tbuckley/cabot-search huggingface dataset:
Clostridium difficile toxin A excites enteric neurones and suppresses sympathetic neurotransmission in the guinea pig
Authors: Y Xia
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> Evidence suggests that the intestinal actions of <i>Clostridium difficile</i> toxin A—stimulation of secretion and motility, and an acute inflammatory response—have a neurally mediated component. <h3>METHODS</h3> Direct intracellular electrophysiological recording of electrical and synaptic behaviour in enteric neurones was performed in the submucous plexus of guinea pig small intestine during exposure to the toxin. <h3>RESULTS</h3> Application of toxin A affected both the electrical behaviour of the neuronal cell bodies and inhibitory noradrenergic neurotransmission to the cell bodies. Altered electrical behaviour included depolarisation and increased excitability. Tetrodotoxin or a histamine H<sub>2</sub> receptor antagonist did not affect the depolarisation evoked by toxin A. Failure of the histamine antagonist to suppress the actions of toxin A is evidence that its actions were not mediated by degranulation of intramural mast cells. The action of toxin A on neurotransmission was suppression of inhibitory postsynaptic potentials evoked in the neuronal cell bodies by stimulation of sympathetic nerve fibres that synapsed with the cell bodies. The inhibitory postsynaptic potentials were mediated by norepinephrine (noradrenaline) acting at postsynaptic alpha adrenoceptors on the cell bodies. Hyperpolarising responses evoked in the cell bodies by micropressure application of norepinephrine were unaffected by toxin A. This fulfils criteria for a presynaptic inhibitory action of toxin A to suppress release of norepinephrine from sympathetic postganglionic axons. <h3>CONCLUSIONS</h3> Results suggest that the neural component of the action of toxin A involves both direct excitation of enteric neurones and suppression of norepinephrine release from postganglionic sympathetic nerve fibres in the enteric nervous system.
Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study
Authors: Keertan Dheda, Karen Shean, Alimuddin Zumla, Motasim Badri, Elizabeth M Streicher, Liesl Page-Shipp, Paul Willcox, Melanie-Anne John, Gary Reubenson, Darshini Govindasamy, Michelle Wong, Xavier Padanilam, Alicia Dziwiecki, Paul D van Helden, Sweetness Siwendu, Julie Jarand, Colin N Menezes, Avril Burns, Thomas Victor, Robin Warren, Martin P Grobusch, Martie van der Walt, Charlotte Kvasnovsky
Journal: The Lancet (2010)
Respiratory viruses in bronchoalveolar lavage: a hospital-based cohort study in adults
Authors: J Garbino, P M Soccal, J-D Aubert, T Rochat, P Meylan, Y Thomas, C Tapparel, P-O Bridevaux, L Kaiser
Journal: Thorax (2009)

<h3>Background:</h3> The epidemiology of respiratory viruses and their potential clinical impact when recovered in lower respiratory specimens has not been established in the hospital setting. A study was performed to investigate the association between positive viral detection and respiratory infection in an at-risk population. <h3>Methods:</h3> 299 adult patients who underwent bronchoalveolar lavage (BAL) procedures were enrolled in a hospital-based prospective cohort study. Descriptive epidemiology is presented of 17 different respiratory viruses detected by reverse transcription-polymerase chain reaction assays in BAL fluid specimens. Multivariate analysis was conducted to identify the clinical characteristics independently associated with the presence of virus. <h3>Results:</h3> Of 522 BAL fluid specimens analysed, 81% were collected in adult transplant recipients or other immunocompromised patients. Overall, PCR assays identified viral nucleic acid in 91 BAL fluid samples (17.4%). Similar rates of virus-positive BAL fluid were found in the different subpopulations studied (p = 0.113). Coronaviruses were the most frequent (32.3%), followed by rhinovirus (22.6%), parainfluenza (19.5%), influenza (9.7%), respiratory synctial virus (8.6%), human metapneumovirus (4.2%) and bocavirus (3.1%). Multivariate analysis using mixed models showed that respiratory viral infections were associated with a lack of antibiotic treatment response (OR 2.2, 95% CI 1.2 to 4.1) and the absence of radiological infiltrate (OR 0.3, 95% CI 0.2 to 0.8). In lung transplant recipients in whom a respiratory infection was suspected, the respiratory viral detection rate was 24.4% compared with 13.8% overall in other patients (p = 0.02). <h3>Conclusions:</h3> In this cohort of hospitalised adults, respiratory viruses detected in BAL fluid specimens were associated with respiratory symptoms, absence of radiological infiltrates and a poor response to antibiotic therapy.
Redox-Sensitive Sulfenic Acid Modification Regulates Surface Expression of the Cardiovascular Voltage-Gated Potassium Channel Kv1.5
Authors: Laurie K. Svoboda, Khalilah G. Reddie, Lian Zhang, Eileen D. Vesely, Elizabeth S. Williams, Sarah M. Schumacher, Ryan P. O'Connell, Robin Shaw, Sharlene M. Day, Justus M. Anumonwo, Kate S. Carroll, Jeffrey R. Martens
Journal: Circulation Research (2012)

Rationale: Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I Kur current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.5 protein expression, as well as with oxidative stress. Formation of sulfenic acid on cysteine residues of proteins is an important, dynamic mechanism for protein regulation under oxidative stress. Kv1.5 is widely reported to be redox-sensitive, and the channel possesses 6 potentially redox-sensitive intracellular cysteines. We therefore hypothesized that sulfenic acid modification of the channel itself may regulate Kv1.5 in response to oxidative stress. Objective: To investigate how oxidative stress, via redox-sensitive modification of the channel with sulfenic acid, regulates trafficking and expression of Kv1.5. Methods and Results: Labeling studies with the sulfenic acid–specific probe DAz and horseradish peroxidase–streptavidin Western blotting demonstrated a global increase in sulfenic acid–modified proteins in human patients with atrial fibrillation, as well as sulfenic acid modification to Kv1.5 in the heart. Further studies showed that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine (C581), and the level of sulfenic acid increases in response to oxidant exposure. Using live-cell immunofluorescence and whole-cell voltage-clamping, we found that modification of this cysteine is necessary and sufficient to reduce channel surface expression, promote its internalization, and block channel recycling back to the cell surface. Moreover, Western blotting demonstrated that sulfenic acid modification is a trigger for channel degradation under prolonged oxidative stress. Conclusions: Sulfenic acid modification to proteins, which is elevated in diseased human heart, regulates Kv1.5 channel surface expression and stability under oxidative stress and diverts channel from a recycling pathway to degradation. This provides a molecular mechanism linking oxidative stress and downregulation of channel expression observed in cardiovascular diseases.
PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability
Authors: Ana Silva, J. Andrés Yunes, Bruno A. Cardoso, Leila R. Martins, Patrícia Y. Jotta, Miguel Abecasis, Alexandre E. Nowill, Nick R. Leslie, Angelo A. Cardoso, Joao T. Barata
Journal: Journal of Clinical Investigation (2008)

Mutations in the phosphatase and tensin homolog (PTEN) gene leading to PTEN protein deletion and subsequent activation of the PI3K/Akt signaling pathway are common in cancer. Here we show that PTEN inactivation in human T cell acute lymphoblastic leukemia (T-ALL) cells is not always synonymous with PTEN gene lesions and diminished protein expression. Samples taken from patients with T-ALL at the time of diagnosis very frequently showed constitutive hyperactivation of the PI3K/Akt pathway. In contrast to immortalized cell lines, most primary T-ALL cells did not harbor PTEN gene alterations, displayed normal PTEN mRNA levels, and expressed higher PTEN protein levels than normal T cell precursors. However, PTEN overexpression was associated with decreased PTEN lipid phosphatase activity, resulting from casein kinase 2 (CK2) overexpression and hyperactivation. In addition, T-ALL cells had constitutively high levels of ROS, which can also downmodulate PTEN activity. Accordingly, both CK2 inhibitors and ROS scavengers restored PTEN activity and impaired PI3K/Akt signaling in T-ALL cells. Strikingly, inhibition of PI3K and/or CK2 promoted T-ALL cell death without affecting normal T cell precursors. Overall, our data indicate that T-ALL cells inactivate PTEN mostly in a nondeletional, posttranslational manner. Pharmacological manipulation of these mechanisms may open new avenues for T-ALL treatment.
VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium
Authors: Tara Karnezis, Ramin Shayan, Carol Caesar, Sally Roufail, Nicole C. Harris, Kathryn Ardipradja, You Fang Zhang, Steven P. Williams, Rae H. Farnsworth, Ming G. Chai, Thusitha W.T. Rupasinghe, Dedreia L. Tull, Megan E. Baldwin, Erica K. Sloan, Stephen B. Fox, Marc G. Achen, Steven A. Stacker
Journal: Cancer Cell (2012)
Rate of Kidney Function Decline Associates with Mortality
Authors: Ziyad Al-Aly, Angelique Zeringue, John Fu, Michael I. Rauchman, Jay R. McDonald, Tarek M. El-Achkar, Sumitra Balasubramanian, Diana Nurutdinova, Hong Xian, Kevin Stroupe, Kevin C. Abbott, Seth Eisen
Journal: Journal of the American Society of Nephrology (2010)

The effect of rate of decline of kidney function on risk for death is not well understood. Using the Department of Veterans Affairs national databases, we retrospectively studied a cohort of 4171 patients who had rheumatoid arthritis and early stage 3 chronic kidney disease (CKD; estimated GFR 45 to 60 ml/min) and followed them longitudinally to characterize predictors of disease progression and the effect of rate of kidney function decline on mortality. After a median of 2.6 years, 1604 (38%) maintained stable kidney function; 426 (10%), 1147 (28%), and 994 (24%) experienced mild, moderate, and severe progression of CKD, respectively (defined as estimated GFR decline of 0 to 1, 1 to 4, and >4 ml/min per yr). Peripheral artery disease predicted moderate progression of CKD progression. Black race, hypertension, diabetes, cardiovascular disease, and peripheral artery disease predicted severe progression of CKD. After a median of 5.7 years, patients with severe progression had a significantly increased risk for mortality (hazard ratio 1.54; 95% confidence interval 1.30 to 1.82) compared with those with mild progression; patients with moderate progression exhibited a similar trend (hazard ratio 1.10; 95% confidence interval 0.98 to 1.30). Our results demonstrate an independent and graded association between the rate of kidney function decline and mortality. Incorporating the rate of decline into the definition of CKD may transform a static definition into a dynamic one that more accurately describes the potential consequences of the disease for an individual.
Absence of sperm RNA elements correlates with idiopathic male infertility
Authors: Meritxell Jodar, Edward Sendler, Sergey I. Moskovtsev, Clifford L. Librach, Robert Goodrich, Sonja Swanson, Russ Hauser, Michael P. Diamond, Stephen A. Krawetz
Journal: Science Translational Medicine (2015)

Absence of required RNA elements in sperm correlates with infertility but can be overcome with assisted reproductive technologies.
The P190, P210, and P230 Forms of the <i>BCR/ABL</i> Oncogene Induce a Similar Chronic Myeloid Leukemia–like Syndrome in Mice but Have Different Lymphoid Leukemogenic Activity
Authors: Shaoguang Li, Robert L. Ilaria, Ryan P. Million, George Q. Daley, Richard A. Van Etten
Journal: The Journal of Experimental Medicine (1999)

The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although all three oncogenes transformed both myeloid (32D cl3) and lymphoid (Ba/F3) interleukin (IL)-3–dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)–like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)–treated donors were used. Analysis of proviral integration showed the CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients, suggesting heterogeneity among the target cell population. In contrast, when marrow from non– 5-FU–treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.
Granulomatous gastritis in Wegener's disease: differentiation from Crohn's disease supported by a positive test for antineutrophil antibodies.
Authors: B Temmesfeld-Wollbrueck, C Heinrichs, A Szalay, W Seeger
Journal: Gut (1997)

BACKGROUND: This report concerns the gastric manifestation of Wegener9s granulomatosis in a 44 year old white female patient who initially presented with abdominal pain, vomiting, and iridocyclitis. FINDINGS: The clinical findings and the histopathological proof of granulomatous gastritis in the absence of necrotising vasculitis were initially considered to be indicative of a diagnosis of Crohn9s disease showing isolated gastric involvement. A five month course of steroids resulted in temporary relief; thereafter the patient developed severe rhinitis with mucosal ulcerations. At this point biopsy of nasal mucosa disclosed the classic histopathological signs of Wegener9s granulomatosis. A positive test for antineutrophil cytoplasmic antibodies (ANCAs) with a cytoplasmic pattern (c-ANCA) and antigenic specificity for proteinase 3 (PR-3) were found. The patient is in complete remission one year after diagnosis and treatment with steroids and cyclophosphamide. CONCLUSIONS: Wegener9s granulomatosis can also involve the gastrointestinal tract. Granulomatous inflammation of the stomach, although a rare finding and non-specific, should include Wegener9s disease in the differential diagnosis. The histological proof of necrotising vasculitis is dependent on the depth of the biopsy and therefore can be easily missed. Differential diagnosis can be clarified by ANCA testing.
The homeless mentally ill. The perspective of the American Psychiatric Association
Authors: H. R. Lamb
Journal: JAMA (1986)

The homeless mentally ill have become one of the greatest problems of present-day society. The American Psychiatric Association's Task Force on the Homeless Mentally Ill concluded that this is not the result of deinstitutionalization per se but of the way it has been carried out; homelessness among the chronically and severely mentally ill is symptomatic of the grave problems facing them generally in this country. Thus, the problem will not be solved until the basic underlying problems are addressed and a comprehensive and integrated system of care for the chronically mentally ill is established. Specific recommendations of the Task Force include an ample range of graded, supervised community housing; comprehensive and accessible psychiatric care and rehabilitation; the availability of general medical assessment and care, crisis services, and a dependable source of income; a system of case management in which one mental health worker is responsible for each patient; changes in commitment laws to make them more responsive to clinical needs; coordination between the various community resources; and ongoing asylum and sanctuary for that small proportion who require it.
Indispensable Role of the Runx1-Cbfβ Transcription Complex for In Vivo-Suppressive Function of FoxP3+ Regulatory T Cells
Authors: Akihiko Kitoh, Masahiro Ono, Yoshinori Naoe, Naganari Ohkura, Tomoyuki Yamaguchi, Hiroko Yaguchi, Issay Kitabayashi, Toshihiko Tsukada, Takashi Nomura, Yoshiki Miyachi, Ichiro Taniuchi, Shimon Sakaguchi
Journal: Immunity (2009)
Acceleration of Telomere Loss by Chemotherapy Is Greater in Older Patients with Locally Advanced Head and Neck Cancer
Authors: Brad M. Unryn, Desiree Hao, Stefan Glück, Karl T. Riabowol
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Chronic viral infection and combinations of chemotherapeutic drugs have been reported to accelerate telomere erosion. Here, we asked if chemoradiotherapy, using the single agent cisplatin, would accelerate telomere loss in head and neck cancer patients, and whether loss was linked to smoking status, age, gender, or stage of disease at diagnosis. Experimental Design: Blood samples were collected from 20 patients with squamous cell cancer of the head and neck before, during, and after chemoradiotherapy. Following DNA isolation from peripheral blood mononuclear cells, telomere length was measured by terminal restriction fragment analysis. Results: Chemoradiotherapy increased the rate of telomere erosion &amp;gt;100-fold. Telomere length before treatment in chemoradiotherapy patients was similar to age-matched controls. Although smokers began with significantly shorter telomeres, smoking status did not affect chemoradiotherapy-induced attrition, nor did gender or stage of disease. We also make the novel observation that a significantly greater telomere loss occurred in response to treatment in older patients, with those younger than 55 years losing an average of 400 bp of telomeric DNA compared with the 880 bp lost by those over 55 years. Conclusions: The lack of telomere length difference before treatment suggests that shortened telomeres may not be a risk factor for development of head and neck cancer in the age range we examined. Chemoradiotherapy caused a severe telomere length reduction in all patients. The significant difference seen in the elderly (P = 0.018) suggests that chemoradiotherapy may have more severe effects on the replicative capacity of blood cells in older patients.
Differential contribution of HLA-DR, DQ, and TAP2 alleles to systemic lupus erythematosus susceptibility in Spanish patients: role of TAP2*01 alleles in Ro autoantibody production
Authors: J. M Martin-Villa, J. Martinez-Laso, M. A Moreno-Pelayo, M. J Castro-Panete, N. Martinez-Quiles, M. Alvarez, M. D de Juan, J. J Gomez-Reino, A. Arnaiz-Villena
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> To study the influence MHC class II and TAP2 alleles exert on systemic lupus erythematosus (SLE) susceptibility and on the clinical and serological manifestations of the disease, in a cohort of Spanish patients. <h3>METHODS</h3> HLA-DR serological typing and HLA-DQA, DQB, and TAP2 DNA sequence specific oligotyping, were carried out in 85 unrelated Spanish SLE patients and 186 healthy controls. Autoantibodies detection was carried out by indirect immunofluorescence and counter immunoelectrophoresis. <h3>RESULTS</h3> Total SLE group: the frequency of HLA-DR3 and HLA-DQA1*0501 is significantly increased in this group (p<sub>c</sub>&lt;0.005, δ=0.34 and p<sub>c</sub>&lt;0.005, δ= 0.45, respectively) although the highest δ value (δ=0.87) is obtained when the TAP2*01 alleles are considered. No DQB allele shows significant deviation from the control group. Renal damage: it mainly occurs in HLA-DR3 patients (p<sub>c</sub>&lt;0.0005 and δ=0.72). HLA-DQA1*0501 (p<sub>c</sub>&lt;0.05, δ=0.57) and DQB1*0201 (p<sub>c</sub> NS, δ=0.56) are weaker susceptibility factors. Ro+ (but not La) group: this autoantibody response is associated with TAP2*01 alleles in homozygosity (p&lt;0.05, δ=0.81). Ro/La+ group: it has a different genetic background as HLA-DQA1*0501 (δ=1) and HLA-DQB1*0201 (δ=1) are the main susceptibility factors. <h3>CONCLUSIONS</h3> A differential association between HLA-DR, DQA1, and DQB1 alleles and SLE or its clinical and serological manifestations are found. Furthermore, the associations are different to the ones reported in other ethnic groups. Finally, TAP2*01 group of alleles are associated with the highest susceptibility to SLE (higher than HLA-DR3) and may influence Ro (but not La) autoantibodies production, whereas HLA-DQA1*0501 and DQB1*0201 mediates concomitant Ro and La production.
Selective transport of polymeric immunoglobulin A in bile. Quantitative relationships of monomeric and polymeric immunoglobulin A, immunoglobulin M, and other proteins in serum, bile, and saliva.
Authors: D L Delacroix, H J Hodgson, A McPherson, C Dive, J P Vaerman
Journal: Journal of Clinical Investigation (1982)

In 17 adults, serum, hepatic bile, and saliva samples were analyzed for their sedimentation profile of IgA and secretory component (SC), and for their concentrations of albumin, orosomucoid, transferrin, IgG, IgA, alpha 2-macroglobulin (alpha 2M), IgM, and SC. Polymeric IgA(p-IgA) averaged 13% (50-700 micrograms/ml) of total IgA in serum, 70% (43-88%) in bile, and 93% (74-98%) in saliva. Most of the p-IgA in bile sedimented with SC, which also occurred free (8-44%), and with IgM. In bile, albumin (155-1,485 micrograms/ml) was the predominant protein, followed by IgG (32-480 micrograms/ml), and total IgA (37-209 micrograms/ml). In saliva, p-IgA (72-902 micrograms/ml) predominated, followed by albumin (16-385 micrograms/ml) and IgG (9-178 micrograms/ml). Secretion-to-serum albumin-relative concentration ratios (S/S-ARCR = 1 for albumin) in bile averaged 22 for p-IgA, 1.91 for IgM, 1.28 for monomeric IgA (m-IgA), 0.70 for IgG, and 0.57 for alpha 2M, indicating for p-IgA, IgM, and to a lesser extent for m-IgA, a selective excretion into bile. In saliva, a 16-fold greater selective excretion of p-IgA (mean S/S-ARCR = 354) was found. Labeled m- and p-IgA were injected intravenously into five patients. Specific activities indicated that for p-IgA 50% was serum derived in bile, as compared with 2% in saliva, and to 85% for m-IgA in bile. In the patient with the highest excretion of 125I-p-IgA in bile, only 2.8% of the injected dose was recovered in bile within 24 h after injection. Compared with rats and rabbits, the serum-to-bile transport of p-IgA in humans is much smaller.