tbuckley/cabot-search huggingface dataset:
Sleep-related breathing disorders: definitions and measurements
Authors: W.T. McNicholas, P. Levy
Journal: European Respiratory Journal (2000)

sleep medicine from around the world for the specific purpose of developing recommendations for the definition of clinical syndromes related to sleep-related breathing disorders in adults, and also to provide recommendations concerning the most appropriate measurement techniques to be used in the evaluation of these disorders. The work of the Task Force involved a number of meetings of the members, including working groups to evaluate particular aspects of the brief in detail. In addition, feedback was sought from members of the participating societies, usually by means of open discussion forums during annual meetings of the relevant societies. Finally, peer review of the draft report was obtained from a large number of outside experts. The final report was published in the journal Sleep in late 1999 [6], and has been described by many as a landmark in the evolution of the approach to the diagnosis and assessment of sleep-related breathing disorders. In addition to sleep apnoea syndrome, the report also addressed other sleep-related breathing disorders such as upper airway resistance syndrome, Cheyne‐Stokes respiration, and sleep hypoventilation syndrome. Standard approaches to the evaluation of levels of evidence were utilized in the evaluation of the scientific literature relevant to each aspect of the brief. In some instances, the scientific literature available allowed clear evidence-based recommendations to be provided in the report. In other instances, the scientific literature was regarded as sufficiently weak that no clear evidence-based recommendations could be provided. In these circumstances, recommendations were made by a consensus drawn from the task force membership as a whole. The Task Force considered the potential clinical significance of recurring episodes of increased upper airway resistance associated with arousal and sleep fragmentation, but not apnoea or hypopnoea, as originally described by GUILLEMINAULT et al. [7]. The Task Force agreed that these upper airway resistance episodes should be called respiratory effort-related arousals (RERA) and be considered part of obstructive sleep apnoea/hypopnoea syndrome (OSAHS). The definition of hypopnoea has been variable and unclear for many years. An important recommendation was that a hypoponea should be scored in the case of a reduction in flow of >50% measured by a validated means, or a reduction of 30‐50% associated with either an arousal or a desaturation of >3%. The definition of OSAHS severity in the report categorizes the syndrome into mild, moderate and severe categories, with mild OSAHS including a combined apnoea, hypopnoea and RERA frequency of as low as 5 events.h -1 , providing other symptoms such as daytime sleepiness are also present. This diagnostic threshold is lower than many
Enalapril and Carvedilol for Preventing Chemotherapy-Induced Left Ventricular Systolic Dysfunction in Patients With Malignant Hemopathies
Authors: Xavier Bosch, Montserrat Rovira, Marta Sitges, Ariadna Domènech, José T. Ortiz-Pérez, Teresa M. de Caralt, Manuel Morales-Ruiz, Rosario J. Perea, Mariano Monzó, Jordi Esteve
Journal: Journal of the American College of Cardiology (2013)
Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
Authors: Yan Feng, Amit Roy, Eric Masson, Tai-Tsang Chen, Rachel Humphrey, Jeffrey S. Weber
Journal: Clinical Cancer Research (2013)

Abstract Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure–response relationships for measures of efficacy and safety in patients with advanced melanoma. Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady–state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional–hazards model. Results: The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P &amp;lt; 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively. Conclusions: Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial. Clin Cancer Res; 19(14); 3977–86. ©2013 AACR.
Effect of Chronic Intermittent Intravenous Insulin Therapy on Antihypertensive Medication Requirements in IDDM Subjects With Hypertension and Nephropathy
Authors: Thomas T Aoki, Eugen O Grecu, Joseph J Prendergast, Michael A Arcangeli, Ronald Meisenheimer
Journal: Diabetes Care (1995)

OBJECTIVE The prevalence of systemic hypertension is increased in patients with diabetes. In this prospective, randomized, crossover clinical trial, we assessed antihypertensive effects of chronic intermittent intravenous insulin therapy (CIIIT) on insulin-dependent diabetes mellitus (IDDM) subjects with hypertension and nephropathy by monitoring the amount of antihypertensive medication (AHM) required to maintain blood pressure (BP) ≤ 140/90 mmHg. RESEARCH DESIGN AND METHODS After a stabilization period, 26 hypertensive IDDM subjects were randomly assigned to a control or treatment phase for 3 months and then crossed over into the opposite phase for another 3 months. Addition of CIIIT during the treatment phase was the only procedural difference between the control and treatment phases. RESULTS The AHM dosage requirements for maintenance of the baseline BP levels decreased significantly (46% P &amp;lt; 0.0001) and linearly over time (P &amp;lt; 0.0058) during the treatment phase, while remaining essentially unchanged during the control phase. CONCLUSIONS Our data suggest that CIIIT markedly improves BP control, as evidenced by the significantly reduced AHM dosage requirements in subjects with IDDM and hypertension, possibly through an improvement in vascular reactivity.
Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid.
Authors: K Sletten, P Westermark, J B Natvig
Journal: The Journal of Experimental Medicine (1976)

Amyloid fibrils were studied from two different tissues of medullary carcinoma of the thyroid (MCT). The fibrils mainly consisted of a low molecular weight protein, AMCT, which was immunologically distinct and did not react with various antisera against known amyloid fibril proteins. A specific antiserum raised against the MCT amyloid proteins gave a reaction of identity with the degraded MCT amyloid fibrils from two patients, as well as with the isolated AMCT protein, but showed no reaction with other known amyloid proteins. The AMCT protein had a blocked N terminus, but the sequence analysis of a cyanogen bromide fragment revealed identity with human calcitonin in the 11 positions studied. Although the amino acid composition was similar, there were also distinct differences, and the mol wt of 5,700 daltons was considerably larger than that of calcitonin. For these reasons the AMCT protein may represent a prohormone of calcitonin.
Species specificity and augmentation of responses to class II major histocompatibility complex molecules in human CD4 transgenic mice.
Authors: E Barzaga-Gilbert, D Grass, S K Lawrance, P A Peterson, E Lacy, V H Engelhard
Journal: The Journal of Experimental Medicine (1992)

Murine T cell responses to human class II major histocompatibility complex (MHC) molecules were shown to be a minimum of 20-70-fold lower than responses to allogeneic molecules. Transgenic mice expressing slightly below normal (75-95%) or very high (250-380%) cell surface levels of human CD4 were utilized to determine whether this was due to a species-specific interaction between murine CD4 and class II molecules. Human CD4 was shown to function in signal transduction events in murine T cells based on the ability of anti-human CD4 antibody to synergize with suboptimal doses of anti-murine CD3 antibody in stimulating T cell proliferation. In mice expressing lower levels of human CD4, T cell responses to human class II molecules were enhanced up to threefold, whereas allogeneic responses were unaltered. In mice expressing high levels of human CD4, responses to human class II molecules were enhanced at least 10-fold, whereas allogeneic responses were between one and three times the level of normal responses. The relatively greater enhancement of the response to human class II molecules in both lines argues for a preferential interaction between human CD4 and human class II molecules. In mice expressing lower levels of human CD4, responses to human class II molecules were blocked by antibodies to CD4 of either species, indicating participation by both molecules. In mice expressing high levels of human CD4, responses to both human and murine class II molecules were almost completely blocked with anti-human CD4 antibody, whereas anti-murine CD4 antibody had no effect. However, anti-murine CD4 continued to synergize with anti-CD3 in stimulating T cell proliferation in these mice. Thus, overexpression of human CD4 selectively impaired the ability of murine CD4 to assist in the process of antigen recognition. The ability of human CD4 to support a strong allogeneic response under these conditions indicates that this molecule can interact with murine class II molecules to a significant extent. Despite the fact that human CD4 appeared to be the only functional coreceptor in these mice, responses to human class II molecules were still much lower than those to murine class II alloantigens. This indicates that species-specific interactions between class II molecules and CD4 expressed on peripheral T cells are not sufficient to account for the low xenogeneic response and that intrinsic differences in T cell receptor structures or the need for species specificity in the interaction between CD4 and class II molecules during positive selection are also important.
Benoxaprofen: side-effect profile in 300 patients.
Authors: J P Halsey, N Cardoe
Journal: BMJ (1982)

Out of 300 patients who had taken benoxaprofen for a mean of 6.4 months, 196 (65.3%) reported side effects, resulting in 104 patients (34.6%) having the drug withdrawn. Out of 42 patients aged over 70, 35 (83.3%) had side effects and 29 (69.0%) had the drug withdrawn because of them. cutaneous side effects accounted for 180 (69.5%) of all 259 side effects reported. The commonest cutaneous side effect was photosensitivity, which occurred in 86 patients (28.6%). Photosensitivity, which occurred in half of the patients treated in the summer, resulted in withdrawal of benoxaprofen in 26 (30.2%) of the patients who experienced it. Onycholysis was observed in 38 patients (12.6%) and was frequently unnoticed by patients. The overall incidence of gastric side effects was 12.6% (38 patients), and the figure rose to 40.5% (17 cases) in patients over 70. During treatment with benoxaprofen one patient developed an active duodenal ulcer but no cases of major gastrointestinal haemorrhage occurred. Multiple subepidermal cysts (milia) were observed in 16 patients, who had been treated for a mean of 10.8 months. These findings show that benoxaprofen is a potent phototoxic drug and that the manufacturers' recommended dosage of 600 mg daily is associated with an unacceptable incidence of side effects in the elderly.
INFORMING TREATMENT DECISIONS IN RELAPSED PEDIATRIC MALIGNANCIES USING NEXT-GENERATION DIAGNOSTICS
Authors: S. M. Pfister, D. T. W. Jones, D. Capper, R. Witt, C. van Tilburg, A. von Deimling, A. Eggert, P. Lichter, O. Witt
Journal: Neuro-Oncology (2014)

BACKGROUND: Although childhood malignancies have become curable in about 75% of cases due to empirically developed multi-modal therapeutic concepts applied in nation-wide collaborative trials, for children with a relapse, cure remains the exception. In the framework of the ICGC project PedBrain many new potentially druggable genetic lesions have been identified. However, it will not be feasible to conduct traditional phase I trials for all these new drugs in these overall rare entities. To still have our young patients participating in the recent advances in molecular targeted drug treatment, we initiated a novel innovative way of introducing these drugs in a clinical setting based on an individualized molecular rationale, a concept called INFORM (INdividualized therapy For Relapsed Malignancies in childhood). METHODS: Exome- and low-coverage whole-genome sequencing, RNA sequencing, gene expression profiling, DNA methylation profiling, bioinformatic prediction of drug targets and compound selection are carried out aiming at a turnaround time of 4 weeks or less after re-biopsy of the tumor. In the current feasibility phase, drug targets and prioritization are offered to the treating physician in the local hospital for individual treatment decisions. RESULTS: Ten patients were recruited to the INFORM-pilot study by now. For all but two, druggable targets have been identified. The first two patients with early follow-up MRIs after 6 weeks had stable disease (medulloblastoma) and 50% tumor volume reduction (myofibroblastc tumor), respectively. In an additional case with pontine glioma, molecular diagnostics significantly contributed to the establishment of an unambiguous diagnosis. CONCLUSIONS: This is the first population-based study using next-generation sequencing technologies to guide treatment decisions in a clinical setting. In addition to this advance in “next-generation” clinical oncology, INFORM will also reveal the largest comprehensive molecular datasets of relapsed tumors to date, and since primary tumor material from the same patient will also be analyzed whenever available, will likely identify key biological properties of relapsing malignancies and recurrent mechanisms of drug resistance across entities. SECONDARY CATEGORY: Pediatrics.
Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells
Authors: Yingyu Ma, Wei-Dong Yu, Rui-Xian Kong, Donald L. Trump, Candace S. Johnson
Journal: Cancer Research (2006)

Abstract Vitamin D is a steroid hormone that regulates calcium homeostasis and bone metabolism. The active form of vitamin D [1α,25-dihydroxyvitamin D3 (1,25D3)] acts through both genomic and nongenomic pathways. 1,25D3 has antitumor effects in a variety of cancers, including colorectal, prostate, breast, ovarian, and skin cancers. 1,25D3 exerts growth-inhibitory effects in cancer cells through the induction of apoptosis, cell cycle arrest, and differentiation. The mechanisms regulating 1,25D3-induced apoptosis remain unclear. We investigated the role of nongenomic signaling in 1,25D3-mediated apoptosis in squamous cell carcinoma (SCC) cells. 1,25D3 induced rapid and sustained activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 pathways in SCC cells. These effects were nongenomic: they occurred rapidly and were not inhibited by cycloheximide or actinomycin D. To examine whether the nongenomic activation of Akt and ERK1/2 plays a role in 1,25D3-mediated apoptosis, the expression of Akt or ERK1/2 was reduced by small interfering RNA (siRNA). siRNA-Akt significantly enhanced 1,25D3-induced apoptosis as indicated by increased levels of Annexin V–positive cells and increased sub-G1 population and DNA fragmentation. In contrast, siRNA-ERK1/2 had no effects on 1,25D3-induced apoptosis. In addition, siRNA-Akt transfection followed by 1,25D3 treatment induced apoptosis much sooner than 1,25D3 alone. siRNA-Akt and 1,25D3 induced caspase-10 activation, suppressed the expression of c-IAP1 and XIAP, and promoted 1,25D3-induced caspase-3 activation. These results support a link between 1,25D3-induced nongenomic signaling and apoptosis. 1,25D3 induces the activation of phosphatidylinositol 3-kinase/Akt, which suppresses 1,25D3-mediated apoptosis and prolongs the survival of SCC cells. (Cancer Res 2006; 66(16): 8131-8)
Microsporidia, amitochondrial protists, possess a 70-kDa heat shock protein gene of mitochondrial evolutionary origin
Authors: E. Peyretaillade, V. Broussolle, P. Peyret, G. Metenier, M. Gouy, C. P. Vivares
Journal: Molecular Biology and Evolution (1998)

An intronless gene encoding a protein of 592 amino acid residues with similarity to 70-kDa heat shock proteins (HSP70s) has been cloned and sequenced from the amitochondrial protist Encephalitozoon cuniculi (phylum Microsporidia). Southern blot analyses show the presence of a single gene copy located on chromosome XI. The encoded protein exhibits an N-terminal hydrophobic leader sequence and two motifs shared by proteobacterial and mitochondrially expressed HSP70 homologs. Phylogenetic analysis using maximum likelihood and evolutionary distances place the E. cuniculi sequence in the cluster of mitochondrially expressed HSP70s, with a higher evolutionary rate than those of homologous sequences. Similar results were obtained after cloning a fragment of the homologous gene in the closely related species E. hellem. The presence of a nuclear targeting signal-like sequence supports a role of the Encephalitozoon HSP70 as a molecular chaperone of nuclear proteins. No evidence for cytosolic or endoplasmic reticulum forms of HSP70 was obtained through PCR amplification. These data suggest that Encephalitozoon species have evolved from an ancestor bearing mitochondria, which is in disagreement with the postulated presymbiotic origin of Microsporidia. The specific role and intracellular localization of the mitochondrial HSP70-like protein remain to be elucidated.
The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice
Authors: Mitsuyasu Iwasawa, Tsuyoshi Miyazaki, Yuichi Nagase, Toru Akiyama, Yuho Kadono, Masaki Nakamura, Yasushi Oshima, Tetsuro Yasui, Takumi Matsumoto, Takashi Nakamura, Shigeaki Kato, Lothar Hennighausen, Kozo Nakamura, Sakae Tanaka
Journal: Journal of Clinical Investigation (2009)

The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells — including osteoclasts, which are of hematopoietic origin — and other cellular processes remain unknown. Here we report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, we generated mice with osteoclast-specific conditional deletion of Bcl-x (referred to herein as Bcl-x cKO mice) by mating Bcl-xfl/fl mice with mice in which the gene encoding the Cre recombinase has been knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. Although the Bcl-x cKO mice grew normally with no apparent morphological abnormalities, they developed substantial osteopenia at 1 year of age, which was caused by increased bone resorption. Bcl-x deficiency increased the bone-resorbing activity of osteoclasts despite their high susceptibility to apoptosis, whereas Bcl-xL overexpression produced the opposite effect. In addition, Bcl-x cKO osteoclasts displayed increased c-Src activity, which was linked to increased levels of vitronectin and fibronectin expression. These results suggest that Bcl-xL attenuates osteoclastic bone-resorbing activity through the decreased production of ECM proteins, such as vitronectin and fibronectin, and thus provide evidence for what we believe to be a novel cellular function of Bcl-xL.
Mobility Impairment in Type 2 Diabetes
Authors: Rhonda Orr, Tracey Tsang, Paul Lam, Elizabeth Comino, Maria Fiatarone Singh
Journal: Diabetes Care (2006)

The increasing prevalence of type 2 diabetes is a major health concern. Reducing the vascular complications of diabetes has been a primary focus of treatment. However, the less-recognized complications of physical disability, cognitive impairment, and depression that impact on quality of life (QOL) are also important primary care considerations in older patients with diabetes.

Diabetes has been associated with a greater risk of decline in function and increased prospect of severe disability (1,2). Studies have sought to identify relationships or causal pathways between the syndromes of mobility, disability, and neuropsychological function in adults with type 2 diabetes (1,3). Few have simultaneously examined these factors potentially modifiable by physical activity (4) across multiple domains or at more than one point in time.

The dose of aerobic and resistance exercise necessary to achieve metabolic benefits in clinical trials has sometimes led to poor compliance (5). Older adults with diabetes, often characterized by long-term sedentariness, overweight/obesity, and multiple comorbidities, may demonstrate better adherence to a low-intensity, low-impact exercise, such as Tai Chi. Although Tai Chi has demonstrated improved balance, gait speed, muscle strength, cardiorespiratory fitness, and QOL in older adults (6–13), it has never been tested specifically in a diabetic cohort for benefits across multiple domains.

If Tai Chi was shown to be effective for mobility and other health outcomes relevant to this cohort, it may present a viable alternative exercise modality. The aim of this study was to examine the physiologic impairments associated …
Serum aspartate transaminase changes following open-heart surgery with ischaemic arrest (with and without coronary artery perfusion)
Authors: W. A. Littler, J. B. Meade, C. C. Evans, G. Davies
Journal: Thorax (1972)

Patients with aortic disease irrespective of whether they had coronary perfusion or not showed a significant difference in the level of postoperative SGOT levels compared with other groups. Aortics with coronary perfusion did not show a correlation between SGOT levels and total perfusion time while the other groups did. The levels were not of prognostic significance.