tbuckley/cabot-search huggingface dataset:
Human-macaque comparisons illuminate variation in neutral substitution rates
Authors: Svitlana Tyekucheva, Kateryna D Makova, John E Karro, Ross C Hardison, Webb Miller, Francesca Chiaromonte
Journal: Genome biology (2008)

The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates. Here we investigate the human-macaque neutral substitution rate as a function of a number of genomic parameters.Using regression analyses we find that male mutation bias, male (but not female) recombination rate, distance to telomeres and substitution rates computed from orthologous regions in mouse-rat and dog-cow comparisons are prominent predictors of the neutral rate. Additionally, we demonstrate that the previously observed biphasic relationship between neutral rate and GC content can be accounted for by properly combining rates at CpG and non-CpG sites. Finally, we find the neutral rate to be negatively correlated with the densities of several classes of computationally predicted functional elements, and less so with the densities of certain classes of experimentally verified functional elements.Our results suggest that while female recombination may be mainly responsible for driving evolution in GC content, male recombination may be mutagenic, and that other mutagenic mechanisms acting near telomeres, and mechanisms whose effects are shared across mammalian genomes, play significant roles. We also have evidence that the nonlinear increase in rates at high GC levels may be largely due to hyper-mutability of CpG dinucleotides. Finally, our results suggest that the performance of conservation-based prediction methods can be improved by accounting for neutral rates.
Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion
Authors: Kimiyoshi Ichida, Makoto Hosoyamada, Ichiro Hisatome, Atsushi Enomoto, Miho Hikita, Hitoshi Endou, Tatsuo Hosoya
Journal: Journal of the American Society of Nephrology (2004)

Renal hypouricemia is an inherited and heterogeneous disorder characterized by increased urate clearance (Cua). The authors recently established that urate was reabsorbed via URAT1 on the tubular apical membrane and that mutations in SLC22A12 encoding URAT1 cause renal hypouricemia. This study was undertaken to elucidate and correlate clinical and genetic features of renal hypouricemia. The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and Cua/creatinine clearance (Ccr) to SLC22A12 genotype were examined. Uricosuric (probenecid and benzbromarone) and anti-uricosuric drug (pyrazinamide) loading tests were also performed in some patients. Three patients had exercise-induced acute renal failure (9.4%), and four patients had urolithiasis (12.5%). The authors identified eight new mutations and two previously reported mutations that result in loss of function. Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes. Mutation G774A dominated SLC22A12 mutations (74.1% in 54 alleles). Serum urate levels were significantly lower and Cua/Ccr was significantly higher in heterozygotes compared with healthy subjects; these changes were even more significant in homozygotes and compound heterozygotes. These Cua/Ccr relations demonstrated a gene dosage effect that corresponds with the difference in serum urate levels. In contrast to healthy subjects, the Cua/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid. The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo . E-mail: ichida@jikei.ac.jp
Cooperative Binding of KLF4, pELK-1, and HDAC2 to a G/C Repressor Element in the SM22α Promoter Mediates Transcriptional Silencing During SMC Phenotypic Switching In Vivo
Authors: Morgan Salmon, Delphine Gomez, Elizabeth Greene, Laura Shankman, Gary K. Owens
Journal: Circulation Research (2012)

Rationale: We previously identified conserved G/C Repressor elements in the promoters of most smooth muscle cell (SMC) marker genes and demonstrated that mutation of this element within the SM22α promoter nearly abrogated repression of this transgene after vascular wire injury or within lesions of ApoE−/− mice. However, the mechanisms regulating the activity of the G/C Repressor are unknown, although we have previously shown that phenotypic switching of cultured SMC is dependent on Krupple-like factor (KLF)4. Objective: The goals of the present studies were to ascertain if (1) injury-induced repression of SM22α gene after vascular injury is mediated through KLF4 binding to the G/C Repressor element and (2) the transcriptional repressor activity of KLF4 on SMC marker genes is dependent on cooperative binding with pELK-1 (downstream activator of the mitogen-activated protein kinase pathway) and subsequent recruitment of histone de-acetylase 2 (HDAC2), which mediates epigenetic gene silencing. Methods and Results: Chromatin immunoprecipitation (ChIP) assays were performed on chromatin derived from carotid arteries of mice having either a wild-type or G/C Repressor mutant SM22α promoter-LacZ transgene. KLF4 and pELK-1 binding to the SM22α promoter was markedly increased after vascular injury and was G/C Repressor dependent. Sequential ChIP assays and proximity ligation analyses in cultured SMC treated with platelet-derived growth factor BB or oxidized phospholipids showed formation of a KLF4, pELK-1, and HDAC2 multiprotein complex dependent on the SM22α G/C Repressor element. Conclusions: Silencing of SMC marker genes during phenotypic switching is partially mediated by sequential binding of pELK-1 and KLF4 to G/C Repressor elements. The pELK-1-KLF4 complex in turn recruits HDAC2, leading to reduced histone acetylation and epigenetic silencing.
Imaging Pulmonary Gene Expression with Positron Emission Tomography
Authors: Jean-Cristophe Richard, Zhaohui Zhou, Datta E. Ponde, Carmen S. Dence, Philip Factor, Paul N. Reynolds, Gary D. Luker, Vijay Sharma, Tom Ferkol, David Piwnica-Worms, Daniel P. Schuster
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We evaluated positron emission tomographic imaging of pulmonary transgene expression, using an enhanced mutant herpes simplex virus-1 thymidine kinase as the reporter gene, in the lungs of normal rats. Sixteen rats were studied 3 days after an intratracheal administration of 5 × 109 to 1 × 1011 viral particles of a replication-incompetent adenovirus containing a fusion gene of the mutant kinase and green fluorescent protein. Three rats infected with adenovirus containing no insert (null vector) served as control subjects. Images were obtained 1 hour after an intravenous injection of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine, an imaging substrate for the viral kinase. After euthanasia, tissue radioactivity was determined in a γ counter, and thymidine kinase activity and green fluorescent protein levels were measured in lung tissue samples. Imaging and γ counting radioactivity measurements were strongly and linearly correlated (r2 = 0.96, p < 0.001). Imaging detected thymidine kinase expression above background (null vector) in 15 of 16 rats, even at low viral doses that produced little to no measurable green fluorescent protein expression. Lung 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine uptake (as assessed by imaging) correlated with in vitro assays of both kinase activity (r2 = 0.48, p < 0.001) and fluorescent protein (r2 = 0.46, p < 0.001). We conclude that positron emission tomographic imaging is a sensitive and quantitative method for detecting pulmonary reporter gene expression noninvasively.
Surgical rates among older people in England vary widely across CCGs
Authors: Z. Kmietowicz
Journal: BMJ (2014)

Rates of surgery for six procedures known to be effective in older people vary widely in people aged over 65 and 75 depending on where they live in England, a new analysis has found.1

The report, by the Royal College of Surgeons and the charity Age UK, builds on a report published in 2012, which warned that decisions about patients’ suitability for surgery should be based on their overall health rather than their age.2

The latest report broke down the surgical rates for breast excision, colorectal excision, cholecystectomy, hernia repairs, hip replacements, and knee replacements during 2011-12 across England’s 211 clinical commissioning groups (CCGs). It found that, in people over 65, those with breast cancer faced the biggest variation in access to surgery. The highest surgery …
Maturation of bone marrow lymphocytes. II. Development of Fc and complement receptors and surface immunoglobulin studied by rosetting and radioautography.
Authors: W C Yang, S C Miller, D G Osmond
Journal: The Journal of Experimental Medicine (1978)

Radioautographic DNA labeling and rosetting techniques were combined to study the development of surface IgM, Fc, and complement receptors (FcR, CR) on small lymphocyte populations in mouse bone marrow. [3H]thymidine was either infused continuously to label newly formed cells for periods up to 4 days, or injected daily, 21--35 days before use, to label a sample of long-lived cells. Bone marrow cells were incubated with sensitized sheep erythrocytes to detect surface IgM, FcR, and CR, respectively, and examined radioautographically after cytocentrifugation. During [3H]thymidine infusion, marrow small lymphocytes lacking surface markers were the first to show [3H]thymidine labeling. Most of these cells became labeled by 4 days (IgM--ve, 89%; FcR--ve, 92%; Cr--ve, 88%). Labeling of small lymphocytes bearing surface IgM, FcR, and Cr began after an initial lag and increased to high values by 4 days (IgM + ve, 73%; FcR + ve, 82%; CR + ve, 83%). Labeled IgM + ve small lymphocytes formed progressively larger rosettes as cell age increased. Some proliferating large lymphoid cells formed rosettes for IgM, FcR, and CR. Labeled long-lived small lymphocytes expressed surface IgM, FcR, and CR, the incidence of each receptor being uniformly high (38--43%) and the rosettes tending to be larger than those formed by newly formed lymphocytes. In double-surface marker studies, FcR and CR rosettes were formed by some IgM--ve small lymphocytes as well as IgM + ve cells in the marrow. After transfusion of marrow cells from donor mice infused with [3H]thymidine for 24 h, many labeled newly formed lymphocytes homed into the splenic red pulp of unlabeled syngeneic recipients. Subsequently, these cells showed a rapid increase in the incidence of rosettes for surface IgM, FcR, and CR, together with a progressive enlargement of each type of rosette. Although all the labeled small lymphocytes recovered from the spleen developed both surface IgM and FcR by 3 days, only approximately one-half developed CR. The results demonstrate that most of the small lymphocytes bearing FcR, CR, and surface IgM in mouse bone marrow are newly formed indigenous cells. Each receptor becomes detectable by rosetting soon after the small lymphocytes are first produced. The newly formed, marrow-derived small lymphocytes are able to continue their development of surface IgM, FcR, and CR after migrating into the spleen, consistent with a maturation of primary B lymphocytes. In addition, the data indicate the genesis in mouse marrow of a non-B lineage of lymphocytes (notably, IgM--ve FcR + ve cells.). A minority of small lymphocytes bearing IgM, FcR, and CR in mouse marrow are long-lived cells, presumptive recirculating immigrants, differing in receptor status from the newly formed cells. The results are discussed with regard to the heterogeneity of marrow lymphocytes and proposed models of primary B lymphocyte and null lymphocyte production.
Release from Prison — A High Risk of Death for Former Inmates
Authors: Ingrid A. Binswanger, Marc F. Stern, Richard A. Deyo, Patrick J. Heagerty, Allen Cheadle, Joann G. Elmore, Thomas D. Koepsell
Journal: New England Journal of Medicine (2007)

The U.S. population of former prison inmates is large and growing. The period immediately after release may be challenging for former inmates and may involve substantial health risks. We studied the risk of death among former inmates soon after their release from Washington State prisons.We conducted a retrospective cohort study of all inmates released from the Washington State Department of Corrections from July 1999 through December 2003. Prison records were linked to the National Death Index. Data for comparison with Washington State residents were obtained from the Wide-ranging OnLine Data for Epidemiologic Research system of the Centers for Disease Control and Prevention. Mortality rates among former inmates were compared with those among other state residents with the use of indirect standardization and adjustment for age, sex, and race.Of 30,237 released inmates, 443 died during a mean follow-up period of 1.9 years. The overall mortality rate was 777 deaths per 100,000 person-years. The adjusted risk of death among former inmates was 3.5 times that among other state residents (95% confidence interval [CI], 3.2 to 3.8). During the first 2 weeks after release, the risk of death among former inmates was 12.7 (95% CI, 9.2 to 17.4) times that among other state residents, with a markedly elevated relative risk of death from drug overdose (129; 95% CI, 89 to 186). The leading causes of death among former inmates were drug overdose, cardiovascular disease, homicide, and suicide.Former prison inmates were at high risk for death after release from prison, particularly during the first 2 weeks. Interventions are necessary to reduce the risk of death after release from prison.
INSULOT
Authors: Noriaki Aoki, Sachiko Ohta, Taisuke Okada, Mariko Oishi, Tsuguya Fukui
Journal: Diabetes Care (2005)

A particular type of education needs to be designed to encourage, motivate, and boost the confidence of type 1 diabetic patients. “Edutainment” has been recognized as an attractive approach to improving educational outcomes for such patients (1). As an edutainment tool, we have developed a cellular phone-based “game” that we call “INSULOT,” a term coined to denote “insulin” and “slot machine.” This tool has been implemented and preliminarily evaluated.

INSULOT is a special, three-window slot machine designed to teach the relationships among plasma glucose level, food (carbohydrate grams), and insulin dosage. INSULOT uses algorithms to simulate postprandial glucose levels, while considering distributions to incorporate clinical uncertainties. The first step is to calculate the “carbohydrate grams” in …
Lung volume reduction coil treatment for patients with severe emphysema: a European multicentre trial
Authors: Gaëtan Deslee, Karin Klooster, Martin Hetzel, Franz Stanzel, Romain Kessler, Charles-Hugo Marquette, Christian Witt, Stefan Blaas, Wolfgang Gesierich, Felix J F Herth, Juergen Hetzel, Eva M van Rikxoort, Dirk-Jan Slebos
Journal: Thorax (2014)

<h3>Background</h3> The lung volume reduction (LVR) coil is a minimally invasive bronchoscopic nitinol device designed to reduce hyperinflation and improve elastic recoil in severe emphysema. We investigated the feasibility, safety and efficacy of LVR coil treatment in a prospective multicentre cohort trial in patients with severe emphysema. <h3>Methods</h3> Patients were treated in 11 centres. Safety was evaluated by recording all adverse events, efficacy by the St George9s Respiratory Questionnaire (SGRQ) as primary endpoint, and pulmonary function testing, modified Medical Research Council dyspnoea score (mMRC) and 6-min walk distance (6MWD) up to 12 months after the final treatment. <h3>Results</h3> Sixty patients (60.9 ± 7.5 years, forced expiratory volume in 1 s (FEV<sub>1</sub>) 30.2 ± 6.3% pred) were bronchoscopically treated with coils (55 bilateral, 5 unilateral), with a median of 10 (range 5–15) coils per lobe. Within 30 days post-treatment, seven chronic obstructive pulmonary disease exacerbations (6.1%), six pneumonias (5.2%), four pneumothoraces (3.5%) and one haemoptysis (0.9%) occurred as serious adverse events. At 6 and 12 months, respectively, ΔSGRQ was −12.1±12.9 and −11.1±13.3 points, Δ6MWD was +29.7±74.1 m and +51.4±76 m, ΔFEV<sub>1</sub> was +0.11±0.20 L and +0.11±0.30 L, and ΔRV (residual volume) was −0.65±0.90 L and −0.71±0.81 L (all p&lt;0.01). Post hoc analyses showed significant responses for SGRQ, 6MWD and RV in patients with both heterogeneous and homogeneous emphysema. <h3>Conclusions</h3> LVR coil treatment results in significant clinical improvements in patients with severe emphysema, with a good safety profile and sustained results for up to 1 year. <h3>Trial registration number:</h3> NCT01328899.
Frozen shoulder: a long-term prospective study.
Authors: A I Binder, D Y Bulgen, B L Hazleman, S Roberts
Journal: Annals of the Rheumatic Diseases (1984)

As the natural history of frozen shoulder is poorly documented, a prospective study of 40 patients followed up for 40-48 months (mean 44 months) is described. The range of movement was significantly less than age- and sex-matched controls. Objective restriction was severe in five patients and mild in a further 11. Patients were often unaware that shoulder range was impaired. Dominant arm involvement, manual labour, and mobilisation physiotherapy were associated with a less satisfactory outcome. We conclude that, while objective restriction persists, there is little functional impairment in the late stage of frozen shoulder.
Should CLIPPERS Be Considered a Prelymphoma State or a New Inflammatory Disease?—Reply
Authors: Hjalmar J. De Graaff, Mike P. Wattjes, Annemieke J. Rozemuller, Axel Petzold, Joep Killestein
Journal: JAMA Neurology (2013)

In Reply With great interest we read the letter by Taieb et al further discussing whether chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) should be considered a prelymphoma state or a new inflammatory disease.
Enrollment of African Americans Onto Clinical Treatment Trials: Study Design Barriers
Authors: Lucile L. Adams-Campbell, Chiledum Ahaghotu, Melvin Gaskins, Fitzroy W. Dawkins, Duane Smoot, Octavius D. Polk, Robert Gooding, Robert L. DeWitty
Journal: Journal of Clinical Oncology (2004)

African Americans have the highest cancer mortality rates and poorest survival and are more often uninsured and underinsured compared with other ethnic groups. Minority participation in clinical trials has traditionally been low, with reports ranging from 3% to 20%. The present study systematically assesses 235 consecutively diagnosed African American cancer patients regarding recruitment onto cancer treatment clinical trials at Howard University Cancer Center between January 1, 2001, and December 31, 2002. Our intent is to determine the rate-limiting factors associated with enrolling African Americans onto clinical trials at a historically black medical institution.Two hundred thirty-five consecutively diagnosed African American cancer patients were assessed for participation in clinical trials at Howard University Hospital and Cancer Center. The study population comprised 165 women and 70 men.The overall eligibility rate was 8.5% (20 of 235 patients); however, among those eligible, the enrollment rate (ie, enrollment among the eligible population) was 60.0% (12 of 20 patients). Comorbidities rendered 17.1% of the patient population ineligible for the trials. Advanced disease stage, associated with poor performance status, premature death, and short life expectancy, made an additional 10% of the patient population ineligible. Respiratory failure, HIV positivity, and anemia accounted for 37.8% of the comorbidities in this population. Cardiovascular diseases and renal insufficiency represented 16.2% of the comorbidities.It was evident that study design exclusion and inclusion criteria rendered the majority of the study population ineligible. Among African Americans, comorbidity is a major issue that warrants considerable attention.
Quality of Life Among Disease-Free Survivors of Rectal Cancer
Authors: Philippe Rauch, Joelle Miny, Thierry Conroy, Lionel Neyton, Francis Guillemin
Journal: Journal of Clinical Oncology (2004)

To identify factors affecting the quality of life (QoL) of disease-free survivors of rectal cancer.One hundred twenty-one patients in complete remission more than 2 years after diagnosis were asked to complete three QoL questionnaires: the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30; its colorectal module, QLQ-CR38; and the Duke generic instrument.Patients reported less pain (P =.002) than did controls drawn from the general population. EORTC QLQ-C30 physical scores were also higher among rectal cancer survivors than in the general Norwegian or German population (P =.0005 and P =.002, respectively). Unexpectedly, stoma patients reported better social functioning than did nonstoma patients (P =.005), with less anxiety (P =.008) and higher self-esteem (P =.0002). In the present authors' experience, the QLQ-CR38 does not discriminate between these groups. Residual abdominal or pelvic pain and constipation had the most negative influence on QoL.QoL is high among rectal cancer survivors, including stoma patients. Simultaneous use of several QoL questionnaires appears to have value in follow-up and in monitoring the effects of therapy. The impact of residual pain and constipation on long-term QoL should be considered when establishing a treatment regimen.
An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses
Authors: Alexandre Harari, Pierre-Alexandre Bart, Wolfgang Stöhr, Gonzalo Tapia, Miguel Garcia, Emmanuelle Medjitna-Rais, Séverine Burnet, Cristina Cellerai, Otto Erlwein, Tristan Barber, Christiane Moog, Peter Liljestrom, Ralf Wagner, Hans Wolf, Jean-Pierre Kraehenbuhl, Mariano Esteban, Jonathan Heeney, Marie-Joelle Frachette, James Tartaglia, Sheena McCormack, Abdel Babiker, Jonathan Weber, Giuseppe Pantaleo
Journal: The Journal of Experimental Medicine (2008)

The EuroVacc 02 phase I trial has evaluated the safety and immunogenicity of a prime-boost regimen comprising recombinant DNA and the poxvirus vector NYVAC, both expressing a common immunogen consisting of Env, Gag, Pol, and Nef polypeptide domain from human immunodeficiency virus (HIV)-1 clade C isolate, CN54. 40 volunteers were randomized to receive DNA C or nothing on day 0 and at week 4, followed by NYVAC C at weeks 20 and 24. The primary immunogenicity endpoints were measured at weeks 26 and 28 by the quantification of T cell responses using the interferon γ enzyme-linked immunospot assay. Our results indicate that the DNA C plus NYVAC C vaccine regimen was highly immunogenic, as indicated by the detection of T cell responses in 90% of vaccinees and was superior to responses induced by NYVAC C alone (33% of responders). The vaccine-induced T cell responses were (a) vigorous in the case of the env response (mean 480 spot-forming units/106 mononuclear cells at weeks 26/28), (b) polyfunctional for both CD4 and CD8 T cell responses, (c) broad (the average number of epitopes was 4.2 per responder), and (d) durable (T cell responses were present in 70% of vaccinees at week 72). The vaccine-induced T cell responses were strongest and most frequently directed against Env (91% of vaccines), but smaller responses against Gag-Pol-Nef were also observed in 48% of vaccinees. These results support the development of the poxvirus platform in the HIV vaccine field and the further clinical development of the DNA C plus NYVAC C vaccine regimen.