tbuckley/cabot-search huggingface dataset:
Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance.
Authors: A M Yahanda, K M Alder, G A Fisher, N A Brophy, J Halsey, R I Hardy, M P Gosland, B L Lum, B I Sikic
Journal: Journal of Clinical Oncology (1992)

To determine the maximum-tolerated dose (MTD) of cyclosporine (CsA) infusion administered with etoposide for 3 days in patients with cancer.Of the 72 registered patients, 26 were treated initially with CsA and etoposide. Forty-six received etoposide alone until disease progression, and 31 of these proceeded to CsA and etoposide. CsA was administered as a 2-hour loading dose (LD) and as a 3-day continuous infusion (CI); doses were escalated from 2 to 8 mg/kg LD and 5 to 24 mg/kg/d CI.Fifty-seven patients were treated with 113 cycles of CsA with etoposide. Steady-state serum CsA levels (nonspecific immunoassay) more than 2,000 ng/mL were achieved in 91% of the cycles at CsA doses > or = 5 mg/kg LD and > or = 15 mg/kg/d CI. The major dose-related toxicity of CsA was reversible hyperbilirubinemia, which occurred in 78% of the courses with CsA levels > 2,000 ng/mL. Myelosuppression and nausea were more severe with CsA and etoposide. Other CsA toxicities included hypomagnesemia, 60%; hypertension, 29%; and headache, 21%. Nephrotoxicity was mild in 12% and severe in 2% of the cycles. Tumor regressions occurred in four patients after the addition of CsA (one non-Hodgkin's lymphoma, one Hodgkin's disease, and two ovarian carcinomas). Biopsy procedures for tumors from three of the four patients who responded were performed, and the results were positive for mdr1 expression.Serum CsA levels of up to 4 mumol/L (4,800 ng/mL) are achievable during a short-term administration with acceptable toxicities when administered in combination with etoposide. The CsA dose that is recommended in adults is a LD of 5 to 6 mg/kg, followed by a CI of 15 to 18 mg/kg/d for 60 hours. CsA blood levels should be monitored and the doses should be adjusted to achieve CsA levels of 2.5 to 4 mumol/L (3,000 to 4,800 ng/mL). Reversible hyperbilirubinemia may be a useful marker of inhibition by CsA of P-glycoprotein function. When used with high-dose CsA, etoposide doses should be reduced by approximately 50% to compensate for the pharmacokinetic effects of CsA on etoposide (Lum et al, J Clin Oncol, 10:1635-1642, 1992).
Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family
Authors: O. Messaoud, M. Ben Rekaya, R. Kefi, S. Chebel, A. Boughammoura-Bouatay, H. Bel Hadj Ali, N. Gouider-Khouja, J. Zili, M. Frih-Ayed, I. Mokhtar, S. Abdelhak, M. Zghal
Journal: British Journal of Dermatology (2010)

Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP‐A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP‐A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype–genotype correlation for this new phenotypic expression of XP‐A.
Lesions Characteristic of Secondary Disease In Germfree Heterologous Radiation Chimeras&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: D. W. van Bekkum, M. J. de Vries, D. van der Waay
Journal: JNCI Journal of the National Cancer Institute (1967)

Germfree Swiss mice were given a lethal dose of X radiation and then treated with rat bone-marrow cells. A histologic study of the tissues of these mice at various intervals up to 80 days after irradiation revealed lesions in the lymphatic tissues, the skin, the intestinal tract, and the liver that were characteristic of graft-versus-host disease. In contrast to previous findings in conventional animals, these lesions were not complicated by inflammatory changes.
GP leaders unite in calling for inspections of surgeries to be suspended
Authors: Z. Kmietowicz
Journal: BMJ (2015)

The BMA and the Royal College of General Practitioners have both called for the current inspection regime of general practices to be suspended.

Delegates at the BMA’s annual representative meeting this week overwhelmingly passed a motion describing the healthcare inspectorate the Care Quality Commission (CQC) as “unfit for purpose.” On the same day the royal college said that a pause in inspections was needed to relieve the pressure on surgeries, which it warned were “on the brink of meltdown.”

The motion at the BMA meeting asserted that the CQC had continued to damage the morale and professionalism of all doctors and had failed …
High-Resolution Computed Tomography of the Lungs: A Pattern Approach
Authors: A. Bankier
Journal: European Respiratory Journal (2006)

Edited by D. Karthikeyan    Published by London, Hodder Arnold 2006    Pages: 223. Price: \#8364;75.00, $94.55. ISBN: 0-340-90580-8

High-Resolution Computed Tomography of the Lungs: A Pattern Approach     “High-Resolution Computed Tomography of the Lungs: A Pattern Approach” enters into the increasingly long line of books dealing with high-resolution computed tomography (HRCT). The expanding clinical applications of this fascinating imaging technique certainly justify the newly emerging publications dedicated to this topic. The book is accompanied by a CD.

The first part of the book …
Features detection of tuberculosis in HIV-patients in the region with a high prevalence of tuberculosis
Authors: Svetlana Naryshkina, Tatyana Chikurova
Journal: European Respiratory Journal (2014)

The incidence of TB/HIV-infection is continuing to increase in Novosibirsk. A system of prevention of tuberculosis in HIV-patients has been developed and implemented in our region: systematic preventive examinations for tuberculosis, detection and treatment of latent tuberculosis infection.  Aim: to investigate a detection of TB in HIV-patients to develop further steps in reduced the incidence of co-infection  Materials and methods. The retrospective analysis of 231 patients with HIV and newly diagnosed tuberculosis in 2012 in the Novosibirsk region.  Results. In 60.6% cases HIV-infection and tuberculosis were detected simultaneously (r=0,9). Greater number patients had level CD4+ less 350 cells. (66.3%), 42,9% of patients had expressed immunodeficiency (r=-1,0). TB diagnosed in preventive examination at 26.8% of cases only. Most of patients is detected during the development of pronounced symptoms of TB intoxication (r=0,98), which had required emergency hospitalizations in 35.5% cases. 77.9% of patients were active injectable illicit drug users and did not seek medical attention promptly. A period between the occurrence of symptoms and health care was 2.2 months. 49.5% of patients living with HIV more than 3 years refused treatment (HAART and preventive TB).  Conclusion. Program to reduce the incidence of TB patients with HIV need to be adjusted. It should join efforts for the early detection of HIV infection among risk groups, the motivation of patients for HAART and TB preventive therapy.
Abstract 1006: Impact of a Change to Global Cardiovascular Risk Estimation in Lipid-Lowering Guidelines: Findings From the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006
Authors: Amanda K Marma, Hongyan Ning, Donald M Lloyd-Jones
Journal: Circulation (2009)

Background:  Current ATP-III guidelines use absolute risk for hard coronary heart disease (CHD) to determine need for lipid-lowering therapy. It is unknown how many more US adults would potentially be eligible for therapy (i.e., 10-year risk ≥10%) with a broader focus on risk for global cardiovascular disease (CVD; all CHD, stroke, TIA, claudication and heart failure).   Methods:  We included 6,685 nonpregnant, nondiabetic, CVD-free participants aged 30 to 74 years from NHANES 2001–2006, representing 168 million US adults. We estimated 10-year predicted risk for hard CHD (using the Framingham risk score [FRS]) and global CVD (using the updated Framingham risk profile [UFRP]) in each participant. We compared the numbers of US adults in each of four predicted risk categories (0- 20%) by FRS vs. UFRP for ages 30 – 49 and 50 –74 years.   Results:  For those aged 50 –74 years (see Table), 27% have 10-year predicted risk for hard CHD ≥10% by FRS, whereas 47% have 10-year predicted risk for global CVD ≥10% using UFRP. In other words, 16 million men and women are changed from    Conclusions:  Use of an expanded endpoint of global CVD (rather than hard CHD) for risk estimation results in 20.2 million men and women moving from lower (
Characteristics in Youth Predictive of Adult-Onset Malignant Lymphomas, Melanomas, and Leukemias: Brief Communications 2 3
Authors: Ralph S. Paffenbarger, Alvin L. Wing, Robert T. Hyde
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Characteristics in Youth Predictive of Adult-Onset Malignant Lymphomas, Melanomas, and Leukemias: Brief Communications Get access Ralph S. Paffenbarger, Jr., Ralph S. Paffenbarger, Jr. 4Department of Biomedical and Environmental Health Sciences, University of California School of Public Health, 303 Earl Warren Hall, Berkeley, Calif. 94720. 5Department of Epidemiology, Harvard University School of Public Health, 677 Huntington Ave., Boston, Mass. 02115. 6Address reprint requests to Dr. Paffenbarger, California State Department of Health, 2151 Berkeley Way, Berkeley, Calif. 94704. Search for other works by this author on: Oxford Academic PubMed Google Scholar Alvin L. Wing, Alvin L. Wing 5Department of Epidemiology, Harvard University School of Public Health, 677 Huntington Ave., Boston, Mass. 02115. Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert T. Hyde Robert T. Hyde 4Department of Biomedical and Environmental Health Sciences, University of California School of Public Health, 303 Earl Warren Hall, Berkeley, Calif. 94720. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 1, January 1978, Pages 89–92, https://doi.org/10.1093/jnci/60.1.89 Published: 01 January 1978 Article history Received: 10 May 1977 Accepted: 01 August 1977 Published: 01 January 1978
Patterns of delays in diagnosis amongst patients with smear-positive pulmonary tuberculosis at a teaching hospital in Turkey
Authors: E. Okur, A. Yilmaz, A. Saygi, A. Selvi, F. Süngün, E. Öztürk, G. Dabak
Journal: Clinical Microbiology and Infection (2006)

In total, 151 newly diagnosed patients with smear-positive pulmonary tuberculosis were studied. The mean time from the onset of symptoms to the first visit to a physician was 46.4 days; the mean referral delay was 28.9 days; the mean delay in diagnosis was 2.4 days; and the mean delay in treatment initiation was 0.8 days. There was a delay in consulting a physician by 49% of patients. A low index of suspicion for tuberculosis on the part of the physician and healthcare system and laboratory delays were the most common reasons for delays in diagnosis.
Renal sodium handling with cyclosporin A and FK506 after orthotopic liver transplantation.
Authors: V J Canzanello, S C Textor, S J Taler, D J Wilson, L Schwartz, R H Wiesner, M K Porayko, R A Krom
Journal: Journal of the American Society of Nephrology (1995)

Hypertension is common after orthotopic liver transplantation and may be due, in part, to cyclosporin A-induced renal dysfunction and/or enhanced proximal tubular sodium reabsorption. To determine whether enhanced proximal tubular sodium reabsorption is central to the development of posttransplant hypertension, measurements of renal hemodynamics and fractional clearances of lithium and sodium were compared 1 month after orthotopic liver transplantation in previously normotensive patients receiving either cyclosporin A (N = 24) or FK506 (N = 18), an immunosuppressive agent that is structurally unlike cyclosporin A and that has a lower reported incidence of hypertension. Median prednisone doses were 20 and 13 mg/day in the cyclosporin A and FK506 groups, respectively (P < 0.05). At 1 month, mean arterial blood pressure was higher in the cyclosporin A versus the FK506 group: 108 +/- 2 versus 95 +/- 3 mm Hg (P < 0.05). GFR, RBF, and renal vascular resistance were not different between the two groups: 59 +/- 4 and 53 +/- 5 mL/min per 1.73 m2, 439 +/- 28 and 440 +/- 41 mL/min per 1.73 m2, and 22,429 +/- 1,822 and 22,977 +/- 3,506 dyne s/cm5 per 1.73 m2, respectively. Fractional lithium excretion was similar in the cyclosporin A and FK506 groups: 19.9 +/- 2.2 and 19.4 +/- 2.0% (P = not significant) although both values were lower than those of normal controls (25.5 +/- 1.1%) (P < 0.05). Fractional sodium excretion was 2.7 +/- 0.3 and 2.3 +/- 0.4% in the cyclosporin A and FK506 groups, respectively (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)
A new device for inspiratory muscle training in patients with tracheostomy tube in ICU: A randomized trial
Authors: Ivete Alonso Bredda Saad, Rodrigo Tonella, Ligia Santos Roceto, Lilian E.B. Delazari, Luciana Castilho, Antonio Luis Eiras Falcão, Paula S. Silva
Journal: European Respiratory Journal (2014)

Background : Evaluation and training of the respiratory muscles are essential to reducing time of weaning invasive mechanical ventilation (VMI) in intensive care units (ICU). Powerbreathe® is indicated for inspiratory muscle training (IMT) with a progressive resistance and adjustable load in respiratory disease patients. Objective : Compare the inspiratory muscle strength between two groups of tracheostomy patients: IMT with Powerbreathe® and breathing through a humidified t-piece (T-tube). Methods : 25 tracheostomy patients were selected under VMI and randomized into two groups: T-tube (control) and IMT with Powerbreathe®. Patients of both groups received respiratory physical therapy and the MIP measurements with a digital manometer (MVD300, Globalmed®), with a one-way valve connected to tracheostomy, with occlusion for 20 seconds. In control group patients underwent T-tube until complete 48 hours of continuous nebulization. In the IMT group was used Powerbreathe® KH2 model (Powerbreathe®, IMT Technologies Ltd., Birmingham, England) for 30 cycles (three sets of 10 cycles with 1 minute interval between them), adjusted load 30% of the initial MIP, increasing 10% daily. For statistical analysis, were applied Wilcoxon test for comparison of related and Mann-Whitney test for independent samples variables. P values <0.05 were considered statistically significant. Results : Of 19 patients, 8 in the IMT group with 7 men and 11 in the control, with 8 men. Were increased final MIP compared to initial in IMT group (p=0.017), with no significant difference for the control group (p=0.304). Conclusion : The IMT with Powerbreathe® in tracheostomy patients promotes increased muscle strength.
Trials are best, ignore the rest: safety and efficacy of digoxin:
Authors: Graham D Cole, Darrel P Francis
Journal: BMJ (2015)

Observational data might have misled doctors for years.

Research, doi:10.1136/bmj.h4451

Nearly 20 years after the digoxin in heart failure (DIG) trial showed that digoxin reduced hospital admissions for heart failure by 28% with no effect on mortality,1 many clinicians still see this drug as a last resort—reflected in guidelines that reserve it only for those with severe or worsening heart failure when first and second line treatments have failed.2 One reason might have been the numerous observational studies indicating the potentially worrying trade-off that digoxin is associated with an increased risk of death.

The linked article by Ziff and colleagues (doi:10.1136/bmj.h4451), a meta-analysis of digoxin treatment for heart failure or atrial fibrillation (or both), sheds light on the discordant findings between randomised and observational studies.3 They show that the mechanism of the association with mortality in observational studies is that clinicians preferentially gave digoxin to sicker patients: when these patients died, there was therefore a true but misleading association between death and digoxin. The paper paints …
Abstract PR06: A co-clinical assessment of patterns of BRAF inhibitor resistance
Authors: Lawrence N. Kwong, Genevieve Boland, Dennie T. Frederick, Timothy Helms, John P. Miller, Shan Jiang, Zachary A. Cooper, Alexei Protopopov, Gordon B. Mills, Keith Flaherty, Jennifer A. Wargo, Lynda Chin
Journal: Clinical Cancer Research (2015)

Abstract The acquired resistance of melanomas to BRAF inhibitors is now well-described, indicating many mechanisms including point mutations, amplifications, and alternative splicing. Here, we present a combined assessment of patient samples at both the RNA and protein levels. In parallel, we conducted a co-clinical mouse trial using a novel BRAF-driven model. We demonstrate that the response and resistance of the mouse melanomas closely parallels that of the human patient samples on both phenotypic and molecular levels, demonstrating multiple mechanisms of resistance that mirror the patient findings. On the basis of the combined data, we suggest that BRAF inhibitor-resistant melanomas can readily be categorized using economical and rapid protein array technology. This suggests that analyzing protein patterns offers a means of categorizing tumor resistance mechanisms even in the absence of identified driving genetic or epigenetic lesion(s). In summary, our results demonstrate the utility of a co-clinical assessment system and offer a cost-efficient means of categorizing patterns of BRAF inhibitor resistance in human patient samples within a clinically-meaningful timeframe. Citation Format: Lawrence N. Kwong, Genevieve Boland, Dennie T. Frederick, Timothy Helms, John P. Miller, Shan Jiang, Zachary A. Cooper, Alexei Protopopov, Gordon B. Mills, Keith Flaherty, Jennifer A. Wargo, Lynda Chin. A co-clinical assessment of patterns of BRAF inhibitor resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR06.
Vasoactive Peptides and Substrates and Their Relation to Protein Handling by the Kidney
Authors: RAMON B. M.D.
Journal: Circulation Research (1963)

The properties of anephrotensin, a polypeptide liberated by acid incubation of serum, are reviewed. Experiments with antirenin rule out the possibility that renin is the enzyme that liberates anephrotensin. Serum anephrotensinogen increases after bilateral nephrectomy or after several weeks of treatment with desoxycorticosterone (DCA). There are perallel changes under these conditions in the amounts of anephrotensinogen and angiotensinogen in the serum, suggesting that a common substrate may be involved. The increase in substrate is in accord with the possibility that DCA treatment results in some deficiency in the handling of proteins by the kidney. There is an increase in urine vasoactive peptides and total proteins in DCA-treated rats. These increases are probably related to deficiency in tubular reabsorption. The increase in the albumin/globulin ratio of the urine proteins under these circumstances supports this idea. The changes described above are not necessarily related to the onset of hypertension. Whether the changes in protein handling by the kidney are related to the hypertension produced by DCA treatment is an unsettled question.
Expression of ERK2 and p38α kinases in pleural mesothelial cells after exposure to asbestos fibers
Authors: Lisete Teixeira, Milena Acencio, Roberta Sales, Francisco Vargas, Leila Antonangelo, Carlos Silva, Karina Pereira, Evaldo Marchi
Journal: European Respiratory Journal (2011)

Asbestos is known to stimulate gene expression in a variety of cell types via downstream intracellular signaling cascades. This mechanism includes the mitogen-activated protein kinases, which can lead to increased transcriptional activation of genes related to cell proliferation, apoptosis and inflammation.

Objectives: To quantify and to compare the expression of ERK2 and p38α in pleural mesotelial cells (PMC) exposed to crocidolite or chrysotile fibers.

Material and methods: C57/Bl6 mice received intrapleural injection of crocidolite or chrysotile fibers (3.0 ug/cm2) or PBS (control). After 1, 7, 14 and 30 days the animals were euthanized and PMC were extracted. ERK2 and p38α levels were measured by ELISA. Results are expressed in mean ± SD using t-test (p <0.05).

Results: In the control group ERK2 and p38α levels were undetectable. Both crodidolite and chrysotile stimulated PMC to produce kinases, as shown in the table.

View this table:



Conclusions: Our data demonstrated that crocidolite produced higher levels of ERK2 and p38α than chrysotile, in a time-dependent fashion. More studies are needed to examine whether activation of this pathway is functionally linked to cell inflammation and cellular apoptosis induced by asbestos fibers and its role in the carcinogenesis of mesothelioma.
Increased coagulation activity of the pleura after tube drainage and quinacrine instillation in malignant pleural effusion
Authors: V Agrenius, J Chmielewska, O Widstrom, M Blomback
Journal: European Respiratory Journal (1991)

Chronic malignant pleural effusions are usually treated with an intrapleurally administered irritant that creates an inflammatory reaction. The induced inflammation results in fibrin deposition and termination of fluid exudation. In the present study several factors in the coagulation system in the pleural fluid were followed during treatment with tube drainage and quinacrine instillation into the pleural space. In the chronic exudative phase before treatment, both thrombin activity and fibrinopeptide A (FPA), were present at low levels. During treatment the levels increased markedly. Beta-thromboglobulin, a platelet marker, showed a similar pattern. Prothrombin, antithrombin III, prekallikrein and kallikrein inhibiting activity showed no such variations in activity. The high thrombin activity and FPA level induced by treatment reflect an active process of fibrin formation which seems to play an important role in arresting chronic pleural exudation.
Autologous bone marrow transplantation for acute lymphoblastic leukemia.
Authors: S E Sallan, C M Niemeyer, A L Billett, J M Lipton, N J Tarbell, R D Gelber, C Murray, T P Pittinger, L C Wolfe, R C Bast
Journal: Journal of Clinical Oncology (1989)

Forty-four children with acute lymphoblastic leukemia (ALL) who had relapsed (N = 43) or had refractory disease (N = 1) were intensively treated with combination chemotherapy, had remission bone marrow (BM) harvested and purged in vitro with monoclonal antibodies specific for leukemia-associated antigens, underwent postharvest ablative chemotherapy and radiotherapy and subsequently were infused with their autologous marrow. Of the 44 patients treated between November 1980 and January 1988, 19 relapsed, 10 died of complications, and 15 remained in complete remission for a median of 28.5 months (range, 10+ to 94+). Event-free survival (EFS) (+/- SE) at 5 years after autologous transplantation was 29 +/- 8%. For the 26 patients whose initial remission was greater than 2 years, event-free survival was 51 +/- 10%. These results compare favorably with allogeneic transplantation and chemotherapy trials for patients with relapsed ALL, and provide an alternative transplantation option for children without histocompatible donors.