tbuckley/cabot-search huggingface dataset:
Glycemic Control in Simultaneous Islet-Kidney Versus Pancreas-Kidney Transplantation in Type 1 Diabetes: A Prospective 13-Year Follow-up
Authors: Roger Lehmann, Jessica Graziano, Jens Brockmann, Thomas Pfammatter, Philipp Kron, Olivier de Rougemont, Thomas Mueller, Richard A. Zuellig, Giatgen A. Spinas, Philipp A. Gerber
Journal: Diabetes Care (2015)

OBJECTIVE In patients with type 1 diabetes and end-stage renal disease, combined transplantation of a kidney together with a pancreas or isolated pancreatic islets are options to improve glycemic control. The aim of this study was to compare their long-term outcome with regard to metabolic control and surgical complication rate, as well as function of the transplanted kidney. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study in consecutive patients receiving either a pancreas or islet transplant simultaneously with or after kidney transplantation (simultaneous pancreas-kidney [SPK]/pancreas-after-kidney [PAK] or simultaneous islet-kidney [SIK]/islet-after-kidney [IAK] transplantation). RESULTS Ninety-four patients who had undergone SPK/PAK transplantation were compared with 38 patients who had undergone SIK/IAK transplantation over a period of up to 13 years. HbA1c levels declined from 7.8 ± 1.3% (62 ± 14 mmol/mol) to 5.9 ± 1.1% (41 ± 12 mmol/mol), and from 8.0 ± 1.3% (64 ± 14 mmol/mol) to 6.5 ± 1.1% (48 ± 12 mmol/mol), respectively, in the SPK/PAK and SIK/IAK groups (P &amp;lt; 0.001 for both) and remained stable during follow-up, despite a reduction in the rate of severe hypoglycemia by &amp;gt;90%. The 5-year insulin independence rate was higher in the SPK/PAK group (73.6 vs. 9.3% in the SIK/IAK group), as was the rate of relaparotomy after transplantation (41.5 vs. 10.5% in the SIK/IAK group). There was no difference in the rate of kidney function decline. CONCLUSIONS During a long-term follow-up, SPK/PAK transplantation as well as SIK/IAK transplantation resulted in a sustained improvement of glycemic control with a slightly higher glycated hemoglobin level in the SIK/IAK group. While insulin independence is more common in whole-organ pancreas recipients, islet transplantation can be conducted with a much lower surgical complication rate and no difference in kidney function decline.
Insulin resistance and response to telaprevir plus peginterferon α and ribavirin in treatment-naïve patients infected with HCV genotype 1
Authors: Lawrence Serfaty, Xavier Forns, Tobias Goeser, Peter Ferenci, Frederik Nevens, Giampiero Carosi, Joost P Drenth, Isabelle Lonjon-Domanec, Ralph DeMasi, Gaston Picchio, Maria Beumont, Patrick Marcellin
Journal: Gut (2012)

<h3>Objective</h3> Insulin resistance is a predictor of poor response to peginterferon/ribavirin in patients infected with the chronic hepatitis C virus (HCV). There are no data on direct-acting antivirals. This exploratory analysis assessed the effect of metabolic factors and insulin resistance, measured by homoeostatic model assessment (HOMA), on virological response to telaprevir in Study C208. <h3>Design</h3> Overall, 161 HCV genotype 1-infected, treatment-naïve patients received 12 weeks of telaprevir plus peginterferon/ribavirin, then 12/36 weeks of peginterferon/ribavirin depending on on-treatment response criteria. The prognostic significance of several factors, including HOMA-insulin resistance (HOMA-IR), on virological response at weeks 4 and 12, end of treatment and 24 weeks after treatment was explored by multiple regression analysis. <h3>Results</h3> Baseline HOMA-IR data were available for 147 patients; baseline characteristics were consistent with the overall population. Baseline HOMA-IR &lt;2, 2–4 and &gt;4 was seen in 54%, 30% and 16% of patients, respectively. Neither response rates (any time point) nor week 4 viral load decline were significantly influenced by baseline HOMA-IR. In multivariate analyses, fibrosis stage and low-density lipoprotein cholesterol level were predictive of sustained virological response (OR 0.47 and 1.02, respectively). After the end of treatment, HOMA-IR was significantly lower in patients with sustained virological response than in those without (0.61 vs 1.34 for relapsers and 1.15 for non-responders; p&lt;0.05). <h3>Conclusion</h3> In this study, baseline HOMA-IR was not predictive of virological response to telaprevir in HCV genotype 1-infected, treatment-naïve patients, while sustained virological response was associated with improved HOMA-IR. These results suggest that metabolic factors and insulin resistance do not have a significant effect on telaprevir-based treatment efficacy.
ROLE OF COMPLEMENT IN HIV INFECTION
Authors: Heribert Stoiber, Alberto Clivio, Manfred P. Dierich
Journal: Annual Review of Immunology (1997)

In human plasma, HIV activates the complement system, even in the absence of specific antibodies. Complement activation would, however, be harmful to the virus if the reactions were allowed to go to completion, since their final outcome would be virolysis. This is avoided by complement regulatory molecules, which either are included in the virus membrane upon budding from the infected cells (e.g. DAF/CD55) or are secondarily attached to HIV envelope glycoproteins as in the case of factor H. By using this strategy of interaction with complement components, HIV takes advantage of human complement activation for enhancement of infectivity, for follicular localization, and for broadening its target cell range at the same time that it displays an intrinsic resistance against the lytic action of human complement. This intrinsic resistance to complement-mediated virolysis can be overcome by monoclonal antibodies inhibiting recruitment of human factor H to the virus surface, suggesting a new therapeutic principle.
Estimating vaccination coverage in the absence of immunisation registers – the German experience
Authors: A Siedler, T Rieck, A Reuss, D Walter, G Poggensee, C Poethko-Müller, S Reiter
Journal: Eurosurveillance (2012)

Immunisation registers are regarded as an appropriate solution to measure vaccination coverage on a population level. In Germany, a decentralised healthcare system and data protection regulations constrain such an approach. Moreover, shared responsibilities in the process of immunisation and multiple providers form the framework for public health interventions on vaccination issues. On the national level, those interventions consist mainly of conceptualising immunisation strategies, establishing vaccination programmes, and issuing recommendations. This paper provides an overview on sources and methods for collecting appropriate coverage data at national level and their public health relevance in Germany. Methods of data collection and available information on immunisations are described for three approaches: school entrance health examination, population surveys and insurance refund claim data. School entrance health examinations allow regional comparisons and estimation of trends for a specific cohort of children and for all recommended childhood vaccinations. Surveys deliver population based data on completeness and timeliness of selected vaccinations in populations defined by age or socio-demographic parameters and on knowledge and attitudes towards vaccination. Insurance refund claim data inform continuously on immunisation status (e.g. of children aged two years) or on vaccination incidence promptly after new or modified recommendations. In a complex healthcare system, the German National Public Health Institute (Robert Koch Institute, RKI) successfully compiles coverage data from different sources, which complement and validate one another. With the German approach of combining different data sources in the absence of immunisation registers, it is possible to gain solid and reliable data on the acceptance of vaccination programmes and target groups for immunisation. This approach might be of value for other countries with decentralised healthcare systems.
Tandem repeat copy-number variation in protein-coding regions of human genes.
Authors: Colm T O'Dushlaine, Richard J Edwards, Stephen D Park, Denis C Shields
Journal: Genome biology (2005)

Abstract Background Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles. Results Protein-coding tandem repeat copy-number polymorphisms were detected in 249 tandem repeats found in 218 UniGene clusters; observed length differences ranged from 2 to 144 nucleotides, with unit copy lengths ranging from 2 to 57. This corresponded to 1.59% (218/13,749) of proteins investigated carrying detectable polymorphisms in the copy-number of protein-coding tandem repeats. We found no evidence that tandem repeat copy-number polymorphism was significantly elevated in defense-response proteins ( p = 0.882). An association with the Gene Ontology term 'protein-binding' remained significant after covariate adjustment and correction for multiple testing. Combining this analysis with previous experimental evaluations of tandem repeat polymorphism, we estimate the approximate mean frequency of tandem repeat polymorphisms in human proteins to be 6%. Because 13.9% of the polymorphisms were not a multiple of three nucleotides, up to 1% of proteins may contain frameshifting tandem repeat polymorphisms. Conclusion Around 1 in 20 human proteins are likely to contain tandem repeat copy-number polymorphisms within coding regions. Such polymorphisms are not more frequent among defense-response proteins; their prevalence among protein-binding proteins may reflect lower selective constraints on their structural modification. The impact of frameshifting and longer copy-number variants on protein function and disease merits further investigation.
Sushi Syncope Schusser Gets Wedeler's Valve at Vail
Authors: Daniel E. Spitzer
Journal: JAMA (1994)

<h3>To the Editor.</h3> — A 68-year-old man was involved in a severe frontal impact with another skier while "wedeling" at a high rate of speed in Vail, Colo. Medical history was unremarkable, other than having developed "sushi syncope" at 63 years of age.<sup>1</sup>While prior to the accident he had experienced no difficulty skiing expert trails at an elevation of over 3600 m (10000 ft), afterward he became dyspneic while walking at the base of the mountain. On returning to sea level, he noted continued dyspnea on exertion; examination revealed V waves in the jugulars evident at 30° and a prominent murmur of tricuspid insufficiency. Transesophageal echocardiography demonstrated a flail tricuspid leaflet, and angiography revealed wide-open tricuspid regurgitation. Fortunately, his dyspnea gradually resolved, and by 3 months after the event he had returned to playing tennis without difficulty. Serial echocardiograms reveal that his right ventricular size has remained stable,
I couldn't believe my eyes
Authors: Liam Farrell
Journal: BMJ (2004)

I have advice for prospective patients—if you get sick, your word on its own may not be enough, so make sure that you have some concrete evidence of infirmity, or that your symptoms conform to an accepted pattern. The word “atypical” is pejorative in the medical world, implying one of three things: imagining it, deliberately making it up, or expensive and time consuming investigations will prove it to be benign. We doctors are scientifically trained; …
Improved Therapeutic Responses in a Xenograft Model of Human B Lymphoma (Namalwa) for Liposomal Vincristine<b><i>versus</i></b>Liposomal Doxorubicin Targeted via Anti-CD19 IgG2a or Fab′ Fragments
Authors: Puja Sapra, Elaine H. Moase, Jie Ma, Theresa M. Allen
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates. Experimental Design: SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[αCD19]) or its Fab′ fragments (SIL[Fab′]). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model. Results: SIL[αCD19] or SIL[Fab′] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab′] had longer circulation times than SIL[αCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab′] had better therapeutic outcomes than SIL[αCD19] for the drug DXR but were equally efficacious for the drug VCR. Conclusions: Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab′] versus SIL[αCD19] led to superior therapeutics for DXR-loaded immunoliposomes.
Role of the Renin-Angiotensin System In the Pathogenesis of Severe Hypertension in Rats
Authors: O. A. Carretero, P. Kuk, S. Piwonska, J. A. Houle, M. Marin-Grez
Journal: Circulation Research (1971)

Plasma renin levels are elevated in accelerated or malignant hypertension. To see if this increase of renin is a concurrent phenomenon or a pathogenetic factor in the increase of blood pressure, severe hypertension was produced in rats by occluding the aorta between the origins of the renal arteries. Eight days later, these animals had developed severe hypertension (mean blood pressure = 201 ± 3 mm Hg) and markedly elevated plasma renin levels (151 ± 35 ng angiotensin II/ml hr -1 ; normal range = 11 ± 0.6). When the kidney distal to the ligature was excised at the time of the coarctation, the animals developed only a moderate increase in blood pressure (mean = 120 ± 1.3 mm Hg) and their plasma renin levels remained in the normal range. When the nonnephrectomized animals with severe hypertension were injected with antibodies against angiotensin II, blood pressure decreased, reaching its lowest point (126 ± 12 mm Hg) 2 days later. This work demonstrates that the severe increase in blood pressure is not due to the mechanical increase in resistance caused by complete coarctation of the aorta; rather, it is due to a humoral factor produced by the kidney, and this factor is renin.
Trends in<i>Neisseria gonorrhoeae</i>Susceptibility to Cephalosporins in the United States, 2006-2014
Authors: Robert D. Kirkcaldy, Edward W. Hook, Olusegun O. Soge, Carlos del Rio, Grace Kubin, Jonathan M. Zenilman, John R. Papp
Journal: JAMA (2015)

This study describes gonococcal cephalosporin susceptibility trends using 2006-2014 data from the US Centers for Disease Control and Prevention (CDC) Gonococcal Isolate Surveillance Project and changes in gonorrhea treatment following publication in 2012 of a CDC treatment guideline update.
Peptide influences the folding and intracellular transport of free major histocompatibility complex class I heavy chains.
Authors: R P Machold, S Andrée, L Van Kaer, H G Ljunggren, H L Ploegh
Journal: The Journal of Experimental Medicine (1995)

Class I major histocompatibility complex molecules require both beta 2-microglobulin (beta 2m) and peptide for efficient intracellular transport. With the exception of H-2Db and Ld, class I heavy chains have not been detectable at the surface of cells lacking beta 2m. We show that properly conformed class I heavy chains can be detected in a terminally glycosylated form indicative of cell surface expression in H-2b, H-2d, and H-2s beta 2m-/- concanavalin A (Con A)-stimulated splenocytes incubated at reduced temperature. Furthermore, we demonstrate the presence of Kb molecules at the surface of beta 2m-/- cells cultured at 37 degrees C. The mode of assembly of class I molecules encompasses two major pathways: binding of peptide to preformed "empty" heterodimers, and binding of peptide to free heavy chains, followed by recruitment of beta 2m. In support of the existence of the latter pathway, we provide evidence for a role of peptide in intracellular transport of free class I heavy chains, through analysis of Con A-stimulated splenocytes from transporter associated with antigen processing 1 (TAP1)-/-, beta 2m-/-, and double-mutant TAP1/beta 2m-/- mice.
Decreased T cell precursor frequencies to Epstein-Barr virus glycoprotein gp110 in peripheral blood correlate with disease activity and severity in patients with rheumatoid arthritis
Authors: E. Toussirot
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVES</h3> Rheumatoid arthritis (RA) is a chronic joint disease associated with certain HLA-DR alleles expressing the QK/RRAA motif or shared epitope. The Epstein-Barr virus (EBV) has been suspected to be a causative factor for RA. The EBV gp110, a glycoprotein of the replicative cycle that contains a copy of the shared epitope, constitutes an important target in the immune control of EBV replication. This study evaluated the specific T cell response to EBV gp110 in patients with RA expressing or not the shared epitope and examined whether this immune cellular response might be related to disease activity and severity. <h3>METHODS</h3> 25 patients with RA were studied and compared with 25 healthy controls. Disease activity was assessed by biochemical markers of inflammation (erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) levels). Disease severity was defined by extra-articular disease (vasculitis, subcutaneous nodules, or other organ disease). The frequencies of peripheral blood T cells specific for EBV gp110 and a control protein (total protein extract from<i>Escherichia coli</i>) were determined by direct limiting dilution analysis without preliminary bulk culture. <h3>RESULTS</h3> The gp110 precursor frequencies ranged from 0 to 20 × 10<sup>−6</sup>in patients with RA and controls. The mean gp110 T cell precursor frequency was lower in patients with RA (SD 3.2 (4.4) × 10<sup>-6</sup>) than in healthy controls (4.1 (3.8) × 10<sup>-6</sup>) (p = 0.02). No difference was found for the control protein (p = 0.09). Both shared epitope positive and negative patients with RA responded to gp110, without significant difference. A negative correlation between both ESR and CRP levels and the gp110 T cell response was found (r = –0.71, p&lt;0.0001 and r = –0.42, p = 0.038, respectively). Finally, patients with extra-articular disease displayed the lowest immune cellular response to EBV gp110. <h3>CONCLUSION</h3> These results suggest that patients with RA have a decreased T cell response to EBV gp110. Since gp110 is an important protein in the control of EBV replication, this might lead to a poor control of EBV infection, chronic exposure to other EBV antigens, and thus to a chronic inflammatory response in patients with RA.
Chromogranin-A and N-Terminal Pro-Brain Natriuretic Peptide: An Excellent Pair of Biomarkers for Diagnostics in Patients With Neuroendocrine Tumor
Authors: Catharina M. Korse, Babs G. Taal, Cornelis A. de Groot, Robert H. Bakker, Johannes M.G. Bonfrer
Journal: Journal of Clinical Oncology (2009)

For the last decade chromogranin-A (CgA) has been a well-established marker for neuroendocrine tumor (NET), and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been a useful marker for left ventricular dysfunction. This study examined the diagnostic value of CgA and NT-proBNP for carcinoid heart disease (CHD), and their prognostic value for overall survival in NET patients.Serum samples were obtained and cardiac ultrasound studies performed in 102 NET patients. The criterion for mild and severe CHD was tricuspid regurgitation stage I/II and III/IV, respectively. Proportional odds and Cox proportional hazards models were constructed respectively to identify the association between CHD and overall survival with patient characteristics and the two markers.Severe CHD was found in 15 (15%) of 102 patients, 13 of whom had elevated NT-proBNP levels. In the univariate proportional odds model CHD was correlated with age (P = .007), CgA (P = .002), and NT-proBNP (P < .001), whereas in the multivariate model NT-proBNP and CgA were significantly associated with CHD (P < .001 and P = .01). In the univariate Cox models, age (P = .04), sex (P = .03), CgA (P = .003), and NT-proBNP (P = .04) were related to overall survival, and in the multivariate model CgA and NT-proBNP remained significantly related to overall survival (P = .002 and P = .04, respectively).NT-proBNP and CgA are very important markers in the diagnosis of CHD in patients with NET. Furthermore, patients with elevated NT-proBNP in addition to elevated CgA levels showed worse overall survival than patients with elevated CgA alone.
Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons
Authors: Hyang-Sook Hoe, Jacob Freeman, G William Rebeck
Journal: Molecular Neurodegeneration (2006)

Abstract Apolipoprotein E (apoE) receptors act as signaling molecules in neurons, altering phosphorylation of numerous proteins after extracellular ligand binding and affecting neurite outgrowth, synapse formation, and neuronal migration. Since apoE is important in the pathogenesis of Alzheimer's disease (AD), we tested whether apoE treatment of neurons affected molecules important to phosphorylation of tau, such as GSK 3β, P35, and CDK5, and the phosphorylation of tau itself. Treatment of primary neurons with 2 uM apoE (or an apoE-derived peptide) decreased levels of phospho-GSK 3β, P35 and CDK5, and decreased levels of phosphorylated forms of tau. A lower concentration of apoE (100 nM) had no effect on these molecules. The alteration of tau phosphorylation by apoE was blocked by an inhibitor of the low-density lipoprotein receptor family, demonstrating the effects were due to receptor interactions. These results demonstrate that apoE affects several downstream signaling cascades in neurons: decreased tau kinases phosphorylation and inhibition of tau phosphorylation at Thr171 and Ser202/Thr205 epitopes. We conclude that apoE can alter levels of tau kinases and phospho-tau epitopes, potentially affecting tau neuropathological changes seen in AD brains.