tbuckley/cabot-search huggingface dataset:
Pneumatic Dilation versus Laparoscopic Heller's Myotomy for Idiopathic Achalasia
Authors: Guy E. Boeckxstaens, Vito Annese, Stanislas Bruley des Varannes, Stanislas Chaussade, Mario Costantini, Antonello Cuttitta, J. Ignasi Elizalde, Uberto Fumagalli, Marianne Gaudric, Wout O. Rohof, André J. Smout, Jan Tack, Aeilko H. Zwinderman, Giovanni Zaninotto, Olivier R. Busch
Journal: New England Journal of Medicine (2011)

Many experts consider laparoscopic Heller's myotomy (LHM) to be superior to pneumatic dilation for the treatment of achalasia, and LHM is increasingly considered to be the treatment of choice for this disorder.We randomly assigned patients with newly diagnosed achalasia to pneumatic dilation or LHM with Dor's fundoplication. Symptoms, including weight loss, dysphagia, retrosternal pain, and regurgitation, were assessed with the use of the Eckardt score (which ranges from 0 to 12, with higher scores indicating more pronounced symptoms). The primary outcome was therapeutic success (a drop in the Eckardt score to ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for retreatment, pressure at the lower esophageal sphincter, esophageal emptying on a timed barium esophagogram, quality of life, and the rate of complications.A total of 201 patients were randomly assigned to pneumatic dilation (95 patients) or LHM (106). The mean follow-up time was 43 months (95% confidence interval [CI], 40 to 47). In an intention-to-treat analysis, there was no significant difference between the two groups in the primary outcome; the rate of therapeutic success with pneumatic dilation was 90% after 1 year of follow-up and 86% after 2 years, as compared with a rate with LHM of 93% after 1 year and 90% after 2 years (P=0.46). After 2 years of follow-up, there was no significant between-group difference in the pressure at the lower esophageal sphincter (LHM, 10 mm Hg [95% CI, 8.7 to 12]; pneumatic dilation, 12 mm Hg [95% CI, 9.7 to 14]; P=0.27); esophageal emptying, as assessed by the height of barium-contrast column (LHM, 1.9 cm [95% CI, 0 to 6.8]; pneumatic dilation, 3.7 cm [95% CI, 0 to 8.8]; P=0.21); or quality of life. Similar results were obtained in the per-protocol analysis. Perforation of the esophagus occurred in 4% of the patients during pneumatic dilation, whereas mucosal tears occurred in 12% during LHM. Abnormal exposure to esophageal acid was observed in 15% and 23% of the patients in the pneumatic-dilation and LHM groups, respectively (P=0.28).After 2 years of follow-up, LHM, as compared with pneumatic dilation, was not associated with superior rates of therapeutic success. (European Achalasia Trial Netherlands Trial Register number, NTR37, and Current Controlled Trials number, ISRCTN56304564.).
The prince and the pauper. A tale of anticancer targeted agents
Authors: Alfonso Dueñas-González, Patricia García-López, Luis Herrera, Jose Medina-Franco, Aurora González-Fierro, Myrna Candelaria
Journal: Molecular Cancer (2008)

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.
Psychiatric and Psychosocial Outcome of Orthotopic Liver Transplantation
Authors: Hans-Bernd Rothenhäusler, Sigrid Ehrentraut, Hans-Peter Kapfhammer, Christina Lang, Reinhart Zachoval, Manfred Bilzer, Gustav Schelling, Alexander L. Gerbes
Journal: Psychotherapy and Psychosomatics (2002)

&lt;i&gt;Background:&lt;/i&gt; The study aimed to explore the prevalence of psychiatric disorders among orthotopic liver transplantation (OLT) recipients, and to investigate how psychiatric morbidity was linked to health-related quality of life (HRQOL). &lt;i&gt;Methods:&lt;/i&gt; We recruited 75 patients who had undergone OLT a median of 3.8 years previously (range = 5–129 months). Psychiatric morbidity was assessed using the Structural Clinical Interview for the DSM-III-R. Psychometric observer-rating and self-rating scales were administered to evaluate cognitive functioning (SKT), depressive symptomatology (HAMD&lt;sub&gt;17&lt;/sub&gt;), posttraumatic stress symptoms (PTSS-10), social support (SSS), and HRQOL (SF-36 Health Status Questionnaire). Treatment characteristics were obtained from medical records. &lt;i&gt;Results:&lt;/i&gt; 22.7% (n = 17) of our sample had a current or probable psychiatric diagnosis according to DSM-III-R: 2.7% full posttraumatic stress disorder (PTSD) (n = 2), 2.7% major depressive disorder (MDD) comorbid to full PTSD (n = 2), 1.3% MDD comorbid to partial PTSD (n = 1), and 16% partial PTSD (n = 12). Patients with PTSD symptoms demonstrated lower cognitive performance, higher severity of depressive symptoms and more unfavorable perception of social support. OLT-related PTSD symptomatology was associated with maximal decrements in HRQOL. The duration of intensive care treatment, the number of medical complications, and the occurrence of acute rejection were positively correlated with the risk of PTSD symptoms subsequent to OLT. &lt;i&gt;Conclusion:&lt;/i&gt; OLT-related PTSD symptomatology impairing HRQOL is a complication for a subgroup of OLT recipients. Health-care providers should be aware of the possible presence of PTSD in OLT survivors.
Genetics of Biliary Tract Cancers and Emerging Targeted Therapies
Authors: Aram F. Hezel, Vikram Deshpande, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2010)

Biliary tract cancers (BTC), which encompass intra- and extrahepatic cholangiocarcinomas and gallbladder carcinomas, are a genetically diverse collection of cancers. Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in BTC. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here, we summarize the molecular pathogenesis and genetics of BTCs and animal modeling and relate these to recent and ongoing clinical trials with targeted agents.
The scleroatrophic syndrome of Huriez: a cancer-prone genodermatosis
Authors: H. HAMM, H. TRAUPE, E.-B. BRÖCKER, H. SCHUBERT, G. KOLDE
Journal: British Journal of Dermatology (1996)

We report a 24‐year‐old woman, her 6‐year‐old son and her 1 7‐month ‐old daughter, who all suffer from a rare congenital genodermatosis first delineated by Huriez et al. in the 1960s. The clinical features of this autosomal dominant condition include scleroatrophy of the hands and feel, nail hypoplasia, mild palmoplantar keratoderma and hypohidrosis. Histological changes are non‐specific, but immunohistological and ultrastructural examination in our index patient revealed an almost complete absence of epidermal Langerhans cells in the affected skin. This new finding may be linked to the cancer proneness of the scleroatrophic skin. In this family, the grandmother had died at the age of 37 years from metastatic squamous cell carcinoma which had arisen on the thenar eminence.
Implications of the Human Genome Project for Medical Science
Authors: Francis S. Collins
Journal: JAMA (2001)

The year 2000 marked both the start of the new millennium and the announcement that the vast majority of the human genome had been sequenced. Much work remains to understand how this "instruction book for human biology" carries out its multitudes of functions. But the consequences for the practice of medicine are likely to be profound. Genetic prediction of individual risks of disease and responsiveness to drugs will reach the medical mainstream in the next decade or so. The development of designer drugs, based on a genomic approach to targeting molecular pathways that are disrupted in disease, will follow soon after. Potential misuses of genetic information, such as discrimination in obtaining health insurance and in the workplace, will need to be dealt with swiftly and effectively. Genomic medicine holds the ultimate promise of revolutionizing the diagnosis and treatment of many illnesses.
Home based exercise programme for knee pain and knee osteoarthritis: randomised controlled trial
Authors: K S Thomas, K R Muir, M Doherty, A C Jones, S C O'Reilly, E J Bassey
Journal: BMJ (2002)

To determine whether a home based exercise programme can improve outcomes in patients with knee pain.Pragmatic, factorial randomised controlled trial of two years' duration.Two general practices in Nottingham.786 men and women aged >/=45 years with self reported knee pain.Participants were randomised to four groups to receive exercise therapy, monthly telephone contact, exercise therapy plus telephone contact, or no intervention. Patients in the no intervention and combined exercise and telephone groups were randomised to receive or not receive a placebo health food tablet.Primary outcome was self reported score for knee pain on the Western Ontario and McMaster universities (WOMAC) osteoarthritis index at two years. Secondary outcomes included knee specific physical function and stiffness (scored on WOMAC index), general physical function (scored on SF-36 questionnaire), psychological outlook (scored on hospital anxiety and depression scale), and isometric muscle strength.600 (76.3%) participants completed the study. At 24 months, highly significant reductions in knee pain were apparent for the pooled exercise groups compared with the non-exercise groups (mean difference -0.82, 95% confidence interval -1.3 to -0.3). Similar improvements were observed at 6, 12, and 18 months. Regular telephone contact alone did not reduce pain. The reduction in pain was greater the closer patients adhered to the exercise plan.A simple home based exercise programme can significantly reduce knee pain. The lack of improvement in patients who received only telephone contact suggests that improvements are not just due to psychosocial effects because of contact with the therapist.
Mechanism of attenuated pressure-flow autoregulation in right coronary circulation of dogs.
Authors: S Yonekura, N Watanabe, J L Caffrey, J F Gaugl, H F Downey
Journal: Circulation Research (1987)

Right coronary autoregulation was assessed in 14 open-chest, anesthetized dogs. In Group 1 (n = 5), the left common and right coronary arteries were cannulated and perfused independently. As coronary perfusion pressures varied simultaneously between 70 and 120 mm Hg, right coronary blood flow changed by 48%, whereas left coronary flow changed by 13%. In this pressure range, the autoregulatory closed-loop gain of the right coronary circulation averaged 0.37 +/- 0.01, reflecting a modest autoregulatory capability but significantly less than that of the left coronary circulation, 0.78 +/- 0.08. In Group 2 (n = 9), only the right coronary artery was perfused, and right coronary venous blood was collected for determining arteriovenous oxygen extraction. Autoregulatory gain was similar to that of Group 1, indicating that collateral flow associated with intercoronary pressure gradients does not mask right coronary autoregulation. Right ventricular myocardial oxygen consumption varied directly with perfusion pressure, ranging from 7.1 +/- 1.0 to 2.9 +/- 0.8 ml O2/min/100 g as pressure was reduced from 160 to 40 mm Hg. Thus, right coronary autoregulation is masked by an opposing change in oxygen demand. When right ventricular oxygen consumption was altered by pacing, a linear flow-oxygen consumption relationship was observed (8.2 +/- 0.4 ml/min/100 g per ml O2/min/100 g). Subtraction of flows associated with pressure-induced changes in metabolism revealed a potential autoregulatory capability of the right coronary circulation similar to that manifested by the left coronary circulation.
Dust Exposure Assessed by a Job Exposure Matrix Is Associated with Increased Annual Decline in FEV<sub>1</sub>
Authors: Helle Laier Johnsen, Siri M. Hetland, Jūratė Šaltytė Benth, Johny Kongerud, Vidar Søyseth
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

The relationship between dust exposure and annual decline in lung function among employees in the smelting industry is unknown.The aim of the study was to investigate the relationship between annual change in lung function and occupational dust exposure among workers in 15 Norwegian smelters.All employees (n = 2,620) were examined annually for 5 years (11,335 health examinations). At each examination spirometry was performed and a respiratory questionnaire was completed. The smelters were grouped as follows: (1) ferrosilicon alloys (FeSi) and silicon metal (Si-metal); and (2) silicon manganese (SiMn), ferromanganese (FeMn), and ferrochromium (FeCr). A job exposure matrix was available on the basis of 2,619 personal dust exposure measurements. The association between lung function expressed as FEV(1) and FVC per squared height (height(2)) and dust exposure was investigated using multivariate linear mixed model analyses.The annual change in FEV(1)/height(2) (deltaFEV(1)) related to dust exposure in the FeSi/Si-metal and SiMn/FeMn/FeCr smelters was -0.42 (95% confidence interval, -0.95 to 0.11) and -1.1 (-2.1 to -0.12) (ml/m(2)) x (mg/m(3))(-1) x year(-1), respectively. The annual decline in FEV(1)/height(2) was 1.6 ml/m(2) (0.15 to 3.1) steeper in smokers than in nonsmokers. The median geometric mean of the time-weighted dust exposure concentration levels of the employees was 2.3 mg/m(3) in the FeSi/Si-metal smelters and 1.6 mg/m(3) in the SiMn/FeMn/FeCr smelters. Among nonsmokers, deltaFEV(1) was -0.86 (-1.6 to -0.10) and -1.1 (-2.5 to 0.25) (ml/m(2)) x (mg/m(3))(-1) x year(-1) in the FeSi/Si-metal and SiMn/FeMn/FeCr smelters, respectively. Thus, for a 1.80 m tall employee the annual decline in FEV(1) associated with average dust exposure was 5.7 ml/year in the SiMn/FeMn/FeCr smelters, and 6.4 ml/year for a nonsmoker in the FeSi/Si-metal smelters.In all smelters combined, the annual change in FEV(1) was negatively associated with increasing dust exposure. This association was also significant among workers in SiMn/FeMn/FeCr smelters and among nonsmokers in the FeSi/Si-metal smelters.
A type I interferon autocrine–paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells
Authors: Grégory Gautier, Martine Humbert, Florence Deauvieau, Mathieu Scuiller, John Hiscott, Elizabeth E.M. Bates, Giorgio Trinchieri, Christophe Caux, Pierre Garrone
Journal: The Journal of Experimental Medicine (2005)

Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-kappaB (NF-kappaB)-dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-beta mRNA accumulation by mouse bone marrow-derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1(-/-) and IFNAR(-/-) mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-beta mRNA accumulation were strongly inhibited in IFNAR(-/-) BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-lambda1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-kappaB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.
Transforming growth factor-β and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes
Authors: Yung-Hsin Yeh, Chi-Tai Kuo, Ting-Hsiang Chan, Gwo-Jyh Chang, Xiao-Yan Qi, FengChun Tsai, Stanley Nattel, Wei-Jan Chen
Journal: Cardiovascular Research (2011)

Atrial fibrillation (AF), a common tachyarrhythmia in clinical practice, is associated with increased oxidative stress. Structural remodelling in atrial myocytes, including myofibril degradation, is an important characteristic of AF. However, the mechanism underlying AF-induced cellular structural remodelling remains unclear. The aim of this study was to investigate the role of oxidative stress and related factors in tachycardia-induced atrial structural remodelling. Cultured atrial-derived myocytes (HL-1 cell line) were subjected to electrical stimulation. Immunofluorescence and immunoblotting were used to evaluate oxidative stress, myofibril degradation, and transforming growth factor-β (TGF-β) expression. Tachypacing in HL-1 cells induced TGF-β expression, pronounced oxidative stress including up-regulation of NADPH oxidases (Nox2/4), and myofibril degradation. Oxidative stress scavenger, NADPH oxidase inhibitors, and small-interfering RNAs for Nox2/4 blocked tachypacing-induced myofibril degradation, suggesting that Nox-derived oxidative stress may lead to tachycardia-induced myofibril degradation. Blockade of TGF-β signalling by neutralizing TGF-β antibodies attenuated myofibril loss in response to tachypacing, implicating autocrine and/or paracrine roles for TGF-β in such effects. Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-β) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signalling pathways. Furthermore, TGF-β expression, oxidative stress, and myofibril loss were greater in the atria of patients with AF than those with sinus rhythm. Rapid activation in atrial myocytes promotes myofibril degradation through autocrine/paracrine TGF-β signalling and increased oxidative stress. These findings provide an important mechanistic insight into AF-related structural remodelling.
Regulation of the endothelial cell cycle by the ubiquitin-proteasome system
Authors: P. Fasanaro, M. C. Capogrossi, F. Martelli
Journal: Cardiovascular Research (2009)

Degradation of poly-ubiquitinated proteins by the 26S-proteasome complex represents a crucial quantitative control mechanism. The ubiquitin-proteasome system (UPS) plays a pivotal role in the complex molecular network regulating the progression both between and within each cell-cycle phase. Two major complexes are involved: the SKP1-CUL1-F-box-protein complex (SCF) and the anaphase-promoting complex/cyclosome (APC/C). Notwithstanding structural similarities, SCF and APC/C display different cellular functions and mechanisms of action. SCF modulates all cell-cycle stages and plays a prominent role at G1/S transition mainly through three regulatory subunits: Skp2, Fbw7, and beta-TRCP. APC/C, regulated by Cdc20 or Cdh1 subunits, has a crucial role in mitosis. In this review, we will describe how the endothelial cell cycle is regulated by the UPS. We will illustrate the principal SCF- and APC/C-dependent molecular mechanisms that modulate cell growth, allowing a unidirectional cell-cycle progression. Then, we will focus our attention on UPS modulation by oxidative stress, a pathogenic stimulus that causes endothelial dysfunction and is involved in numerous cardiovascular diseases.
A HISTOLOGICAL STUDY OF TYPHOID FEVER
Authors: F. B. Mallory
Journal: The Journal of Experimental Medicine (1898)

The typhoid bacillus produces a mild diffusible toxine, partly within the intestinal tract, partly within the blood and organs of the body. This toxine produces proliferation of endothelial cells which acquire for a certain length of time malignant properties. The new-formed cells are epithelioid in character, have irregular, lightly staining, eccentrically situated nuclei, abundant, sharply defined, acidophilic protoplasm, and are characterized by marked phagocytic properties. These phagocytic cells are produced most abundantly along the line of absorption from the intestinal tract, both in the lymphatic apparatus and in the blood-vessels. They are also produced by distribution of the toxine through the general circulation, in greatest numbers where the circulation is slowest. Finally, they are produced all over the body in the lymphatic spaces and vessels by absorption of the toxine eliminated from the blood-vessels. The swelling of the intestinal lymphoid tissue of the mesenteric lymph nodes, and of the spleen is due almost entirely to the formation of phagocytic cells. The necrosis of the intestinal lymphoid tissue is accidental in nature and is caused through occlusion of the veins and capillaries by fibrinous thrombi, which owe their origin to degeneration of phagocytic cells beneath the lining endothelium of the vessels. Two varieties of focal lesions occur in the liver: one consists of the formation of phagocytic cells in the lymph spaces and vessels around the portal vessels under the action of the toxine absorbed by the lymphatics; the other is due to obstruction of liver capillaries by phagocytic cells derived in small part from the lining endothelium of the liver capillaries, but chiefly by embolism through the portal circulation of cells originating from the endothelium of the blood-vessels of the intestine and spleen. The liver cells lying between the occluded capillaries undergo necrosis and disappear. Later the foci of cells degenerate and fibrin forms between them. Invasion with polymorphonuclear leucocytes is rare. Many of the phagocytic cells pass through the liver and lungs, and get into the general circulation. A few come from the abdominal lymphatics through the thoracic duct.