tbuckley/cabot-search huggingface dataset:
Respiratory muscle wasting in the ICU: is it time to protect the diaphragm?
Authors: Theodoros Vassilakopoulos
Journal: Thorax (2016)

Mechanical ventilation is a life-saving ‘therapeutic’ intervention for patients with respiratory failure. The vast majority of critically ill patients are mechanically ventilated (MV) and a significant part of time is spent in weaning patients from mechanical ventilation. It is during weaning that the diaphragm becomes so important becoming a major pathophysiological determinant of weaning failure or success.1 ,2

Various insults can render the diaphragm weak in critically ill patients such as sepsis, multiorgan failure and/or inflammation, electrolyte disturbances, hyperinflation, to name a few out of a long list.3 Extensive animal research4 and few human studies5–8 have provided evidence that controlled mechanical ventilation (CMV), a form of ventilation where the ventilator assumes all the work of breathing and the respiratory muscles are theoretically completely unloaded, can also cause dysfunction of the diaphragm, an entity named ventilator-induced diaphragm dysfunction (VIDD).9

VIDD has been described in the laboratory in previously healthy animals subjected to CMV4 and in brain-dead patients free of infection and other derangements so as to be eligible for organ donation.5–8 The mechanisms of VIDD are not fully elucidated, but include muscle atrophy (lysosomal, autophagy, cysteine protease and ubiquitin–proteasome activation having all been described), oxidative stress, structural injury (disrupted myofibrils, lipid vacuoles and abnormally small and disrupted mitochondria), myofibre remodelling and mitochondrial dysfunction. The animal data have shown that these insults result in the decline of the pressure-generating capacity of the diaphragm, that is, reduced diaphragmatic contractility. The extent to which this happens in humans and thus is clinically relevant is largely unknown.

Much of the uncertainty in proving the concept that mechanical ventilation per se can cause contractile dysfunction of the diaphragm derives from the difficulty in accurately studying the performance of the diaphragm in critically ill patients. Diaphragm contractility in MV …
Epidemiology of Breast Cancer in India&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;
Authors: J. C. Paymaster, F.R.C.S., F.A.C.S., J. C. Gangadharan, M.Sc., M.S.
Journal: JNCI Journal of the National Cancer Institute (1972)

Data from India indicate that among females the most common site of cancer is the cervix, with the second most common site being the breast. Among the females suffering from cancer, the cervix was affected in 40%, whereas the breast was affected in 18%. The most common histologic type of breast cancer was the infiltrating duct carcinoma. The relative frequencies of cancer of the breast and cervix varied widely among different religious communities of Western India. In Hindu women, the breast was affected in 13% and the cervix in 48%. In the Parsee women the breast was affected in 49% and the cervix in only 11%. The socioeconomic and demographic characteristics of the community differed greatly. The observed differences in the incidence of breast cancer are believed due to certain unknown factors and also to habits and customs prevalent in the community. Case-control studies of various suspected etiologic factors are presented, especially those relating to marital status and the child-bearing process.
Abstract 1228: Identification of a novel p53 target regulating p53-induced apoptotic pathway
Authors: Jinichi Mori, Paulysally Lo, Chizu Tanikawa, Yusuke Nakamura, Koichi Matsuda
Journal: Cancer Research (2015)

Abstract In response to various cellular stresses, p53 induces its target genes and suppresses tumor development. However, the anti-tumor function of p53 has not been fully elucidated. The purpose of our study is the identification and functional analysis of novel p53 downstream targets. We conducted cDNA microarray analysis by using Hct116p53+/+ and p53-/- cells treated with adriamycin and identified p53 inducible protein (p53IP) as a novel p53 downstream target. Induction of p53IP mRNA was confirmed by qRT-PCR. We also found that p53IP protein was increased only in Hct116p53+/+ cells by adriamycin treatment. The result of reporter assay and ChIP assay revealed the direct binding of p53 to p53-binding sequence within p53IP promoter. Colony formation assay by using HCT116 cells indicated that ectopic expression of p53IP significantly inhibited tumor cell growth. Furthermore, knockdown of p53IP with siRNA inhibited apoptosis of tumor cells induced by DNA damage. Our findings indicated that p53IP as a important mediator of p53-dependent apoptotic pathway. Citation Format: Jinichi Mori, Paulysally Lo, Chizu Tanikawa, Yusuke Nakamura, Koichi Matsuda. Identification of a novel p53 target regulating p53-induced apoptotic pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2015-1228
Case 6-2002
Authors: Robert Weinstein, Mohammad Mahmood
Journal: New England Journal of Medicine (2002)

Presentation of CaseA 54-year-old woman was admitted to the hospital because of occlusion of the central retinal vein in her left eye, followed by occlusion of the central retinal vein in her right eye.The patient had been well until about two years earlier, when she was found to have anemia; no further evaluation was undertaken. One year before admission, fatigue developed, with weakness that progressively worsened to the extent that she could barely walk. During that year, epistaxis occurred with increasing frequency, and she took aspirin for occasional headaches.Seven months before admission, the patient experienced impaired central . . .
Prinzmetal’s Variant Angina
Authors: Masahiro Endo, Koshichiro Hirosawa, Noboru Kaneko, Kasuo Hase, Yasuo Inoue, Soji Konno
Journal: New England Journal of Medicine (1976)

Recently, in Prinzmetal's variant angina, many cases with normal coronary arteries have been reported. The anginal attacks frequently relapse after aortocoronary bypass grafting. It is frequently possible to induce an anginal attack by parasympathomimetic agents such as methacholine and pilocarpine. In this study, methacholine (0.13 mg per kilogram) was injected subcutaneously in three cases of this disease to induce an angina attack, and coronary arteriograms and left ventriculograms were recorded. In all cases a coronary arterial spasm corresponding to the site of the ST-segment elevation in the electrocardiogram was observed. Complete occlusion due to the spasm was observed even in the normal coronary artery. Asynergy was seen in the left ventricular wall corresponding to the site of the ST-segment elevation in the electrocardiogram.
Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma
Authors: Yusuke Takayama, Noboru Hattori, Hironobu Hamada, Takeshi Masuda, Keitaro Omori, Shin Akita, Hiroshi Iwamoto, Kazunori Fujitaka, Nobuoki Kohno
Journal: Cancer Research (2016)

Abstract Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285–94. ©2016 AACR.
Effect of Pravastatin on Outcomes after Cardiac Transplantation
Authors: Jon A. Kobashigawa, Steven Katznelson, Hillel Laks, Jay A. Johnson, Lawrence Yeatman, Xiu Ming Wang, David Chia, Paul I. Terasaki, Alejandro Sabad, Gregory A. Cogert, Kevin Trosian, Michele A. Hamilton, Jaime D. Moriguchi, Nobuyuki Kawata, Antoine Hage, Davis C. Drinkwater, Lynne W. Stevenson
Journal: New England Journal of Medicine (1995)

Hypercholesterolemia is common after cardiac transplantation and may contribute to the development of coronary vasculopathy. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to be effective and safe in lowering cholesterol levels after cardiac transplantation. Cell-culture studies using inhibitors of HMG-CoA reductase have suggested an immunosuppressive effect.
Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254
Authors: Gita Thanarajasingam, Pamela J Atherton, Paul J Novotny, Charles L Loprinzi, Jeff A Sloan, Axel Grothey
Journal: The Lancet Oncology (2016)
Results of Single-Lung Transplantation for Bilateral Pulmonary Fibrosis
Authors: R.F. Grossman, A. Frost, N. Zamel, G.A. Patterson, J.D. Cooper, P.R. Myron, C.L. Dear, J. Maurer
Journal: New England Journal of Medicine (1990)

Between November 1983 and August 1989, we performed single-lung transplantation for end-stage pulmonary fibrosis in 20 patients. Nine patients (45 percent) who survived for more than one year form the basis of this report. Before surgery, the nine survivors had severe restrictive lung disease, with a mean (+/- SD) vital capacity (VC) of 43 +/- 9 percent, a forced expiratory volume in one second (FEV1) of 50 +/- 9 percent, and a single-breath diffusing capacity (DLCO) of 36 +/- 9 percent of predicted values. One year after transplantation, the patients' VC had reached 69 +/- 10 percent, FEV1 79 +/- 15 percent, and DLCO 62 +/- 16 percent of predicted values. Relative perfusion to the transplanted lung rose from 63 +/- 14 percent (three days after surgery) to 77 +/- 7 percent within three months and stayed constant or increased slightly thereafter. Before surgery, despite supplemental oxygen at flow rates varying from 1 to 9 liters per minute, none of the patients could exercise beyond stage 1/2 (2.7 km [1.7 miles] per hour, 5 percent grade) on a modified Bruce treadmill-exercise protocol. All eight patients tested one year or more after transplantation achieved at least stage 1 (2.7 km [1.7 miles] per hour, 10 percent grade), and usually a higher stage, without supplemental oxygen. Arterial oxygen tension returned to normal values in most patients (87 +/- 13 mm Hg), and supplemental oxygen, which all patients required before surgery, was no longer needed by any patient after transplantation. We conclude that in carefully selected patients with end-stage pulmonary fibrosis, single-lung transplantation is an effective treatment.
Factor IX Deficiency and Prolonged Bleeding Time
Authors: Lamont W. Gaston, John R. Edson, John R. Hartmann
Journal: New England Journal of Medicine (1966)

VON Willebrand's disease is manifested by a deficiency of factor VIII (antihemophilic factor) and a prolonged bleeding time and is inherited as an autosomal dominant trait of variable penetrance.1 Such patients are characterized by a prolonged rise in plasma factor VHIin response to transfusion with either normal or hemophilia A plasma,1 , 2 and their platelets show a diminished ability to adhere to glass.3 The association of a prolonged bleeding time with a deficiency of factor IX (plasma thromboplastin component) has occasionally been reported,4 5 6 7 and a prolonged bleeding time has also been described with a deficiency of factor X (Stuart-Prower)8 or factor . . .
Prolonged Apnea after Administration of Succinylcholine
Authors: Herbert M. Rubinstein, Murray K. Rosenberg, Julius H. Bolgla, Bernard M. Cohen
Journal: New England Journal of Medicine (1960)

SUCCINYLCHOLINE is a potent neuromuscular blocking agent of the depolarizing type. Ordinarily, its effects are of short duration, and for this reason it is widely used as a muscle relaxant during anesthesia. Since the clinical introduction of the drug in 1951, cases of prolonged apnea after its use have been reported. Most of the cases are cited and discussed in the excellent review of Foldes and his co-workers.1 Prolonged apnea after succinylcholine may be due to a marked deficiency of pseudocholinesterase, the plasma enzyme that normally hydrolyzes and inactivates the drug. Low pseudocholinesterase levels have been ascribed to several causes, . . .
Type 2 Diabetes: Why We Are Winning the Battle but Losing the War? 2015 Kelly West Award Lecture
Authors: K.M. Venkat Narayan
Journal: Diabetes Care (2016)

Diabetes is among the biggest of the 21st-century global health challenges. In the U.S. and other high-income countries, thanks to investments in science, dedication to implementing these findings, and measurement of quality of care, there have been improvements in diabetes management and declines in rate of diabetes complications and mortality. This good news, however, is overshadowed by the ever-increasing absolute numbers of people with diabetes and its complications and the unprecedented growth of diabetes in low- and middle-income countries of the world. To comprehensively win the war against diabetes requires 1) concerted attention to prevention and 2) expansion of global research to better inform population-level policies to curb diabetes but also to better understand individual- and population-level variations in pathophysiology and phenotypes globally so that prevention and treatment can be tailored. For example, preliminary data show that thin people in low- and middle-income countries such as India commonly experience type 2 diabetes. Global studies comparing these thin Asian Indians with other high-risk groups such as Pima Indians, a population with a high mean BMI, suggest that type 2 diabetes may not be a single pathophysiological entity. Pima Indians may represent the well-studied phenotype of poor insulin action (type 2A), whereas Asian Indians represent the grossly understudied phenotype of poor insulin secretion (type 2B). This has major implications for diagnosis, prevention, and treatment and highlights the mismatch between where diabetes burdens occur (i.e., low- and middle-income countries) and where research happens (i.e., high-income countries). Correcting this imbalance will advance our knowledge and arsenal to win the global war against diabetes.
Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001.
Authors: Adil Daud, Antoni Ribas, Caroline Robert, F. Stephen Hodi, Jedd D. Wolchok, Anthony M Joshua, Wen-Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Richard Wayne Joseph, Roxana Stefania Dronca, Amita Patnaik, Hassane M. Zarour, Richard Kefford, Jill Ann Lindia, Xiaoyun Nicole Li, Scot Ebbinghaus, Soonmo Peter Kang, Omid Hamid
Journal: Journal of Clinical Oncology (2015)

9005 Background: The anti–PD-1 antibody pembro is approved in the US for treating unresectable or metastatic MEL that progressed following ipilimumab (IPI) and, if BRAF V600 mutant, a BRAF inhibitor. Pembro has demonstrated robust antitumor activity and manageable toxicity in IPI- treated (IPI-T) and naive (IPI-N) pts. In KEYNOTE-002, pembro significantly prolonged PFS over chemotherapy in IPI-refractory MEL. Here we present long-term follow-up data for all pts with MEL enrolled in KEYNOTE-001 (NCT01295827). Methods: IPI-T and IPI-N pts received pembro 2 mg/kg every 3 weeks (Q3W), 10 mg/kg Q3W, or 10 mg/kg Q2W until unacceptable toxicity, disease progression, or investigator decision. Treatment could continue beyond initial radiographic progression in eligible pts. Response was assessed every 12 wks. Pts were followed for survival every 3 mo after discontinuation. Primary end point was ORR per RECIST v1.1 by central review; secondary end points included PFS, OS, and duration of response (DOR). Results: 655 pts enrolled: 342 IPI-T, 313 IPI-N. Medianfollow-up duration was 14.8 mo (range, 7.5-29). Median duration of exposure was 5.6 mo (range, 0.03-28.3). At the time of analysis, 217 (33%) pts remained on therapy. ORR was 34% (29% IPI-T, 38% IPI-N), with a 6% CR rate. Median time to response was 2.8 mo (range, 1.6-19.3). 80% of responses were ongoing at the time of analysis, and median DOR was not reached (range, 6+ to 98+ wk). Median PFS was 5.2 mo (95% CI 3.6-5.5) (IPI-T, 4.9 mo [3.0-5.5]; IPI-N, 5.4 mo [3.1-6.9]). PFS rates at 6 and 12 mo were 44% and 34% (41% and 32% IPI-T, 47% and 36% IPI-N). The 1-y OS rate was 67% (63% IPI-T, 71% IPI-N); the rate at 2 y was 50% (46% IPI-T, 53% IPI-N). Overall, 14% of pts experienced grade 3-4 treatment-related AEs, and there were no treatment-related deaths. In randomized cohorts, there were no significant differences in efficacy and safety between doses/schedules. Conclusions: Pembro provides robust and durable antitumor activity, promising long-term survival data, and a manageable safety profile in pts with IPI-T and IPI-N metastatic MEL. These results support the approved indication for pembro and its further exploration in other MEL populations. Clinical trial information: NCT01295827.
Safety and Clinical Efficacy Of Rapidly-Generated Virus-Specific T Cells With Activity Against Adv, EBV, CMV, HHV6 and BK Virus Administered After Allogeneic Hematopoietic Stem Cell Transplant
Authors: Anastasia Papadopoulou, Usha L Katari, Ulrike Gerdemann, Caridad Martinez, Kathryn Leung, George Carrum, Adrian P. Gee, Juan F Vera, Robert A. Krance, Malcolm K. Brenner, Cliona M Rooney, Helen E. Heslop, Ann Leen
Journal: Blood (2013)
Pain management was the subject of a special issue of JAMA last week: Painkillers before knee surgery improve outcomes
Authors: Janice Hopkins Tanne
Journal: BMJ (2003)

Patients who had pre-emptive treatment of pain with a cyclooxygenase-2 (COX 2) inhibitor before knee replacement surgery had less pain and vomiting after the surgery, needed fewer opioids, slept better, had better knee flexion, and needed less physical therapy. The randomised controlled trial was reported by Dr Asokumar Buvanendran and colleagues at Rush-Presbyterian-St Luke's Medical Center, Chicago (JAMA 2003;290: 2411-8 [PubMed]).

Knee replacement is among the most painful of operations, Dr Buvanendran said. The 70 patients, aged 44 to 77 years, were assigned to placebo treatment or to treatment with 50 mg of oral rofecoxib 24 hours before surgery, another 50 mg an hour or two before surgery, 50 mg daily for five days after surgery, and 25 mg daily for the next eight days. All patients were given epidural anaesthesia and self controlled analgesia after surgery.

Range of motion is an important outcome measure after knee replacement. The degree of knee flexion needed for climbing stairs is 83°, for descending stairs 90°, and for tying shoelaces 106°. At discharge, patients in the rofecoxib group had 84.2° of active flexion and patients in the placebo group had 73.2°. One month after surgery the figures were 109.3° and 100.8° respectively.

Dr Buvanendran said that the improvement meant an increase in satisfaction among patients, a quicker return to work or usual activities, and a reduction in the costs of physical therapy.
Refined Method for Collection of Plasma Samples to Evaluate the Role of Plasma Kallikrein in Various Disease States
Authors: Jonathan A. Bernstein, H. James Wedner, Paula J. Busse, Aleena Banerji, Marco Cicardi, C. Sufritti, Edward G. Brooks, Adam Cheifitz, Lawrence B. Schwartz, Cem Akin, Daniel Sexton, Chris Stevens, Leslie E. Stolz, Malini Viswanathan, Ryan Faucette, Joseph C. Biedenkapp, Yung H. Chyung, Burt Adelman
Journal: Journal of Allergy and Clinical Immunology (2016)
Hereditary Hypophosphatemic Rickets with Hypercalciuria
Authors: Martin Tieder, David Modai, Ruth Samuel, Raphael Arie, Aharon Halabe, Itai Bab, Daniela Gabizon, Uri A. Liberman
Journal: New England Journal of Medicine (1985)

We studied a new hereditary syndrome of hypophosphatemic rickets and hypercalciuria in six affected members of one kindred. In all patients, the manifestations of disease began in early childhood. The characteristic features are rickets, short stature, increased renal phosphate clearance (the ratio between the maximal tubular reabsorption rate for phosphorus and the glomerular filtration rate [TmP/GFR] is 2 to 4 S.D. below the age-related mean), hypercalciuria (8.6 mg of urinary calcium per kilogram of body weight per 24 hours vs. the upper normal value of 4.0), normal serum calcium levels, increased gastrointestinal absorption of calcium and phosphorus, an elevated serum concentration of 1,25-dihydroxyvitamin D (390 +/- 99 pg per milliliter vs. the upper normal value of 110), and suppressed parathyroid function (an immunoreactive parathyroid hormone level of 0.33 +/- 0.1 ng per milliliter and a cyclic AMP level of 1.39 +/- 0.12 nmol per deciliter of glomerular filtrate vs. the lower normal values of 0.3 and 1.5, respectively). Long-term phosphate supplementation as the sole therapy resulted in reversal of all clinical and biochemical abnormalities except the decreased TmP/GFR. We propose that the pivotal defect in this syndrome is a renal phosphate leak resulting in hypophosphatemia with an appropriate elevation of 1,25-dihydroxyvitamin D levels, which causes increased calcium absorption, parathyroid suppression, and hypercalciuria. This syndrome may represent one end of a spectrum of hereditary absorptive hypercalciuria. Our observations support the importance of phosphate as a mediator in controlling 1,25-dihydroxyvitamin D production in human beings.
Dose-Response Effect of Adjuvant Chemotherapy in Breast Cancer
Authors: Gianni Bonadonna, Pinuccia Valagussa
Journal: New England Journal of Medicine (1981)

We retrospectively analyzed the role of the dose level of CMF (cyclophosphamide, methotrexate, and fluorouracil) in postoperative adjuvant chemotherapy for breast cancer and in chemotherapy for metastatic breast cancer. There was a clear dose-response effect, indicating that CMF was useful only when given in a full or nearly full dose (≥85 per cent of the planned dose). Those given adjuvant therapy with 12 cycles of CMF at this dose level had a five-year relapse-free survival of 77 per cent, as compared with 45 per cent of patients treated only with radical mastectomy (P = 0.0001). In contrast, a subgroup receiving less than 65 per cent of the planned dose had a five-year survival without relapses of 48 per cent and a five-year survival with relapses of 67 per cent. These results are similar to those observed in a control group. With each dose level, the results at five years were influenced by the number of axillary lymph nodes involved but not by menopausal status. Our findings indicate that it is necessary to administer combination chemotherapy at a full dose to achieve clinical benefit. (N Engl J Med. 1981; 304:10–5.)
In Brighton and London — Early to Rise
Authors: John Lister
Journal: New England Journal of Medicine (1956)

BRITAIN has no Atlantic City but Brighton provides a fine conference city by the sea and it was there that the British Medical Association held its annual conference this year.Because a certain Dr. Richard Russell was the founder of modern Brighton the city has had a long association with medicine. In 1750 Dr. Russell published a book entitled, A Dissertation on the Use of Sea Water in the Diseases of the Glands. In this he advocated sea-bathing as a form of treatment for many complaints, and patients soon came from all over England to take the sea-water cure. In . . .