decreased significantly from 103 (68) to 65 (44) U/l in the nandrolone decanoate group, and in the placebo group a smaller reduction from 245 (245) to 201 (194) U/l was observed. Six weeks after the intervention period, Lp(a) concentrations had returned to baseline values in both groups.Self administration of several AASs simultaneously for eight or 14 weeks produces comparable profound unfavourable effects on lipids and lipoproteins, leading to an increased atherogenic lipid profile, despite a beneficial effect on Lp(a) concentration. The changes persist after AAS withdrawal, and normalisation depends on the duration of the drug abuse. Eight weeks of administration of nandrolone decanoate does not affect lipid and lipoprotein concentrations, although it may selectively reduce Lp(a) concentrations. The effect of this on atherogenesis remains to be established.
Clinical Lecture on a Case of Hemiplegia of the Right Side, Anaesthesia of the Left and Unilateral Sweating of that Side of the Face
Authors: T. M. Anderson
Journal: BMJ (1882)

GENTLEMEN, -The case of James K. (from bed 14, of ward II), who lies before you, is one of great interest, whether regard be had to the unusual combination of symptoms which he presents, or to the question of diagnosis and treatment.He is forty-nine years of age, and was admitted on January iith, 1882, suffering from paralysis and from pains in the joints.He seems to have enjoyed good health until December 1867, when he had a severe attack of rheumatic fever, which lasted for seven weeks, but from which he made a good recovery.He remained well for about eight years, and then (1875) he began to suffer from giddiness, with a sense of fulness in the neck, which was accompanied by "twitching and a clicking sound" at the napeespecially on stooping, raising heavy weights, or otherwise exerting himself.This continued until the middle of the following year (I876), when one evening, when returning from work, and ascending a stair, he suddenly experienced a " feeling of weakness"; and, supposing that it would soon pass off, he sat down, but, upon attempting to rise again, he was unable to do so.
Effect of a congregation-based intervention on uptake of HIV testing and linkage to care in pregnant women in Nigeria (Baby Shower): a cluster randomised trial
Authors: Echezona E Ezeanolue, Michael C Obiefune, Chinenye O Ezeanolue, John E Ehiri, Alice Osuji, Amaka G Ogidi, Aaron T Hunt, Dina Patel, Wei Yang, Jennifer Pharr, Gbenga Ogedegbe
Journal: The Lancet Global Health (2015)

BackgroundFew effective community-based interventions exist to increase HIV testing and uptake of antiretroviral therapy (ART) in pregnant women in hard-to-reach resource-limited settings. We assessed whether delivery of an intervention through churches, the Healthy Beginning Initiative, would increase uptake of HIV testing in pregnant women compared with standard health facility referral.MethodsIn this cluster randomised trial, we enrolled self-identified pregnant women aged 18 years and older who attended churches in southeast Nigeria. We randomised churches (clusters) to intervention or control groups, stratified by mean annual number of infant baptisms (<80 vs ≥80). The Healthy Beginning Initiative intervention included health education and on-site laboratory testing implemented during baby showers in intervention group churches, whereas participants in control group churches were referred to health facilities as standard. Participants and investigators were aware of church allocation. The primary outcome was confirmed HIV testing. This trial is registered with ClinicalTrials.gov, identifier number NCT 01795261.FindingsBetween Jan 20, 2013, and Aug 31, 2014, we enrolled 3002 participants at 40 churches (20 per group). 1309 (79%) of 1647 women attended antenatal care in the intervention group compared with 1080 (80%) of 1355 in the control group. 1514 women (92%) in the intervention group had an HIV test compared with 740 (55%) controls (adjusted odds ratio 11·2, 95% CI 8·77–14·25; p<0·0001).InterpretationCulturally adapted, community-based programmes such as the Healthy Beginning Initiative can be effective in increasing HIV screening in pregnant women in resource-limited settings.FundingUS National Institutes of Health and US President's Emergency Plan for AIDS Relief.
Recurrent Membranous Nephropathy in an Allograft Caused by IgG3κ Targeting the PLA2 Receptor
Authors: Hanna Debiec, Melanie Hanoy, Arnaud Francois, Dominique Guerrot, Sophie Ferlicot, Catherine Johanet, Pierre Aucouturier, Michel Godin, Pierre Ronco
Journal: Journal of the American Society of Nephrology (2012)

Up to 80% of patients with idiopathic membranous nephropathy have non-complement-fixing IgG4 autoantibodies to the phospholipase A2 receptor (PLA2R). Membranous nephropathy recurs in approximately 40% of patients after kidney transplantation, but the mechanism is unknown. Here, we describe a patient with recurrent membranous nephropathy 13 days after kidney transplantation whose graft biopsy specimen showed granular staining for C3, C5b-9, C1q, and IgG3κ; electron microscopy revealed subepithelial nonorganized deposits. A search for hematologic disorders was negative. Retrospective evaluation of a biopsy sample from the native kidney revealed a similar pattern: monotypic IgG3κ deposits together with C3, C1q, and C5b-9. Glomerular deposits contained PLA2R in both the graft and the native kidney, suggesting that the recurrence was the result of circulating anti-PLA2R antibodies binding to PLA2R antigen expressed on donor podocytes. Confocal analysis of anti-PLA2R and antihuman IgG3 showed co-localization, and the patient had IgG3κ-restricted circulating anti-PLA2R antibodies. Treatment with rituximab stabilized both proteinuria and serum creatinine, and circulating anti-PLA2R became undetectable. In summary, this case of recurrent membranous nephropathy in a graft suggests that circulating monoclonal anti-PLA2R IgG3κ caused the disease and activated complement by the classic pathway.
Serum-mediated transgenerational effects on sperm: Evidence for lamarckian inheritance?
Authors: Yoshiyuki Seki, Roberto J. Groszmann, Yasuko Iwakiri, Tamar H. Taddei
Journal: Hepatology (2013)

Abstract We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor g (PPAR-g) and lower expression of the profibrogenic factor transforming growth factor b1 (TGF-b1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-g chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.
Assessing Antimalarial Efficacy in a Time of Change to Artemisinin-Based Combination Therapies: The Role of Médecins Sans Frontières
Authors: Jean-Paul Guthmann, Francesco Checchi, Ingrid van den Broek, Suna Balkan, Michel van Herp, Eric Comte, Oscar Bernal, Jean-Marie Kindermans, Sarah Venis, Dominique Legros, Philippe J Guerin
Journal: PLoS Medicine (2008)

enrolled in 43 efficacy studies in 18 countries of Asia and Africa between fourth of the overall research output in these countries.on the efficacy of most drug regimens currently in use for uncomplicated treatment policy changes by the concerned countries.in conflict-affected countries of represent the vast majority of available data and where "traditional" academic research institutions were not or barely represented.which shows that research performed in difficult settings can be of a high enough standard to ensure publication and to be useful in policy change.role of non-governmental agencies in collecting the necessary evidence to stimulate and inform policy change in international health.
Deficiency of NRH:Quinone Oxidoreductase 2 Differentially Regulates TNF Signaling in Keratinocytes: Up-regulation of Apoptosis Correlates with Down-regulation of Cell Survival Kinases
Authors: Kwang Seok Ahn, Xing Gong, Gautam Sethi, Madan M. Chaturvedi, Anil K. Jaiswal, Bharat B. Aggarwal
Journal: Cancer Research (2007)

Abstract NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (NQO1), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2−/−) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-κB (NF-κB) and IκBα kinase, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2−/− cells. Deletion of NQO2 also abolished TNF-induced c-Jun NH2-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (MMP-9, cyclin D1, COX-2, IAP1, IAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2−/− cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-κB activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis. [Cancer Res 2007;67(20):10004–11]
BONE GRAFT AND FUSION OPERATIONS FOR THE SPINE
Authors: S. A. S. Malkin
Journal: BMJ (1932)

EM TIHcE JmSR 5 benefit derived from it.It strikes me as a useless and chilling performance.The universal hot-water bottle, though comforting to the patient, must act merely as a counter-irritant, and abdomens are sometimes scarred by its use in cases of extreme pain.DRUGS For drugs I have little use in the treatment of dysmenor- rhoea, and since prescribing the remedial exercises in printed form I have been spared the reproachful look of disappointment from the patient when told that there was no prescription to take away.There are, however, a
Conservative management of persistent postnatal urinary and faecal incontinence: randomised controlled
Authors: C. M A Glazener, G P. Herbison, P D. Wilson, C. MacArthur, G. D Lang, H. Gee, A. M Grant
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To assess the effect of nurse assessment with reinforcement of pelvic floor muscle training exercises and bladder training compared with standard management among women with persistent incontinence three months postnatally. <b>Design:</b> Randomised controlled trial with nine months9 follow up. <b>Setting:</b> Community intervention in three centres (Dunedin, New Zealand; Birmingham; Aberdeen). <b>Participants:</b> 747 women with urinary incontinence three months postnatally, allocated at random to intervention (371) or control (376) groups. <b>Intervention:</b> Assessment by nurses of urinary incontinence with conservative advice on pelvic floor exercises at five, seven, and nine months after delivery supplemented with bladder training if appropriate at seven and nine months. <b>Main outcome measures:</b> Primary: persistence and severity of urinary incontinence 12 months after delivery. Secondary: performance of pelvic floor exercises, change in coexisting faecal incontinence, wellbeing, anxiety, and depression. <b>Results:</b> Women in the intervention group had significantly less urinary incontinence: 167/279 (59.9%) <i>v</i> 169/245 (69.0%), difference 9.1% (95% confidence interval 1.0% to 17.3%, P=0.037) for any incontinence and 55/279 (19.7%) <i>v</i> 78/245 (31.8%), difference 12.1% (4.7% to 19.6%, P=0.002) for severe incontinence. Faecal incontinence was also less common: 12/273 (4.4%) <i>v</i> 25/237 (10.5%), difference 6.1% (1.6% to 10.8%, P=0.012). At 12 months women in the intervention group were more likely to be performing pelvic floor exercises (218/278 (79%) <i>v</i> 118/244 (48%), P&lt;0.001). <b>Conclusions:</b> A third of women may have some urinary incontinence three months after childbirth. Conservative management provided by nurses seems to reduce the likelihood of urinary and coexisting faecal incontinence persisting 12 months postpartum. Further trials for faecal incontinence are needed. <h3>What is already known on this topic</h3> Vaginal delivery is a risk factor for urinary incontinence Three months after childbirth 20-30% of women still experience urinary incontinence Most women do not seek treatment <h3>What this study adds</h3> Women will use conservative treatments such as pelvic floor exercises or bladder training Conservative management prevents persistent urinary incontinence in about one in 10 women who have postnatal incontinence Coexisting persistent faecal incontinence is also improved
Simultaneous Bayesian Estimation of Alignment and Phylogeny under a Joint Model of Protein Sequence and Structure
Authors: Joseph L. Herman, Christopher J. Challis, Ádám Novák, Jotun Hein, Scott C. Schmidler
Journal: Molecular Biology and Evolution (2014)

For sequences that are highly divergent, there is often insufficient information to infer accurate alignments, and phylogenetic uncertainty may be high. One way to address this issue is to make use of protein structural information, since structures generally diverge more slowly than sequences. In this work, we extend a recently developed stochastic model of pairwise structural evolution to multiple structures on a tree, analytically integrating over ancestral structures to permit efficient likelihood computations under the resulting joint sequence–structure model. We observe that the inclusion of structural information significantly reduces alignment and topology uncertainty, and reduces the number of topology and alignment errors in cases where the true trees and alignments are known. In some cases, the inclusion of structure results in changes to the consensus topology, indicating that structure may contain additional information beyond that which can be obtained from sequences. We use the model to investigate the order of divergence of cytoglobins, myoglobins, and hemoglobins and observe a stabilization of phylogenetic inference: although a sequence-based inference assigns significant posterior probability to several different topologies, the structural model strongly favors one of these over the others and is more robust to the choice of data set.