tbuckley/cabot-search huggingface dataset:
Randomized Phase III Study of Pegylated Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed or Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression
Authors: Robert Z. Orlowski, Arnon Nagler, Pieter Sonneveld, Joan Bladé, Roman Hajek, Andrew Spencer, Jesús San Miguel, Tadeusz Robak, Anna Dmoszynska, Noemi Horvath, Ivan Spicka, Heather J. Sutherland, Alexander N. Suvorov, Sen H. Zhuang, Trilok Parekh, Liang Xiu, Zhilong Yuan, Wayne Rackoff, Jean-Luc Harousseau
Journal: Journal of Clinical Oncology (2007)

Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m 2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome. Conclusion PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.
Myopathy in hereditary leiomyomatosis and renal cell cancer in an extended family
Authors: A. España, E. Ornilla, R. Zarate, I. Gil-Bazo, P. Briones
Journal: British Journal of Dermatology (2014)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, Fumarate hydratase (FH) catalyses the conversion of fumarate to malate as part of the tricarboxylic acid (TCA) cycle.1 Germline mutations in the FH gene may lead to autosomal recessive mutations causing FH deficiency (FHD),2 associated with neurological impairment in childhood and muscular hypotonia.3 Patients with heterozygous mutations may develop multiple cutaneous leiomyomas (CLs) and uterine leiomyomas (ULs), and they more frequently have type II papillary renal cell cancer (RCC) [hereditary leiomyomatosis and RCC (HLRCC)].4 In most patients with HLRCC the mutations in FH are located before codon 250, whereas in FHD these mutations usually develop after codon 250.5 Skeletal muscle obtains most of its energy production from the TCA cycle. Therefore it may be postulated that patients with FH mutations might also develop skeletal muscle clinical dysfunction. We describe two patients and an extended family with pain and skeletal muscle cramps (PSMC).
The HMGB1-RAGE axis mediates traumatic brain injury–induced pulmonary dysfunction in lung transplantation
Authors: Daniel J. Weber, Adam S. A. Gracon, Matthew S. Ripsch, Amanda J. Fisher, Bo M. Cheon, Pankita H. Pandya, Ragini Vittal, Maegan L. Capitano, Youngsook Kim, Yohance M. Allette, Amanda A. Riley, Brian P. McCarthy, Paul R. Territo, Gary D. Hutchins, Hal E. Broxmeyer, George E. Sandusky, Fletcher A. White, David S. Wilkes
Journal: Science Translational Medicine (2014)

Traumatic brain injury induces acute lung injury that negatively impacts the physiology of the donor lung before and after lung transplantation.
Allosuppressor- and allohelper-T cells in acute and chronic graft-vs.-host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes.
Authors: A G Rolink, E Gleichmann
Journal: The Journal of Experimental Medicine (1983)

Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. In the present paper we analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. First, nonirradiated F1 mice were used as the recipients. We found that unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients; these cells were capable, however, of inducing a vigorous formation of SLE-like autoantibodies and the formation of severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. In another experiment, the sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and by comparing donor-cell inocula that contained similar numbers of T lymphocytes. In addition, donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients, too, unseparated donor T cells were superior to T cell subsets in inducing LGVHD; Lyt-1-2+ donor cells were completely and Lyt-1+2- donor cells were almost incapable of doing so. In contrast, Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.
Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer
Authors: Lucie E. Jones, Michelle J. Humphreys, Fiona Campbell, John P. Neoptolemos, Mark T. Boyd
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To enable the design of improved inhibitors of matrix metalloproteinases (MMPs) for the treatment of pancreatic cancer, the expression profiles of a range of MMPs and tissue inhibitors of MMPs (TIMPs) were determined. Experimental Design: Nine MMPs (MMPs 1–3, 7–9, 11, 12, and 14) and three TIMPs (TIMPs 1–3) were examined in up to 75 pancreatic ductal adenocarcinomas and 10 normal pancreata by immunohistochemistry. Eighteen additional pancreatic ductal adenocarcinomas and an additional eight normal pancreata were also analyzed by real-time reverse transcription-PCR and additionally for MMP-15. Results: There was increased expression by immunohistochemistry for MMPs 7, 8, 9, and 11 and TIMP-3 in pancreatic cancer compared with normal pancreas (P &amp;lt; 0.0001, 0.04, 0.0009, 0.005, and 0.0001, respectively). Real-time reverse transcription-PCR showed a significant increase in mRNA levels for MMP-11 in tumor tissue compared with normal pancreatic tissue (P = 0.0005) and also significantly reduced levels of MMP-15 (P = 0.0026). Univariate analysis revealed that survival was reduced by lymph node involvement (P = 0.0007) and increased expression of MMP-7 (P = 0.005) and (for the first time) MMP-11 (P = 0.02) but not reduced by tumor grade, tumor diameter, positive resection margins, adjuvant treatment, or expression of the remaining MMPs and TIMPs. On multivariate analysis, only MMP-7 predicted shortened survival (P &amp;lt; 0.05); however, increased MMP-11 expression was strongly associated with lymph node involvement (P = 0.0073). Conclusions: We propose that the principle specificity for effective inhibitors of MMPs in pancreatic cancer should be for MMP-7 with secondary specificity against MMP-11. Moreover, these studies indicate that MMP-7 expression is a powerful independent prognostic indicator and potentially of considerable clinical value.
Measuring patient-relevant benefits in pruritus treatment: development and validation of a specific outcomes tool
Authors: C. Blome, M. Augustin, D. Siepmann, N.Q. Phan, S.J. Rustenbach, S. Ständer
Journal: British Journal of Dermatology (2009)

The assessment of patient-relevant benefit is gaining importance in evaluating treatments. The 'Patient Benefit Index, standard version' questionnaire (PBI-S) is a validated instrument to assess patients' treatment needs and benefits in skin diseases. Before therapy, the patient rates the importance of predefined treatment goals; after therapy, he rates the extent to which these goals have been achieved. Thus far, no such instrument has been developed specifically for pruritus.Development and validation of a patient-relevant benefit questionnaire in the treatment of pruritus.Fifty patients with pruritus were questioned on impairments due to pruritus and treatment needs. Four treatment objectives not already covered by the PBI-S were added to obtain a disease-specific instrument. This was tested for feasibility by 36 patients with pruritus and validated in a sample of 100 patients with pruritus.The instrument was feasible in clinical practice. There were < 2% missing values. Cronbach's alpha of the needs questionnaire was 0.93. Convergent validity was demonstrated with respect to reduction of pruritus and quality of life.The PBI for pruritus is a feasible, reliable and valid instrument that is highly accepted in daily routine for recording patient-reported benefit.
Reproducibility of incremental maximal cycle ergometer testing in patients with restrictive lung disease.
Authors: D D Marciniuk, R E Watts, C G Gallagher
Journal: Thorax (1993)

BACKGROUND--Exercise testing has become an important tool in the diagnosis and treatment of restrictive lung disease. The reproducibility of variables measured during exercise testing was examined in subjects with stable restrictive lung disease. METHODS--Six subjects, who had never previously undergone exercise testing, each underwent three maximal incremental exercise studies on a bicycle ergometer conducted during a 28 day period. RESULTS--Data collected at rest, before exercise, were not significantly different during the three study days. Comparison of results at the end of the exercise tests from the three studies also revealed no evidence of a significant learning effect. Reproducibility of exercise performance by subjects was assessed by the coefficient of variation. The mean within subject coefficient of variation at the end of the exercise tests was 5.6% for work rate, 7.9% for exercise duration, and 9.5% for dyspnoea. The mean within subject coefficient of variation obtained at the end of the exercise tests was 5.3% for oxygen uptake (VO2), 2.5% for oxygen saturation (SaO2), 4.0% for heart rate (HR), 5.5% for minute ventilation (VE), 5.8% for respiratory frequency (f), and 4.6% for tidal volume (VT). The mean within subject coefficient of variation at 40% and 70% of maximal work rates for VO2 was 5.7% and 5.6% respectively, for SaO2 1.3% and 1.5%, for HR 4.8% and 4.0%, for VE 6.3% and 6.6%, for f 10.1% and 7.8%, and for VT 6.0% and 4.5%. CONCLUSIONS--Variables measured during clinical exercise testing in subjects with restrictive lung disease are highly reproducible. No significant learning effect was found on repeated testing in subjects who had never previously undergone exercise testing.
The use of manual hyperinflation in airway clearance
Authors: L. Denehy
Journal: European Respiratory Journal (1999)

Manual lung hyperinflation (MH) is one of a number of techniques which are employed by the physiotherapist in the critical care setting. The technique was first described with physiotherapy 30 yrs ago and commonly involves a slow, deep inspiration, inspiratory pause and fast unobstructed expiration. The use of MH varies between and within countries. It is commonly employed by physiotherapists to assist in the removal of secretions and re-expand areas of atelectasis. Despite the popularity of the technique, research examining its efficacy is conflicting, especially the effect of MH on cardiovascular parameters. Recent studies examining mucociliary transport in intubated and ventilated patients have shown impaired clearance of secretions, but research evaluating the role of MH specifically in airway clearance is scant. The use of the additional physiotherapy techniques, gravity assisted drainage and chest wall vibrations, may enhance the efficacy of MH in promoting airway clearance, but further research is necessary. Controversy exists regarding the safety and effectiveness of application of manual lung hyperinflation in intubated patients. Clearly, more randomized controlled studies are necessary in order to provide a sound scientific rationale for the application of manual lung hyperinflation in the treatment of critically ill patients.
Electromagnetic navigation diagnostic bronchoscopy for small peripheral lung lesions
Authors: D. Makris, A. Scherpereel, S. Leroy, B. Bouchindhomme, J-B. Faivre, J. Remy, P. Ramon, C-H. Marquette
Journal: European Respiratory Journal (2007)

The present study prospectively evaluated the diagnostic yield and safety of electromagnetic navigation-guided bronchoscopy biopsy, for small peripheral lung lesions in patients where standard techniques were nondiagnostic. The study was conducted in a tertiary medical centre on 40 consecutive patients considered unsuitable for straightforward surgery or computed tomography (CT)-guided transthoracic needle aspiration biopsy, due to comorbidities. The lung lesion diameter was mean+/-sem 23.5+/-1.5 mm and the depth from the visceral-costal pleura was 14.9+/-2 mm. Navigation was facilitated by an electromagnetic tracking system which could detect a position sensor incorporated into a flexible catheter advanced through a bronchoscope. Information obtained during bronchoscopy was superimposed on previously acquired CT data. Divergence between CT data and data obtained during bronchoscopy was calculated by the system's software as a measure of navigational accuracy. All but one of the target lesions was reached and the overall diagnostic yield was 62.5% (25-40). Diagnostic yield was significantly affected by CT-to-body divergence; yield was 77.2% when estimated divergence was <or=4 mm. Three pneumothoraces occurred and chest drainage was required in one case. Electromagnetic navigation-guided bronchoscopy has the potential to improve the diagnostic yield of transbronchial biopsies without additional fluoroscopic guidance, and may be useful in the early diagnosis of lung cancer, particularly in nonoperable patients.
Mental Health Symptoms Following War and Repression in Eastern Afghanistan
Authors: Willem F. Scholte
Journal: JAMA (2004)

ContextDecades of armed conflict, suppression, and displacement resulted in a high prevalence of mental health symptoms throughout Afghanistan. Its Eastern province of Nangarhar is part of the region that originated the Taliban movement. This may have had a distinct impact on the living circumstances and mental health condition of the province's population.ObjectivesTo determine the rate of exposure to traumatic events; estimate prevalence rates of symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety; identify resources used for emotional support and risk factors for mental health symptoms; and assess the present coverage of basic needs in Nangarhar province, Afghanistan.Design, Setting, and ParticipantsA cross-sectional multicluster sample survey of 1011 respondents aged 15 years or older, conducted in Nangarhar province during January and March 2003; 362 households were represented with a mean of 2.8 respondents per household (72% participation rate).Main Outcome MeasuresPosttraumatic stress disorder symptoms and traumatic events using the Harvard Trauma Questionnaire; depression and general anxiety symptoms using the Hopkins Symptom Checklist; and resources for emotional support through a locally informed questionnaire.ResultsDuring the past 10 years, 432 respondents (43.7%) experienced between 8 and 10 traumatic events; 141 respondents (14.1%) experienced 11 or more. High rates of symptoms of depression were reported by 391 respondents (38.5%); anxiety, 524 (51.8%); and PTSD, 207 (20.4%). Symptoms were more prevalent in women than in men (depression: odds ratio [OR], 7.3 [95% confidence interval {CI}, 5.4-9.8]; anxiety: OR, 12.8 [95% CI, 9.0-18.1]; PTSD: OR, 5.8 [95% CI, 3.8-8.9]). Higher rates of symptoms were associated with higher numbers of traumas experienced. The main resources for emotional support were religion and family. Medical care was reported to be insufficient by 228 respondents (22.6%).ConclusionsIn this survey of inhabitants of Nangarhar province, Afghanistan, prevalence rates of having experienced multiple traumatic events and having symptoms of anxiety, depression, and PTSD were high. These findings suggest that mental health symptoms in this region should be addressed at the population and primary health care level.
Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
Authors: Hiroaki Masuzaki, Hiroshi Yamamoto, Christopher J. Kenyon, Joel K. Elmquist, Nicholas M. Morton, Janice M. Paterson, Hiroshi Shinyama, Matthew G.F. Sharp, Stewart Fleming, John J. Mullins, Jonathan R. Seckl, Jeffrey S. Flier
Journal: Journal of Clinical Investigation (2003)

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension. Taken together, our findings suggest that overexpression of 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11beta-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.
Horses for courses. Comparative gastroenterology: common ground and collaborative potential
Authors: Neil P H Hudson, Malcolm G Dunlop
Journal: BMJ (2005)

Gastrointestinal diseases, including motility and obstructive disorders, are common in both human1 and veterinary2 medicine. Such disorders tend to be clinically important problems in both disciplines, with extensive impact on veterinary practice as well as having human public health and economic implications. Considerable time is lost from work due to gut disorders. Motor disorders of the gastrointestinal tract are particularly common, and understanding the physiology of motility and gut function is key to examination of the pathophysiology of intestinal disease.3 Few animal models of functional gastrointestinal disorders exist, however, and so there is considerable rationale for comparative study of disease in veterinary and human medicine. Such study affords the opportunity to shed new light on disease processes that so far have proved difficult to study for practical, ethical, and biological reasons. Comparable intestinal disorders between species include postoperative ileus, intestinal obstruction, pseudo-obstruction, irritable bowel syndrome, and inflammatory bowel diseases.

We used personal archives of references and, when appropriate, carried out PubMed searches on relevant veterinary and human gastroenterological topics.

Pseudo-obstruction and enteric dysmotility syndromes are increasingly being recognised in medical gastroenterology and are thought to represent an impairment of the intrinsic neuromuscular or extrinsic control of gut motility.4 5

Constipation is one of the most common digestive disorders in humansw1 and, therefore, animal examples such as feline constipation provide opportunity for novel insight into disease mechanism in humans, free from confounding effects accumulated over the lifespan of a human. Feline constipation is common in small animal veterinary practice. Acquired idiopathic megacolon occurs in middle aged to older cats. The pathogenesis is unclear but may involve an impairment of colonic smooth muscle function.6 The feline syndrome appears to bear many similarities to …
15-Deoxyspergualin in Patients with Refractory ANCA-Associated Systemic Vasculitis
Authors: Rainer Birck, Klaus Warnatz, Hanns M. Lorenz, Mira Choi, Marion Haubitz, Mathias Grünke, Hans H. Peter, Joachim R. Kalden, Ursula Göbel, Johannes M. Drexler, Osamu Hotta, Rainer Nowack, Fokko J. van der Woude
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/μl followed by a rest until at least a WBC of 4000/μl was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count. E-mail: [email protected]