tbuckley/cabot-search huggingface dataset:
On the Molecular Nature of the Lidocaine Receptor of Cardiac Na <sup>+</sup> Channels
Authors: Paul B. Bennett, Carmen Valenzuela, Li-Qiong Chen, Roland G. Kallen
Journal: Circulation Research (1995)

Abstract The mechanism of inhibition of Na + channels by lidocaine has been suggested to involve low-affinity binding to rested states and high-affinity binding to the inactivated state of the channel, implying either multiple receptor sites or allosteric modulation of receptor affinity. Alternatively, the lidocaine receptor may be guarded by the channel gates. To test these distinct hypotheses, inhibition of Na + channels by lidocaine was studied by voltage-clamp methods in both native and heterologous expression systems. Native Na + channels were studied in guinea pig ventricular myocytes, and recombinant human heart Na + channels were expressed in Xenopus laevis oocytes. Fast inactivation was eliminated by mutating three amino acids (isoleucine, phenylalanine, and methionine) in the III-IV interdomain to glutamines or by enzymatic digestion with α-chymotrypsin. In channels with intact fast inactivation, lidocaine block developed with a time constant of 589±42 ms (n=7) at membrane potentials between −50 and +20 mV, as measured by use of twin pulse protocols. The IC 50 was 36±1.8 μmol/L. Control channels inactivated within 20 ms, and slow inactivation developed much later (time constant of slow inactivation, 6.2±0.36 s). The major component of block developed long after activated and open channels were no longer available for drug binding. Control channels recovered fully from inactivation in &lt;50 ms at −120 mV (time constant, 11±0.5 ms; n=50). In 30 μmol/L lidocaine, 49±3% of the current recovered with a second larger time constant of 398±46 ms (n=5). After removal of fast inactivation, either enzymatically or by mutagenesis, the channels were no longer blocked by 50 μmol/L lidocaine (n=8). Much higher concentrations of lidocaine produced a tonic block (IC 50 , 0.4±0.07 mmol/L; n=13) and time dependence suggestive of open-channel block. The results indicate the importance of inactivated state block by therapeutic concentrations of lidocaine and suggest that the molecular site of action is the structural region of the channel that is responsible for inactivation.
Ten-Year Trends in Self-Rated Health Among Spanish Adults With Diabetes, 1993–2003
Authors: Rodrigo Jiménez-Garcia, Isabel Jiménez-Trujillo, Valentin Hernandez-Barrera, Pilar Carrasco-Garrido, Ana Lopez, Angel Gil
Journal: Diabetes Care (2007)

Improving health-related quality of life among individuals with diabetes is a public health goal. This study sought to assess trends in self-rated "fair" and "poor" health among Spanish adults with diabetes and to identify factors associated with fair and poor health using data from all five National Health Surveys conducted from 1993 to 2003.Poisson regression analysis was used to assess the trend in fair or poor health status during the period 1993-2003 and to compare prevalences between diabetes and nondiabetes sufferers.The most relevant finding of this study is that, among Spanish adults with diabetes, prevalence of fair or poor heath is more than double that of individuals without diabetes and that overall prevalence did not vary during the decade 1993-2003 (71.2 to 70.5%). The variables associated with an increased risk of self-rated fair or poor health were as follows: age 54-64 years (odds ratio [OR] 1.5) or >or= 65years (2.1), presence of comorbidity (4.3), female sex (1.2), lower educational level (1.7), obesity (1.3), and no physical activity (1.6).The lack of improvement in self-rated health among Spanish adults with diabetes calls for urgent implementation of health-promotion, prevention, and diabetes-management strategies aimed at enhancing the quality of life of such individuals.
Expression of the Apoptosis Inhibitor Protease Inhibitor 9 Predicts Clinical Outcome in Vaccinated Patients with Stage III and IV Melanoma
Authors: Inge S. van Houdt, Joost J. Oudejans, Alfonsus J.M. van den Eertwegh, Arnold Baars, Wim Vos, Bellinda A. Bladergroen, Donata Rimoldi, Jettie J.F. Muris, Erik Hooijberg, Chad M. Gundy, Chris J.L.M. Meijer, Jean A. Kummer
Journal: Clinical Cancer Research (2005)

Abstract Purpose: There have been reports of successful treatment of metastatic melanoma patients with active specific immunotherapy (ASI) using irradiated autologous tumor cell vaccination. It is still unknown why some patients respond and others do not. Tumor cells can evade the immune system, for example through interference with antigen presentation by down-regulation of MHC molecules or expressing proteins interfering with cytotoxic lymphocyte–induced apoptosis like the granzyme B antagonist protease inhibitor 9 (PI-9). Experimental Design: PI-9 expression was detected in melanoma cell lines. To investigated if PI-9 is important in the response to ASI, paraffin-embedded tissues from stage III or IV melanoma patients were stained. Results: PI-9 is expressed in melanoma cells and expression in metastasized melanoma cells is, in this group of patients, an adverse prognostic marker with regard to overall and disease-free survival. Moreover, loss of MHC-1 expression frequently occurs during tumor progression but is not associated with poor clinical outcome. Interestingly, melanoma patients with a favorable clinical outcome after ASI therapy usually have high percentages of activated (granzyme B–positive) tumor-infiltrating lymphocytes at time of first diagnosis and low percentages of activated lymphocytes at time of recurrent tumor. Conclusions: Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not. Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy.
Positive and Negative Regulation of V(D)J Recombination by the E2A Proteins
Authors: Gretchen Bain, William J. Romanow, Karen Albers, Wendy L. Havran, Cornelis Murre
Journal: The Journal of Experimental Medicine (1999)

A key feature of B and T lymphocyte development is the generation of antigen receptors through the rearrangement and assembly of the germline variable (V), diversity (D), and joining (J) gene segments. However, the mechanisms responsible for regulating developmentally ordered gene rearrangements are largely unknown. Here we show that the E2A gene products are essential for the proper coordinated temporal regulation of V(D)J rearrangements within the T cell receptor (TCR) γ and δ loci. Specifically, we show that E2A is required during adult thymocyte development to inhibit rearrangements to the γ and δ V regions that normally recombine almost exclusively during fetal thymocyte development. The continued rearrangement of the fetal Vγ3 gene segment in E2A-deficient adult thymocytes correlates with increased levels of Vγ3 germline transcripts and increased levels of double-stranded DNA breaks at the recombination signal sequence bordering Vγ3. Additionally, rearrangements to a number of Vγ and Vδ gene segments used predominately during adult development are significantly reduced in E2A-deficient thymocytes. Interestingly, at distinct stages of T lineage development, both the increased and decreased rearrangement of particular Vδ gene segments is highly sensitive to the dosage of the E2A gene products, suggesting that the concentration of the E2A proteins is rate limiting for the recombination reaction involving these Vδ regions.
Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer
Authors: Enrique Rozengurt, James Sinnett-Smith, Krisztina Kisfalvi
Journal: Clinical Cancer Research (2010)

Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis, and proliferation. Crosstalk between these signaling systems depends on mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast, and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration.
Targeted Expression of Cyclin D2 Results in Cardiomyocyte DNA Synthesis and Infarct Regression in Transgenic Mice
Authors: Kishore B.S. Pasumarthi, Hidehiro Nakajima, Hisako O. Nakajima, Mark H. Soonpaa, Loren J. Field
Journal: Circulation Research (2004)

Restriction point transit and commitment to a new round of cell division is regulated by the activity of cyclin-dependent kinase 4 and its obligate activating partners, the D-type cyclins. In this study, we examined the ability of D-type cyclins to promote cardiomyocyte cell cycle activity. Adult transgenic mice expressing cyclin D1, D2, or D3 under the regulation of the α cardiac myosin heavy chain promoter exhibited high rates of cardiomyocyte DNA synthesis under baseline conditions. Cardiac injury in mice expressing cyclin D1 or D3 resulted in cytoplasmic cyclin D accumulation, with a concomitant reduction in the level of cardiomyocyte DNA synthesis. In contrast, cardiac injury in mice expressing cyclin D2 did not alter subcellular cyclin localization. Consequently, cardiomyocyte cell cycle activity persisted in injured hearts expressing cyclin D2, ultimately resulting in infarct regression. These data suggested that modulation of D-type cyclins could be exploited to promote regenerative growth in injured hearts.
Psychiatric Disability Among Tortured Bhutanese Refugees in Nepal
Authors: Suraj Bahadur Thapa, Mark Van Ommeren, Bhogendra Sharma, Joop T V M de Jong, Edvard Hauff
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Most refugees live in low-income countries. There is a lack of data on psychiatric disability among such refugees. The authors compared psychiatric disability in tortured and nontortured Bhutanese refugees living in Nepal and examined factors associated with psychiatric disability among the tortured refugees. METHOD: A cross-sectional survey was conducted among 418 tortured and 392 nontortured Bhutanese refugees, matched for age and gender. The Composite International Diagnostic Interview, version 2.1, and the World Health Organization Short Disability Assessment Schedule were used to measure ICD-10 psychiatric disorders and disability, respectively. RESULTS: Approximately one in five tortured and nontortured Bhutanese refugees were found to be disabled. Posttraumatic stress disorder, specific phobia, and present physical disease were identified as factors associated with disability among the tortured refugees. On the other hand, present physical disease, greater age, and generalized anxiety disorder were associated with disability among the nontortured group. CONCLUSIONS: These findings show that the tortured and nontortured refugees were equally likely to be disabled. Different sets of predictors were identified among tortured and nontortured refugees, indicating the need for comprehensive psychiatric assessment of both tortured and nontortured refugees in clinical practice.
Young people with HIV in Romania face discrimination
Authors: Bucharest Leidig
Journal: BMJ (2006)

Thousands of young Romanians with HIV face a life of discrimination, says a report by an international human rights organisation.

The report by Human Rights Watch says that a study of more than 7200 Romanian teenagers aged 15–19 who are infected with HIV shows that a failure by the government to combat discrimination against these young people has left them open to abuse and neglect.

They are unprepared for adult life, the group said, and the state has no plan for them, despite being aware of the problem for at least a decade.

Human rights groups and other non-governmental organisations have warned for years that thousands …
Asthma control test/Questionnaire for assessing asthma control: Systematic review and meta-analysis
Authors: Cun-E Jia, Hong-Ping Zhang, L.V. Yan, Rui Liang, Yun-Qiu Jiang, Heather Powell, Juan-Juan Fu, Lei Wang, Peter Gerard Gibson, Gang Wang
Journal: European Respiratory Journal (2012)

Background: Currently the cornerstone of asthma management is to achieve and maintain asthma optimal control, but the diagnostic performance of Asthma control test (ACT) and Asthma Control Questionnaire (ACQ) has not systematically been evaluated.

Objective: We explored the diagnostic performance and its comparison between ACT and ACQ.

Methods: Studies concerned with the accuracy of ACT and/or ACQ for assessing asthma control were searched from Pubmed, CENTRAL, Web of Science, Ovid and Embase. The summary estimates of sensitivity, specificity, and diagnostic odds ratios (DORs) at different levels of asthma control were performed by using bivariate random effects model and hierarchical summary receiver operator characteristic (HSROC) model.

Results: Twenty-two studies with 12909 subjects in ACT and 4447 in ACQ were identified. The summary estimates in ACT for assessing controlled, not-well controlled, and uncontrolled asthma were sensitivity (0.81, 0.77 and 0.79), specificity (0.79, 0.78 and 0.73), and DORs (15.56, 12.42 and 10.46), respectively, and those in ACQ were sensitivity (0.93, 0.72 and 0.87), specificity (0.65, 0.83 and 0.66), and DOR (24.92, 11.98 and 12.72), respectively. There were no statistical differences in assessing levels of asthma control between ACT and ACQ by using HSROC areas under the curve (all P>0.05). Subgroup and meta-regression implied that age, settings, asthma severity, and the race could influence the diagnostic accuracy.

Conclusion: The diagnostic performance between ACT and ACQ is not different, but clinicians need to consider the impact of the potential factors when establishing asthma control levels to promote therapies in a real-world setting.
Haemodynamic responses to exercise in patients with COPD
Authors: Janne Mykland Hilde, Ingunn Skjørten, Viggo Hansteen, Morten Nissen Melsom, Jonny Hisdal, Sjur Humerfelt, Kjetil Steine
Journal: European Respiratory Journal (2012)

The present study aimed to explore the prevalence of pre-capillary pulmonary hypertension (PH) and characterise haemodynamic vascular responses to physical exercise in chronic obstructive pulmonary disease (COPD) outpatients, where left ventricular dysfunction and comorbidities were excluded. 98 patients with COPD underwent right heart catheterisation at rest and during supine exercise. Mean pulmonary artery pressure ( P pa ), pulmonary capillary wedge pressure ( P pcw ) and cardiac output (CO) were measured at rest and during exercise. Exercise-induced increase in mean P pa was interpreted relative to increase in blood flow, mean P pa /CO, workload ( W ) and mean P pa / W . Pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC) were calculated. PH at rest was defined as mean P pa at rest ≥25 mmHg and P pcw at rest &lt;15 mmHg. Prevalence of PH was 5%, 27% and 53% in Global Initiative for Chronic Obstructive Lung Disease stages II, III and IV, respectively. The absolute exercise-induced rise in mean P pa did not differ between subjects with and without PH. Patients without PH showed similar abnormal haemodynamic responses to exercise as the PH group, with increased PVR, reduced PAC and steeper slopes for mean P pa /CO and mean P pa / W . Exercise revealed abnormal physiological haemodynamic responses in the majority of the COPD patients. The future definition of PH on exercise in COPD should rely on the slope of mean P pa related to cardiac output and workload rather than the absolute values of mean P pa .
Hepatitis B virus infection in patients with idiopathic liver disease
Authors: Jake T. Liang, Yaacov Baruch, Edna Ben-Porath, Rafael Enat, Lucyna Bassan, Nancy V. Brown, Nurit Rimon, Hubert E. Blum, Jack R. Wands
Journal: Hepatology (1991)

We studied 67 HBsAg-negative Israeli patients (36 negative for all HBV serological markers as group 1 and 31 positive for antibodies to HBs and HBc as group 2) with chronic liver disease and cirrhosis of unknown origin using a rapid, sensitive and specific assay for the detection of low levels of hepatitis B virus in serum. This technique uses a high-affinity monoclonal antibody to HBs against an a domain epitope of HBsAg to capture the virion, followed by hepatitis B virus DNA amplification with the polymerase chain reaction. In addition, 55 subjects without liver disease served as controls: Group 3 (n = 32) was negative for all hepatitis B virus markers; group 4 (n = 23) was positive for antibodies to HBs and HBc. We found 11 individuals in group 1 (31%) and 10 in group 2 (29%) harboring low levels of hepatitis B virus DNA in serum. In contrast, no one in group 3 or group 4 was positive by this technique (p &lt; 0.0001). Using polymerase chain reaction primers spanning other regions of the hepatitis B virus genome and a method of restriction-fragment analysis of polymerase chain reaction-amplified sequences, we detected significant DNA sequence heterogeneity, suggesting infection with distinct hepatitis B virus strains. DNA extracted from paraffin-embedded liver biopsy specimens of 42 patients from groups 1 and 2 was shown to contain hepatitis B virus DNA by polymerase chain reaction in 11 of 12 patients with circulating virion DNA. More important, 18 additional patients whose sera were negative by HBs-antibody capture/polymerase chain reaction amplification had hepatitis B virus DNA sequences in their livers. Hepatitis C virus antibodies were found in 71% of group 1, in 65% of group 2, in 3% of group 3 and in 4% of group 4 (p &lt; 0.0001). Coexistence of hepatitis B virus infection and hepatitis C virus antibodies were common (&gt;30%). We conclude that infection with hepatitis B virus undetectable by conventional assays and with hepatitis C virus may represent important unrecognized causes of idiopathic chronic liver disease in Israel, accounting for the possible origin in more than 90% of patients. (Hepatology 1991;13:1044-1051.)
Portal circulation and portal hypertension.
Authors: S Sherlock
Journal: Gut (1978)

During the last 25 years, there have been important developments in visualising the portal vein, in examining its contents, and in measuring the pressure of blood flowing within it. Radiologists have set the scene and now is the time of the scanner. These technical advances have been applied to the diagnosis and treatment of patients with portal hypertension, and many ingenious surgical techniques have been proposed. The problem of successful treatment of the patient with bleeding oesophageal varices and cirrhosis of the liver, however, has not yet been solved. This report discusses the portal vein in terms of pressure, flow, and regeneration factors. Portal hypertension is classified and methods of relief are discussed.
Identification of Sp2 as a Transcriptional Repressor of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Tumorigenesis
Authors: Dillon Phan, Chien-Jui Cheng, Matthew Galfione, Funda Vakar-Lopez, James Tunstead, Nancy E. Thompson, Richard R. Burgess, Sonia M. Najjar, Li-Yuan Yu-Lee, Sue-Hwa Lin
Journal: Cancer Research (2004)

Abstract Down-regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) tumor suppressor gene expression is common in several malignancies including prostate, colon, and breast cancer. The mechanism that mediates this down-regulation is not known. Here, we report that down-regulation of CEACAM1 expression in prostate cancer cells occurs primarily at the transcriptional level and is mediated by Sp2, a member of the Sp family of transcription factors. Sp2 binds to the CEACAM1 promoter in vitro and in vivo, and transient overexpression of Sp2 down-regulates endogenous CEACAM1 expression in normal prostate epithelial cells. Sp2 appears to repress CEACAM1 gene expression by recruiting histone deacetylase activity to the CEACAM1 promoter. In human prostate cancer specimens, Sp2 expression is high in prostate cancer cells but low in normal prostate epithelial cells and is inversely correlated with CEACAM1 expression. Our studies show that transcriptional repression by Sp2 represents one mechanism by which CEACAM1 tumor suppressor gene is down-regulated in prostate cancer.
Human leucocyte antigen risk alleles for psoriatic arthritis among patients with psoriasis
Authors: Lihi Eder, Vinod Chandran, Fawnda Pellet, Sutha Shanmugarajah, Cheryl F Rosen, Shelley B Bull, Dafna D Gladman
Journal: Annals of the Rheumatic Diseases (2011)

Aim Genes that differentiate patients with psoriatic arthritis (PsA) from those with cutaneous psoriasis (PsC) may serve as markers for the development of PsA in patients with psoriasis. The authors aimed to identify human leucocyte antigen (HLA) alleles that are associated with the development of PsA in patients with psoriasis. Methods 712 adult patients with PsA, 335 adult patients with PsC and 713 healthy controls were genotyped for HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ alleles. Differences in allelic distributions for each of the HLA loci were compared using a likelihood ratio test. Logistic regression analysis of multiple loci was performed to account for linkage disequilibrium. Haplotype information was inferred using the expectation–maximisation algorithm (given HLA-C and HLA-B genotypes) and analysed similarly. Results The following HLA alleles were found to be significantly associated with patients with PsA compared to patients with PsC in multivariate regression analysis: B*08 (OR 1.61, p=0.009), B*27 (OR 5.17, p&lt;0.0001), B*38 (OR 1.65, p=0.026) and C*06 (OR 0.58, p=0.0002). HLA-B*27, HLA-B*38 and HLA-C*06 frequencies were also significantly higher in patients with PsA than in healthy controls (B*27: OR 3.05, p&lt;0.0001; B*38: OR 5.9, p&lt;0.0001; HLA-C*06: OR 1.71, p&lt;0.0001). The following haplotypes were independently associated with PsA compared to PsC: HLA-B*18-C*07 (OR 10.1, p=0.004), HLA-B*27-C*01 (OR 41.1, p&lt;0.0001), HLA-B*27-C*02 (OR 19.9, p&lt;0.0001), HLA-B*38-C*12 (OR 2.9, p=0.01), HLA-B*08-C*07 (OR 2.6, p=0.004) and HLA-B*57-C*06 (OR 0.5, p=0.03). Conclusions Certain HLA-B and HLA-C alleles confer susceptibility to PsA among patients with psoriasis and may be used to identify patients with PsC who may develop PsA.