tbuckley/cabot-search huggingface dataset:
Consequences of the recurrent <i>MYD88L265P</i> somatic mutation for B cell tolerance
Authors: James Q. Wang, Yogesh S. Jeelall, Bruce Beutler, Keisuke Horikawa, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (2014)

MYD88L265P has recently been discovered as an extraordinarily frequent somatic mutation in benign monoclonal IgM gammopathy, Waldenström’s macroglobulinemia, and diffuse large B cell lymphoma. In this study, we analyze the consequences for antigen-activated primary B cells of acquiring MYD88L265P. The mutation induced rapid B cell division in the absence of exogenous TLR ligands and was inhibited by Unc93b13d mutation and chloroquine or TLR9 deficiency, indicating continued dependence on upstream TLR9 activation. Proliferation and NF-κB activation induced by MYD88L265P were nevertheless rapidly countered by the induction of TNFAIP3, an NF-κB inhibitor frequently inactivated in MYD88L265P–bearing lymphomas, and extinguished by Bim-dependent apoptosis. MYD88L265P caused self-reactive B cells to accumulate in vivo only when apoptosis was opposed by Bcl2 overexpression. These results reveal checkpoints that fortify TLR responses against aberrant B cell proliferation in response to ubiquitous TLR and BCR self-ligands and suggest that tolerance failure requires the accumulation of multiple somatic mutations.
Life sustaining technology: making the decisions
Authors: J. Searle
Journal: BMJ (1989)

direct a patient who still needs nursing to a private nursing home it may well be breaking the law.The circulars state that arrangements for dis- charge to other than the patient's home must be made in good time and be acceptable to the patient and, where appropriate, the patient's carers.Where a person moves from hospital to a private nursing home it should be made clear to him or her in writing before the transfer whether or not the health authority will pay the fees under a con- tractual arrangement.No NHS patients should be placed in private nursing homes or residential care homes against their wishes if it means that they or their relatives will be personally responsible for the charges.Up and down Britain cash starved hospitals, desperately trying to cope with an aging population, are discharging patients to nursing homes.They are probably breaking the law by not pro- viding for the sick elderly, and it is an interesting legal point whether the hospital or the consultant could be held responsible for paying the family's expenditure.
Reply to: “Transient elevation of serum bile salts after partial hepatectomy is due to metabolic overload and not to cholestasis”
Authors: Takuya Miura, Norihisa Kimura, Daisuke Yamana, Kenichi Hakamada, Shigeki Tsuchida, Toshiyuki Yamada, Takeshi Shimizu, Naoki Nanashima
Journal: Journal of Hepatology (2011)
Abstract 8903: Six-year Target Systolic Blood Pressure Less Than 120 mmHg For More Than 65 Aged Hypertension Patients With Chronic Renal Disease
Authors: Xianghong Zeng, Xiangji zeng, Yunyun li, Zhauhua liu, Xianghong zeng
Journal: Circulation (2012)

Background: Three year target SBP≦120 mmHg in elderly hypertension patients with chronic kidney disease(CKD) was safety and efficacy was reported in 2009 AHA meeting by us.The six year safety and efficacy of SBP≦120 mmHg in these patient is not reported. Methods: In a prospective, controlled open-label studies, the authors have evaluated the safety and efficacy of six-year treatment on progress of renal disease and risk of development of cardiovascular disease in 122 &gt;65 aged hypertension patients with chronic renal disease III to IV stage and macroproteinuria. Before randomization, all patients have already been treated for one-year with angiotensin converting enzyme inhibitors(ACEI) or angiotensin AT1 receptor blockade(ARBs) and other antihypertensive drugs, but their SBP are above 140 mmHg,less than 150 mmHg. Blood pressure , serum creatinine(Cr) and potassium were monitored every 14 days in the period of follow-up by physician and healthcare nurse and more frequent patient-physician encounters will be improve that patients monitored their BP every day at home and adjusted their own medication according to pre-agreed rules. Results: By the end of six year,medication possession ratio between two groups was similar(94% vs 94%), mean BP in treatment group was 116/66±6/3 mmHg and in control was 146/78±13/9 mmHg, Cr clearance increased from 51±2.0 to 63±3.0 ml/min (p&lt;0.001)in the group of strict control of SBP,by contrast, Cr clearance decreased significantly from 52±1.9 to 34±2.4 ml/min( P&lt;0.01)in the controls. During this time, urine protein excretion decreased from 1.4±0.5 to 0.2±0.4g/24 hours(P0.05)in the controls. Ten patients had got ACS ,17 patients stroke.21 patients had got pneumonia , 10 patients renal dialysis and eight patient died (5 in SCD and 3 in heart failure) in controls, and three patients had got ACS, six patient had stroke ,nine pneumonia, 1 patient renal dialysis and four patients died in non-cardiac causes in the treatment group.Incidence of hyperkalaemia was similar between two groups. Conclusions: SBP≦120 mmHg is safe and was more apparently in decreasing proteinuria, slowing the progress of renal disease and reducing the risk of development of cardiovascular events and pneumonia in elderly hypertensive patients with CKD
Pulsed-High Intensity Focused Ultrasound and Low Temperature–Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect
Authors: Sergio Dromi, Victor Frenkel, Alfred Luk, Bryan Traughber, Mary Angstadt, Monica Bur, Jason Poff, Jianwu Xie, Steven K. Libutti, King C.P. Li, Bradford J. Wood
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between non–thermosensitive liposomes (NTSL) and low temperature–sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.
Humoral immune response against 38-kDa and 16-kDa mycobacterial antigens in tuberculosis
Authors: G. Senol, O. F. Erer, Y. A. Yalcin, M. Coskun, A. T. Gunduz, C. Bicmen, M. Ertas, S. A. Ozkan
Journal: European Respiratory Journal (2006)

Several ELISA tests based on mycobacterial antigens have been used for the rapid diagnosis of tuberculosis (TB), although demonstration of <i>Mycobacterium tuberculosis</i> in a smear or culture is the most reliable method. In the present study, the diagnostic value of 16-kDa and 38-kDa mycobacterial antigens was investigated in patients who were diagnosed with tuberculosis by clinical and/or bacteriological findings in Turkey. The PATHOZYME-TB Complex Plus commercial ELISA kit was used for measuring immunoglobulin G against 38-kDa and 16-kDa recombinant antigens. Humoral immune response was analysed in a group of 179 TB patients (143 smear-positive, 19 smear-negative, eight lymphadenitis and nine pleuritis), 15 inactive TB cases and in control groups consisting of 40 healthy volunteers and 20 subjects with pulmonary diseases other than TB. The sensitivity, specifity, positive predictive value and negative predictive value of the test were determined at 52.5%, 93.3%, 95.9% and 39.7%, respectively in TB cases. Antibodies were detected at above cut-off level in three (20%) out of 15 subjects with inactive TB. In conclusion, the ELISA test has a very good specifity and an acceptable sensitivity and positive predictive value. It is thought that it could be used in combination with other methods to increase diagnostic accuracy, especially for culture-negative tuberculosis cases, which are difficult to diagnose.
Effect of altitude on urinary leukotriene (LT) E4 excretion and airway responsiveness to histamine in children with atopic asthma
Authors: PE Christie, JL Yntema, P Tagari, H Ysselstijn, AW Ford-Hutchinson, TH Lee
Journal: European Respiratory Journal (1995)

Asthmatic subjects who are resident at altitude may experience a deterioration in lung function following a stay at sea level. To determine whether measurement of urinary leukotriene E4 (LTE4) reflects changes in asthma severity and airway responsiveness, 14 allergic asthmatic subjects resident at altitude (1560 m, Davos, Switzerland) were studied. Subjects were randomly divided into two groups. Measurements of baseline forced expiratory volume in one second (FEV1), the concentration of histamine producing a 20% decrease in FEV1, (PC20 FEV1), serum total immunoglobulin E (IgE), eosinophil count, and urinary LTE4 concentration were determined prior to and following a 2 week stay in The Netherlands (sea level) in eight subjects (4 males and 4 females, aged 14 +/- 0.5 yrs) (mean +/- SEM) and over a similar time period in six subjects (4 males and 2 females, aged 15 +/- 0.3 yrs) resident in Davos, Switzerland. There was no significant difference in total IgE and eosinophil count, and no significant correlation between urinary LTE4 and PC20FEV1 histamine, FEV1, total IgE, and eosinophil count. In subjects returning to Davos from The Netherlands there was a significant increase in urinary LTE4 from a baseline value of 16.9 pg.mg-1 creatinine (GM, range 0.3-101.7 pg.mg-1 creatinine) to 52.3 pg.mg-1 creatinine (GM, range 8.8-301.6 pg.mg-1 creatinine), a significant decrease in PC20FEV1 from 1.7 mg.ml-1 (GM, range 0.3-16.4 mg.ml-1) to 0.9 mg.ml-1 (GM, range 0.1-->32 mg.ml-1), and a significant fall in FEV1 from 3.0 +/- 0.3 to 2.8 +/- 0.3 l (mean +/- SEM).(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of inspiratory muscle training with an intermediate load on inspiratory power output in COPD
Authors: C Villafranca, G Borzone, A Leiva, C Lisboa
Journal: European Respiratory Journal (1998)

There is very little information about the effect of inspiratory muscle training on inspiratory flow (V'I) and thus on power output (PO) in patients with chronic obstructive pulmonary disease (COPD). In this study we aimed to evaluate the changes induced by training on the determinants of PO. Thirty one patients with severe COPD were randomly divided into: Group 1, trained with 30% maximal inspiratory pressure (PI,max); Group 2, with 10% PI,max; and Group 3 also trained with 30% PI,max, but the breathing pattern was evaluated while performing the training manoeuvres along inspiratory muscle training (IMT). All groups used a threshold device for 10 weeks. The PO for each of the loads during an incremental threshold test was evaluated prior to and after training. Maximal PO (POmax) increased in all groups, but the increment was higher in groups trained with 30% PI,max (p&lt;0.005), mainly due to an increase in V'I. Group 3 showed a progressive increase in V'I (p&lt;0.001) during the training manoeuvres in spite of an increase in load along IMT. In addition, the load after IMT was overcome with a shorter inspiratory time (tI) (p&lt;0.02), a smaller tI/total duration of the respiratory cycle (t(tot)), (p&lt;0.001) with no change in tidal volume or t(tot). The increment in POmax in this group correlated with the V'I generated while training (r=0.85; p&lt;0.0001). We conclude that in patients with chronic obstructive pulmonary disease, the use of an intermediate threshold load for training improves power output mainly by increasing inspiratory flow, an effect consistent with an increase in shortening velocity of inspiratory muscles.
Cerebrospinal Fluid and Ependymal Neurophysin
Authors: Alan G. Robinson, Earl A. Zimmerman
Journal: Journal of Clinical Investigation (1973)

Neurophysins are "carrier proteins" associated with vasopressin and oxytocin in the neurohypophyseal system. The release of these hormone associated proteins may serve as an indicator of posterior pituitary function. This report describes the measurement of neurophysin in human and monkey plasma and cerebrospinal fluid (CSF) by radioimmunoassay. Tissue neurophysin is also localized in monkey brain by the immunoperoxidase technique. CSF from 68 patients and five monkeys had easily measurable neurophysin in every sample. The concentration of neurophysin in CSF and in plasma of man is 5.4+/-0.30 ng/ml (mean and SEM) and 0.69+/-0.04, respectively. The two means were significantly different (P < 0.001). In paired plasma and CSF specimens which were obtained simultaneously from each of 13 human and five monkey donors, the concentrations of neurophysin in CSF were greater than those of plasma in every case (paired t test, P < 0.001). Neurophysin administered intravenously to dogs did not enter CSF. Using the immunoperoxidase technique, we found neurophysin not only in the supraoptic and paraventricular nuclei, their tracts, and the posterior pituitary, but also in the specialized ependymal tanycytes of the infundibular recess of the third ventricle and in the external layer of the median eminence where capillaries drain into hypophyseal portal vessels. Neurophysin may pass from CSF to portal vessels via tanycytes in a manner similar to that postulated for releasing factors.
Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling
Authors: Katarzyna Mleczko-Sanecka, Franziska Roche, Ana Rita da Silva, Debora Call, Flavia D’Alessio, Anan Ragab, Philip E. Lapinski, Ramesh Ummanni, Ulrike Korf, Christopher Oakes, Georg Damm, Lorenza A. D’Alessandro, Ursula Klingmüller, Philip D. King, Michael Boutros, Matthias W. Hentze, Martina U. Muckenthaler
Journal: Blood (2014)
Chronic Kidney Disease and the Risk for Cardiovascular Disease, Renal Replacement, and Death in the United States Medicare Population, 1998 to 1999
Authors: Robert N. Foley, Anne M. Murray, Shuling Li, Charles A. Herzog, A. Marshall McBean, Paul W. Eggers, Allan J. Collins
Journal: Journal of the American Society of Nephrology (2004)

Knowledge of the excess risk posed by specific cardiovascular syndromes could help in the development of strategies to reduce premature mortality among patients with chronic kidney disease (CKD). The rates of atherosclerotic vascular disease, congestive heart failure, renal replacement therapy, and death were compared in a 5% sample of the United States Medicare population in 1998 and 1999 (n = 1,091,201). Patients were divided into the following groups: 1, no diabetes, no CKD (79.7%); 2, diabetes, no CKD (16.5%); 3, CKD, no diabetes (2.2%); and 4, both CKD and diabetes (1.6%). During the 2 yr of follow-up, the rates (per 100 patient-years) in the four groups were as follows: atherosclerotic vascular disease, 14.1, 25.3, 35.7, and 49.1; congestive heart failure, 8.6, 18.5, 30.7, and 52.3; renal replacement therapy, 0.04, 0.2, 1.6, and 3.4; and death, 5.5, 8.1, 17.7, and 19.9, respectively (P < 0.0001). With use of Cox regression, the corresponding adjusted hazards ratios were as follows: atherosclerotic vascular disease, 1, 1.30, 1.16, and 1.41 (P < 0.0001); congestive heart failure, 1, 1.44, 1.28, and 1.79 (P < 0.0001); renal replacement therapy, 1, 2.52, 23.1, and 38.9 (P < 0.0001); and death, 1, 1.21, 1.38, and 1.56 (P < 0.0001). On a relative basis, patients with CKD were at a much greater risk for the least frequent study outcome, renal replacement therapy. On an absolute basis, however, the high death rates of patients with CKD may reflect accelerated rates of atherosclerotic vascular disease and congestive heart failure.
Relapsed Hodgkin Lymphoma in Older Patients: A Comprehensive Analysis From the German Hodgkin Study Group
Authors: Boris Böll, Helen Goergen, Nils Arndt, Julia Meissner, Stefan W. Krause, Roland Schnell, Bastian von Tresckow, Dennis A. Eichenauer, Stephanie Sasse, Michael Fuchs, Karolin Behringer, Beate C. Klimm, Ralph Naumann, Volker Diehl, Andreas Engert, Peter Borchmann
Journal: Journal of Clinical Oncology (2013)

Progression or relapse of Hodgkin lymphoma (HL) is common among older patients. However, prognosis and effects of second-line treatment are thus far unknown.We investigated second-line treatment and survival in older patients with progressive or relapsed HL. Patients treated within German Hodgkin Study Group first-line studies between 1993 and 2007 were screened for refractory disease or relapse (RR-HL). Patients with RR-HL age ≥ 60 years at first-line treatment were included in this analysis.We identified 105 patients (median age, 66 years); 28%, 31%, and 41% had progressive disease, early relapse, or late relapse, respectively. Second-line treatment strategies included intensified salvage regimens (22%), conventional polychemotherapy and/or salvage-radiotherapy with curative intent (42%), and palliative approaches (31%). Median overall survival (OS) for the entire cohort was 12 months; OS at 3 years was 31% (95% CI, 22% to 40%). A prognostic score with risk factors (RFs) of early relapse, clinical stage III/IV, and anemia identified patients with favorable and unfavorable prognosis (≤ one RF: 3-year OS, 59%; 95% CI, 44% to 74%; ≥ two RFs: 3-year OS, 9%; 95% CI, 1% to 18%). In low-risk patients, the impact of therapy on survival was significant in favor of the conventional polychemotherapy/salvage radiotherapy approach. In high-risk patients, OS was low overall and did not differ significantly among treatment strategies.OS in older patients with RR-HL can be predicted using a simple prognostic score. Poor outcome in high-risk patients cannot be overcome by any of the applied treatment strategies. Our results might help to guide treatment decisions and evaluate new compounds in these patients.
Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases
Authors: Azusa Nagao, Shoko Nakazawa, Hideji Hanabusa
Journal: Journal of Hematology & Oncology (2014)

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder caused by human herpesvirus 8 (HHV8) infection HIV associated MCD (HIV-MCD) presents with various clinical symptoms. Many HIV-negative MCD patients are often treated with anti-human interleukin-6 (IL6) receptor monoclonal antibodies (tocilizumab), and successful results have been reported. IL-6 plays an important role in the development of both HIV-positive and HIV-negative MCD; however, the efficacy of tocilizumab in HIV-MCD patients is unknown. We herein report the clinical and biologic courses of two HIV-MCD patients treated with tocilizumab. In both cases, a significant and rapid clinical improvement was observed after the first infusion. However, the treatment efficacy was not maintained for a long period, and relapse occurred at 15 and 22 weeks, respectively. Both patients received rituximab and subsequently achieved complete clinical remission. Our report, in addition to data presented in the literature, suggests that tocilizumab could be an initial treatment option in patients with HIV-MCD.
R-253 Disrupts Microtubule Networks in Multiple Tumor Cell Lines
Authors: Tarikere L. Gururaja, Dane Goff, Taisei Kinoshita, Eileen Goldstein, Stephanie Yung, John McLaughlin, Erlina Pali, Jianing Huang, Rajinder Singh, Sarkiz Daniel-Issakani, Yasumichi Hitoshi, R.D.G. Cooper, Donald G. Payan
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The design and development of synthetic small molecules to disrupt microtubule dynamics is an attractive therapeutic strategy for anticancer drug discovery research. Loss of clinical efficacy of many useful drugs due to drug resistance in tumor cells seems to be a major hurdle in this endeavor. Thus, a search for new chemical entities that bind tubulin, but neither are a substrate of efflux pump, P-glycoprotein 170/MDR1, nor cause undesired side effects, would potentially increase the therapeutic index in certain cancer treatments. Experimental Design: A high-content cell-based screen of a compound library led to the identification of a new class of compounds belonging to a thienopyrimidine series, which exhibited significant antitumor activities. On structure-activity relationship analysis, R-253 [N-cyclopropyl-2-(6-(3,5-dimethylphenyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine carbothioamide] emerged as a potent antiproliferative agent (average EC50, 20 nmol/L) when examined in a spectrum of tumor cell lines. Results: R-253 is structurally unique and destabilizes microtubules both in vivo and in vitro. Standard fluorescence-activated cell sorting and Western analyses revealed that the effect of R-253 on cell growth was associated with cell cycle arrest in mitosis, increased select G2-M checkpoint proteins, and apoptosis. On-target activity of R-253 on microtubules was further substantiated by immunofluorescence studies and selected counter assays. R-253 competed with fluorescent-labeled colchicine for binding to tubulin, indicating that its binding site on tubulin could be similar to that of colchicine. R-253 neither is a substrate of P-glycoprotein 170/MDR1 nor is cytotoxic to nondividing human hepatocytes. Conclusion: Both biochemical and cellular mechanistic studies indicate that R-253 could become a promising new tubulin-binding drug candidate for treating various malignancies.
The AZFc region of the Y chromosome: at the crossroads between genetic diversity and male infertility
Authors: P. Navarro-Costa, J. Goncalves, C. E. Plancha
Journal: Human Reproduction Update (2010)

BACKGROUNDThe three azoospermia factor (AZF) regions of the Y chromosome represent genomic niches for spermatogenesis genes. Yet, the most distal region, AZFc, is a major generator of large-scale variation in the human genome. Determining to what extent this variability affects spermatogenesis is a highly contentious topic in human reproduction.