tbuckley/cabot-search huggingface dataset:
Reversible hypercapnia in acute exacerbations of chronic obstructive pulmonary disease (COPD)
Authors: E McNally, M Fitzpatrick, S Bourke, R Costello, WT McNicholas
Journal: European Respiratory Journal (1993)

We prospectively studied emergency hospitalizations due to acute exacerbations of chronic obstructive pulmonary disease (COPD) among 74 hypercapnic patients, in order to determine factors which predict reversal to normocapnia as a result of therapy. Clinical, arterial blood gas and pulmonary function data on presentation were compared to predischarge values among those 58 patients who survived the admission. Patients were divided into those who reverted to normocapnia (reversible, 40% of surviving patients), and those who remained hypercapnic (chronic, 60% of surviving patients). Reversible patients had higher admission arterial oxygen tension (PaO2) levels than those with chronic hypercapnia (6.4 +/- 1.3 kPa (mean +/- SD), as compared to 5.7 +/- 1.1 kPa) better pulmonary function (forced expiratory volume in one second (FEV1) 35 +/- 16% predicted, as compared to 26 +/- 7.9), and a lower prevalence of cor pulmonale (30% as compared to 63% of patients). No admission variable(s) distinguished individual patients as reversible or chronic hypercapnic, and, in particular, admission arterial carbon dioxide tension (PaCO2) and pH levels were similar in both groups. Furthermore, there were no differences between survivors and those 16 patients who died during the admission, apart from a higher urea level among those who died. These findings suggest that reversible patients have milder underlying disease than those with chronic hypercapnia. Our data establish the high prevalence of reversible hypercapnia among patients hospitalized with exacerbations of COPD, and, furthermore, indicate that patients who are normocapnic in the stable state can develop similar levels of hypercapnia during exacerbations as those with chronic hypercapnia.
Seventeen years after successful small bowel transplantation: long term graft acceptance without immune tolerance
Authors: F M Ruemmele, F Sauvat, V Colomb, M Jugie, D Jan, D Canioni, D Damotte, S Sarnacki, N Brousse, Y Revillon, O Goulet
Journal: Gut (2006)

The first attempts at small bowel transplantation (SBT) in humans were disappointing1–3 and characterised by severe graft rejection in spite of initially encouraging experience in animals.3–5 Major difficulties were encountered as: (1) the intestine is an immune organ harbouring most immune competent cells of the body; and (2) it is particularly vulnerable to ischaemia, not allowing time consuming HLA matching prior to transplantation (Tx). Therefore, Tx of intestinal allografts into fully immune competent recipients results almost inescapably in terminal graft rejection. With the introduction of tacrolimus in the 1990s, this difficulty was partially overcome, improving small bowel graft survival rates (70% at one year post Tx).6–8 However, on follow up, a large number of grafts are still lost, raising the question of long term success and benefit after SBT. Here we present the first patient with a 17 year follow up after isolated …
EFFECT OF AN INTERNALLY VERSUS EXTERNALLY FOCUSED ACL INJURY PREVENTION PROGRAM ON INJURY RISK
Authors: J Dallinga, A Benjaminse, A Gokeler, E Otten, K Lemmink
Journal: British Journal of Sports Medicine (2014)

Background Anterior cruciate ligament (ACL) injury prevention programs have shown mixed results, which may be in part due to suboptimal training components. Objective Determine effects of a prevention program with external and internal focus of attention on (potential) biomechanical risk factors for ACL injury. Design Pretest-posttest control group. Setting Laboratory and field. Participants 31 elite female soccer players participated. Exclusion criteria included previous ACL injury or current lower extremity injury. Intervention Two teams performed warm-up programs, including strength, agility, balance, plyometric, core and speed exercises twice a week for 12 weeks. One team received instructions to focus attention internally toward movements of the body (INT); another team received instructions to focus attention externally near the body (EXT). The control group (CON) performed their regular warming-up without specific instructions. Main outcome measurements Normalized external knee and ankle joint moments and joint angles on a two-legged jump-landing-rebound task. Results Results of 3x2 repeated measures ANOVA revealed significant group x time interaction for peak knee extension moment (F (2,23)=4.09, P=.03), the EXT group decreased more (–0.90±0.16 to −0.73±0.15 Nm/kg*m) than the CON group (P&lt;.05). Regarding knee flexion angle at peak varus-valgus, a significant interaction was observed (F (2,26)=3.95, P=.03), the INT group increased more (61.58±11.14 to 69.07±1.53°) than the EXT group (P=.08). Differences between groups were found for peak varus-valgus moment (F (2,26)=4.81, P=.02) and ankle flexion-extension moment (F (2,26)=6.40, P&lt;.01). No significant main effects for time were displayed. Conclusions External or internal focused instructions could be beneficial in improving landing technique, which is promising as an external focus of attention requires less time from coaches and has therefore great potential in ACL injury prevention.
Extrapulmonary small cell carcinoma: An indication for prophylactic cranial irradiation?
Authors: B. Kacsir, S. Ess, T. Cerny, L. Plasswilm, R. Rodriguez, M. Fruh
Journal: Journal of Clinical Oncology (2010)

e12040 Background: Extrapulmonary small cell carcinoma (EPSCC) accounts for 2.5-4% of small cell carcinomas. Information about disease presentation, prognosis and treatment is limited. Prophylactic cranial irradiation (PCI) has been adopted in small cell lung cancer (SCLC), but its role in EPSCC remains uncertain. Methods: We retrospectively analyzed all EPSCC at our Hospital between 1990 and 2009. Demographics, stage, therapy, response, recurrence patterns and survival were assessed. Results: Of 30 EPSCC 20% were mixed type carcinomas. Median age was 71years (32–80). Male/female ratio was 58%/42%. Seventeen (57%) had limited disease (LD), 13 (43%) extensive disease (ED). The majority were ex-/never-smokers (73%) in performance status (PS) 0-2 (83%). Location of primary: Gastrointestinal (8), unknown (6), gynaecological (6), urogenital (5) and ear nose throat (ENT) (5). Sites more likely to present as ED: Stomach (1), gall bladder (1), pancreas (1), colon (1) and anal canal (1). Primarily LD: ENT (5), rectal (2), bladder (3), endometrial (2), prostate (1), cervix (1), vagina (1) and breast (1). No patient presented with brain metastases. Four (13%) developed brain metastases (2 ED, 2 LD), including one isolated brain recurrence. Eighty-five percent of ED patients received first-line chemotherapy (CT). Response rate was 91%. Platinum/etoposide was most commonly used (64%). Most LD patients with resection only (5 out of 7) relapsed. Combination of CT and radiotherapy (RT) ± resection resulted in persistent remissions in 67% of LD patients (n = 6). Median survival was 16 months (1-108 months), 18 months (1-108 months) and 9 months (1-25 months) for LD+ED, LD and ED, respectively. Weight loss > 5 kg and PS 3+4 were significantly associated with worse survival (p < 0.001 and p < 0.01). Conclusions: In LD, resection alone results in frequent systemic relapse, but long term survivors exist. Best outcomes result from combined modality treatment including CT and RT. Prognosis is poor in ED with no long-term survivors. PCI should not be applied routinely, because brain metastases, - isolated ones in particular -, seem less frequent than in SCLC. No significant financial relationships to disclose.
Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria.
Authors: M H Holguin, L R Fredrick, N J Bernshaw, L A Wilcox, C J Parker
Journal: Journal of Clinical Investigation (1989)

The observation that type III erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to hemolysis initiated by activated cobra venom factor complexes (CoFBb), whereas normal erythrocytes are resistant, implies that the PNH III cells are deficient in a membrane constituent that regulates this process. To isolate the inhibitory factor from normal erythrocytes, membrane proteins were first extracted with butanol and then subjected to sequential anion exchange, hydroxylapatite, and hydrophobic chromatography. Analysis by SDS-PAGE and silver stain of the inhibitory fractions showed a single band corresponding to a protein with an apparent Mr of 18 kD. PNH erythrocytes were incubated with incremental concentrations of the radiolabeled protein and then washed. In a dose-dependent fashion, the protein incorporated into the cell membrane and inhibited CoFBb-initiated lysis. This protein inhibitor functioned by restricting the assembly of the membrane attack complex at the level of C7 and C8 incorporation. By using a monospecific antibody to block the function of the inhibitor, it was shown that normal erythrocytes are rendered susceptible to CoFBb-initiated hemolysis. Analysis by Western blot of membrane proteins revealed that PNH III erythrocytes are deficient in the 18-kD protein. By virtue of its molecular weight and inhibitory activity, the 18-kD protein appears to be discrete from other previously described erythrocyte membrane proteins that regulate complement. These studies also indicate that the susceptibility of PNH III erythrocytes to reactive lysis is causally related to a deficiency of the 18-kD membrane inhibitor.
SUPPRESSION OF IDIOTYPIC SPECIFICITIES IN ADULT MICE BY ADMINISTRATION OF ANTIIDIOTYPIC ANTIBODY
Authors: David A. Hart, Ai-Lan Wang, Laura L. Pawlak, Alfred Nisonoff
Journal: The Journal of Experimental Medicine (1972)

It has previously been shown that there are extensive idiotypic cross-reactions among antiphenylarsonate antibodies of A/J mice. The present work indicates that administration, into normal, adult A/J mice, of rabbit antiidiotypic antibody directed to A/J antiphenylarsonate antibody suppresses almost completely the subsequent production of antibody of the corresponding idiotype. No effect was noted on the formation of antibodies to the protein carrier or of antiphenylarsonate antibody of a different idiotype. The data are consistent with central suppression of production of the idiotypic antibody mediated through interaction with immunoglobulin receptors on lymphocytes.
Molecular Homology and Difference between Spontaneous Canine Mammary Cancer and Human Breast Cancer
Authors: Deli Liu, Huan Xiong, Angela E. Ellis, Nicole C. Northrup, Carlos O. Rodriguez, Ruth M. O'Regan, Stephen Dalton, Shaying Zhao
Journal: Cancer Research (2014)

Spontaneously occurring canine mammary cancer represents an excellent model of human breast cancer, but is greatly understudied. To better use this valuable resource, we performed whole-genome sequencing, whole-exome sequencing, RNA-seq, and/or high-density arrays on twelve canine mammary cancer cases, including seven simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, seem to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated and are abnormally enriched with active histone modification H4-acetylation, whereas aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the likelihood that canine simple carcinomas arise from genomic aberrations, whereas complex carcinomas originate from epigenomic alterations, reinforcing their unique value. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major cell lineage of the mammary gland. Canine simple carcinomas, which faithfully represent human breast carcinomas at the molecular level, provide indispensable models for basic and translational breast cancer research.
Phase I Trial of Nelarabine in Indolent Leukemias
Authors: Varsha Gandhi, Constantine Tam, Susan O'Brien, Roxanne C. Jewell, Carlos O. Rodriguez, Susan Lerner, William Plunkett, Michael J. Keating
Journal: Journal of Clinical Oncology (2008)

To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses.Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle.Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and nonresponders (50 micromol/L; range, 22 to 178 micromol/L; n = 15).Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.
The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram
Authors: Kiyotaka Matsuo, Masazumi Akahoshi, Eiji Nakashima, Akihiko Suyama, Shinji Seto, Motonobu Hayano, Katsusuke Yano
Journal: Journal of the American College of Cardiology (2001)
Effect of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects.
Authors: J C Pounsford, M J Birch, K B Saunders
Journal: Thorax (1985)

Coughing was induced in seven normal and eight asthmatic subjects by giving successive inhalations of citric acid aerosols of progressively higher concentration (range 0.5-32%). A baseline cough response was obtained on each of four experimental days, and there was no significant difference between days in this respect. Then the subjects received by inhalation either a bronchodilator (salbutamol 5 mg or ipratropium 1 mg) or placebo, in a paired double blind crossover design. A second citric acid run followed and was used for paired drug-placebo comparisons. In the asthmatic subjects the cough response was diminished by both bronchodilators (p less than 0.05), and the cough threshold was significantly higher after ipratropium but not salbutamol. In normal subjects no significant effects were found. Airways calibre was assessed, by an oscillatory technique that measures the resistance of the respiratory system (Siemens Siregnost FD 5), in four of the seven normal and all eight asthmatic subjects. The mean respiratory resistance was higher in asthmatic than in normal subjects, and fell significantly after both bronchodilators. In normal subjects smaller decreases in respiratory resistance occurred, significant only with salbutamol. The simplest hypothesis which explains the results relates change in cough response to altered neuroreceptor sensitivity associated with rapid changes in bronchial calibre.
Variables That Affect the Clinical Use and Abuse of Methylphenidate in the Treatment of ADHD
Authors: Nora D. Volkow, James M. Swanson
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), increases extracellular dopamine in the brain, which is associated with its reinforcing as well as its therapeutic effects. The authors evaluated variables that distinguish these two properties. METHOD: The brain imaging and clinical literatures were analyzed to identify variables that contribute to the abuse liability as well as to the clinical efficacy of methylphenidate. RESULTS: Four variables were identified. 1) Dose—there is a threshold for methylphenidate-induced dopamine increases to be perceived as reinforcing and to produce therapeutic effects. 2) Pharmacokinetics—the reinforcing effects of methylphenidate are associated with rapid changes in serum concentrations and presumably fast dopamine increases (as achieved with intravenous injection or insufflation), whereas the therapeutic effects are associated with slowly ascending serum concentrations and presumably smoothly rising dopamine levels (as achieved with oral administration). 3) Individual differences—sensitivity to methylphenidate varies across individuals and sets a threshold for blood and brain levels required for reinforcing effects (drug liking) and for therapeutic effects (symptom reduction). 4) Context—the effects of methylphenidate are modulated by different settings in abuse (rituals of self-administration and powerful conditioning) and in clinical use (external demands of low activity and focused attention). CONCLUSIONS: Reinforcing effects occur when methylphenidate elicits large and fast dopamine increases that mimic those of phasic dopamine cell firing, whereas therapeutic effects occur when methylphenidate elicits slow, steady-state dopamine increases that mimic those of tonic firing. Thus, the characteristics of clinical use (low doses administered orally and titrated for therapeutic effects) constrain methylphenidate’s abuse.
Role of angiotensin II in potassium-mediated stimulation of aldosterone secretion in the dog.
Authors: J H Pratt
Journal: Journal of Clinical Investigation (1982)

Potassium is known to enhance the aldosterone-stimulating action of angiotensin II. Such a synergistic interaction of potassium with angiotensin II could represent an action by angiotensin II to potentiate potassium as a stimulus. To examine for this effect of angiotensin II on potassium, plasma aldosterone levels were measured before and after an infusion of potassium chloride (15 meq i.v.) into dogs without and with prevention of angiotensin II formation by captopril, an angiotensin converting-enzyme inhibitor. In addition, responses to potassium were measured in a group of dogs receiving angiotensin II plus captopril. After potassium infusion, control dogs showed an increase of 7.7 +/- 1.9 (SEM) ng/dl (P less than 0.001) in the level of plasma aldosterone. In contrast, captopril-treated dogs showed no change in plasma aldosterone concentration in response to potassium. When angiotensin II was administered to captopril-treated dogs responsiveness to potassium administration was restored (plasma aldosterone concentration increased by 7.4 +/- 2.1 ng/dl, P less than 0.002). ACTH stimulated aldosterone secretion despite captopril treatment (P less than 0.001), however, ACTH produced a greater increase in the plasma aldosterone concentration in controls than in captopril-treated animals. It is evident from these results that stimulation of aldosterone secretion by potassium is considerably enhanced by angiotensin II. There appears to exist an important interdependence of these stimuli in the regulation of aldosterone secretion.
Aging, Progenitor Cell Exhaustion, and Atherosclerosis
Authors: Frederick M. Rauscher, Pascal J. Goldschmidt-Clermont, Bryce H. Davis, Tao Wang, David Gregg, Priya Ramaswami, Anne M. Pippen, Brian H. Annex, Chunming Dong, Doris A. Taylor
Journal: Circulation (2003)

Atherosclerosis is largely attributed to chronic vascular injury, as occurs with excess cholesterol; however, the effect of concomitant vascular aging remains unexplained. We hypothesize that the effect of time in atherosclerosis progression is related to obsolescence of endogenous progenitor cells that normally repair and rejuvenate the arteries.Here we show that chronic treatment with bone marrow-derived progenitor cells from young nonatherosclerotic ApoE-/- mice prevents atherosclerosis progression in ApoE-/- recipients despite persistent hypercholesterolemia. In contrast, treatment with bone marrow cells from older ApoE-/- mice with atherosclerosis is much less effective. Cells with vascular progenitor potential are decreased in the bone marrow of aging ApoE-/- mice, but cells injected from donor mice engraft on recipient arteries in areas at risk for atherosclerotic injury.Our data indicate that progressive progenitor cell deficits may contribute to the development of atherosclerosis.
Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?
Authors: Guillermo E. Umpierrez, Mary Korytkowski
Journal: Diabetes Care (2013)

Significant data suggest that overt hyperglycemia, either observed with or without a prior diagnosis of diabetes, contributes to an increase in mortality and morbidity in hospitalized patients. In this regard, goal-directed insulin therapy has remained as the standard of care for achieving and maintaining glycemic control in hospitalized patients with critical and noncritical illness. As such, protocols to assist in management of hyperglycemia in the inpatient setting have become commonplace in hospital settings. Clearly, insulin is a known entity, has been in clinical use for almost a century, and is effective. However, there are limitations to its use. Based on the observed mechanisms of action and efficacy, there has been a great interest in using incretin-based therapy with glucagon-like peptide-1 (GLP-1) receptor agonists instead of, or complementary to, an insulin-based approach to improve glycemic control in hospitalized, severely ill diabetic patients. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Drs. Schwartz and DeFronzo provide an opinion that now is the time to consider GLP-1 receptor agonists as a logical consideration for inpatient glycemic control. In the counterpoint narrative provided below, Drs. Umpierrez and Korytkowski provide a defense of insulin in the inpatient setting as the unquestioned gold standard for glycemic management in hospitalized settings. —William T. Cefalu, MD Editor in Chief, Diabetes Care