tbuckley/cabot-search huggingface dataset:
Pyruvate reverses fatty-acid-induced depression of ventricular function and calcium overload after hypothermia in guinea pig hearts
Authors: E Aasum
Journal: Cardiovascular Research (1997)

Objective: High levels of free fatty acids have been shown to impair mechanical recovery and calcium homeostasis of isolated rat hearts following hypothermic perfusion. The objective of the present study was to investigate whether inhibition of fatty acid oxidation through activation of pyruvate dehydrogenase by millimolar concentrations of pyruvate could influence functional recovery and Ca2+ homeostasis after a hypothermic insult. Methods: Ventricular function and myocardial calcium ([Ca]total) were measured in 3 different groups of Langendorff-perfused guinea pig hearts exposed to 40 min hypothermic (15°C) perfusion, followed by 30 min rewarming at 37°C. The hearts were perfused with either 11.1 mM glucose (G), glucose and 1.2 mM palmitate (GP), or glucose, palmitate and 5 mM pyruvate (GPP) as energy substrates. Results: All groups showed marked elevations in [Ca]total during hypothermia (from 0.6–0.7 μmol·g dry wt−1 to 9.3–12.2 μmol·g dry wt−1 at 40 min hypothermia, P<0.05), associated with a pronounced increase in left ventricular end-diastolic pressure (LVEDP from 0–2 to 50–60 mmHg). Following rewarming, GP-perfused hearts showed significantly lower recovery of mechanical function compared to both G- and GPP-perfused hearts (% recovery of left ventricular developed pressure: 27±8 vs. 62±3 and 62±8%, respectively, P<0.05). The reduced mechanical recovery of GP-perfused hearts was associated with elevated [Ca]total. In separate experiments we found that addition of 1.2 mM palmitate reduced glucose oxidation ([14C]glucose) from 1.77±0.28 μmol·min−1·g dry wt−1 (G-perfused hearts) to 0.15±0.04 μmol·min−1·g dry wt−1 (GP-perfused hearts, P<0.05), implying that fatty acids had become the major substrate for oxidative phosphorylation. Fatty acid oxidation was, however, less pronounced after further addition of 5 mM pyruvate. Thus, palmitate oxidation ([3H]palmitate) was more than 40% lower in GPP-perfused than in GP-perfused hearts (0.83±0.22 vs. 1.41±0.12 μmol·min−1·g dry wt−1, P<0.05). Conclusions: The present results demonstrate impaired ventricular function and calcium homeostasis after hypothermia in guinea pig hearts perfused with fatty acids in addition to glucose, as compared to hearts perfused with glucose alone. Furthermore, we show that these unfavourable effects of fatty acids can be overcome by an exogenous supply of pyruvate.
British Thoracic Society Paediatric Pneumonia Audit: a review of 3 years of data: Table 1
Authors: Sarah-Jane M Bowen, Anne H Thomson
Journal: Thorax (2013)

The British Thoracic Society (BTS) guidelines for the management of community-acquired pneumonia in children are used as the audit standard for the annual BTS Paediatric Pneumonia Audit. This report examines 3 years of data from this national audit, highlighting trends in clinical practice and the impact of the 2011 revisions to the BTS guidelines. The findings suggest an over-reliance on investigations to diagnose pneumonia and underuse of oral antibiotics, particularly amoxicillin. There is inappropriate use of chest physiotherapy, outpatient appointments and repeat chest x-rays. Increasing adherence to the BTS guidelines would improve care and also preserve valuable secondary care resources.
Expression Defect Size among Unclassified <i>MLH1</i> Variants Determines Pathogenicity in Lynch Syndrome Diagnosis
Authors: Inga Hinrichsen, Angela Brieger, Jörg Trojan, Stefan Zeuzem, Mef Nilbert, Guido Plotz
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Lynch syndrome is caused by a germline mutation in a mismatch repair gene, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants with unclear clinical significance. The functionality of these variants can be tested in the laboratory, but the results cannot be used for clinical diagnosis. We therefore aimed to establish a laboratory test that can be applied clinically. Experimental Design: We assessed the expression, stability, and mismatch repair activity of 38 MLH1 missense variants and determined the pathogenicity status of recurrent variants using clinical data. Results: Four recurrent variants were classified as neutral (K618A, H718Y, E578G, V716M) and three as pathogenic (A681T, L622H, P654L). All seven variants were proficient in mismatch repair but showed defects in expression. Quantitative PCR, pulse-chase, and thermal stability experiments confirmed decreases in protein stability, which were stronger in the pathogenic variants. The minimal cellular MLH1 concentration for mismatch repair was determined, which corroborated that strongly destabilized variants can cause repair deficiency. Loss of MLH1 tumor immunostaining is consistently reported in carriers of the pathogenic variants, showing the impact of this protein instability on these tumors. Conclusions: Expression defects are frequent among MLH1 missense variants, but only severe defects cause Lynch syndrome. The data obtained here enabled us to establish a threshold for distinguishing tolerable (clinically neutral) from pathogenic expression defects. This threshold allows the translation of laboratory results for uncertain MLH1 variants into pathogenicity statements for diagnosis, thereby improving the targeting of cancer prevention measures in affected families. Clin Cancer Res; 19(9); 2432–41. ©2013 AACR.
N<scp>UTRITIONAL</scp> I<scp>MPACT OF</scp> I<scp>NTESTINAL</scp> H<scp>ELMINTHIASIS</scp> D<scp>URING THE</scp> H<scp>UMAN</scp> L<scp>IFE</scp> C<scp>YCLE</scp>
Authors: D. W. T. Crompton, M. C. Nesheim
Journal: Annual Review of Nutrition (2002)

▪ Abstract Poor people in developing countries endure the burden of disease caused by four common species of soil-transmitted nematode that inhabit the gastrointestinal tract. Disease accompanying these infections is manifested mainly as nutritional disturbance, with the differing infections having their deleterious effects at different phases during the human life cycle. Reduced food intake, impaired digestion, malabsorption, and poor growth rate are frequently observed in children suffering from ascariasis and trichuriasis. Poor iron status and iron deficiency anemia are the hallmarks of hookworm disease. The course and outcome of pregnancy, growth, and development during childhood and the extent of worker productivity are diminished during hookworm disease. Less is known about the impact of these infections in children under 2 years of age. The severity of disease caused by soil-transmitted nematodes has consistently been found to depend on the number of worms present per person. Cost-effective measures based on highly efficacious anthelminthic drugs are now available to reduce and control disease caused by these infections.
Bone Quality — The Material and Structural Basis of Bone Strength and Fragility
Authors: Ego Seeman, Pierre D. Delmas
Journal: New England Journal of Medicine (2006)

This review discusses advances in knowledge regarding the composition and structure of bone, the modeling and remodeling of bone, the formation of bone during growth and its reconstruction in adults, and how age-related abnormalities in these processes compromise the composition and structure of bone.
Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo
Authors: G. Pozsgai, J. V. Bodkin, R. Graepel, S. Bevan, D. A. Andersson, S. D. Brain
Journal: Cardiovascular Research (2010)

The aim of the study is to investigate transient receptor potential ankyrin 1 (TRPA1)-induced responses in the vasculature and on blood pressure and heart rate (HR), in response to TRPA1 agonists using wild-type (WT) and TRPA1 knockout (KO) mice. TRPA1 agonists allyl isothiocyanate and cinnamaldehyde (CA) significantly increased blood flow in the skin of anaesthetized WT, but not in TRPA1 KO mice. CA also induced TRPA1-dependent relaxation of mesenteric arteries. Intravenously injected CA induced a transient hypotensive response accompanied by decreased HR that was, depending on genotype and dose, followed by a more sustained dose-dependent pressor response (10–320 µmol/kg). CA (80 µmol/kg) induced a depressor response that was significantly less in TRPA1 KO mice, with minimal pressor effects. The pressor response of a higher CA dose (320 µmol/kg) was observed in WT but not in TRPA1 KO mice, indicating involvement of TRPA1. Experiments using TRP vanilloid 1 (TRPV1) KO and calcitonin gene-related peptide (CGRP) KO mice provided little evidence for the involvement of TRPV1 or CGRP, nor did blocking substance P receptors affect responses. However, the cholinergic antagonist atropine sulphate (5 mg/kg) significantly inhibited the depressor response and slowed HR with CA (80 µmol/kg), but had no effect on pressor responses. The pressor response remained unaffected, even in the presence of the ganglion blocker hexamethonium bromide (1 mg/kg). The α-adrenergic blocker prazosin hydrochloride (1 mg/kg) significantly inhibited both components, but not slowed HR. TRPA1 is involved in mediating vasodilation. TRPA1 can also influence changes in blood pressure of possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders.
Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure
Authors: John J.V. McMurray, Milton Packer, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael R. Zile
Journal: New England Journal of Medicine (2014)

We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
Thrombosis in Patients with the Lupus Anticoagulant
Authors: JOHN R. MUEH
Journal: Annals of Internal Medicine (1980)

A retrospective study was carried out to determine the frequency of thrombosis in patients with the lupus anticoagulant. Thirty-five patients fulfilled laboratory criteria for the diagnosis of the lupus anticoagulant. Eight of these patients had evidence of clinically significant thrombosis while their plasma showed a prolonged partial thromboplastin time due to the anticoagulant. Four of the patients with thrombosis had concurrent autoimmune disease and three other patients were receiving phenothiazine medication. Moderate thrombocytopenia was noted in four patients with thrombosis. None of the patients with the lupus anticoagulant bled abnormally. This study suggests that patients with the lupus anticoagulant may be at increased risk of thrombosis.
An Analytical Review of Spontaneous Haemopneumothorax
Authors: R. J. Calvert, E. Smith
Journal: Thorax (1955)

In 1900 Newton Pitt wrote, " There is no refer- ence to spontaneous haemopneumothorax in the Index Catalogue of the U.S. Library, nor is it dis- cussed in any of the standard treatises on medicine, in either English, French, or German."It has remained little discussed even in specialized text- books although about 150 cases, including the present three, have been recorded.Both spon- taneous haemopneumothorax and spontaneous.haemothorax are complications of spontaneous pneumothorax, of which careful follow-up (Kjaer- gaard, 1932; Perry, 1939) has failed to reveal any correlation with tuberculosis.It is also probable that spontaneous haemothorax may at times have no coexistent or immediately antecedent spon- taneous pneumothorax.Both Pitt (1900) and Rolleston (1900) realized that spontaneous haemopneumothorax was poten- tially serious.Each reported a fatal case.Note- worthy contributions to this subject include those of Hyde and Hyde (1951) with 12 case reports, Ross (1952) with six, Louria (1938) with five,
Two N-Terminal Domains of Kv4 K+ Channels Regulate Binding to and Modulation by KChIP1
Authors: Robert H Scannevin, KeWei Wang, Flora Jow, Jennifer Megules, David C Kopsco, Wade Edris, Karen C Carroll, Qiang Lü, Weixin Xu, Zhangbao Xu, Alan H Katz, Stephane Olland, Laura Lin, Meggin Taylor, Mark Stahl, Karl Malakian, Will Somers, Lydia Mosyak, Mark R Bowlby, Pranab Chanda, Kenneth J Rhodes
Journal: Neuron (2004)
Pharmacology of Calcium Channels and Smooth Muscle
Authors: L Hurwitz
Journal: The Annual Review of Pharmacology and Toxicology (1986)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Risk factors of time to sputum smear conversion in multi-drugs resistant tuberculosis patients in Iran
Authors: Parvaneh Baghaei Shiva, Majid Marjani, Payam Tabarsi, Mohammad Reza Masjedi
Journal: European Respiratory Journal (2012)

Objectives: Treatment of multidrug resistant tuberculosis is difficult and expensive. Sputum conversion is a proper monitoring tool in treatment of these patients. Also reducing the time of conversion is an important infection control measure. This study was performed to evaluate the time and predictors of sputum conversion in the pulmonary MDR-TB patients.  Methods: During 2003-2011, all patients with documented MDR-TB in referral center, Tehran, Iran, were recruited. All patients received standard treatment consisted of Ofloxacin, Prothionamide, Amikacin and Cycloserine. All demographic and characteristic factors were studied. Time of sputum conversion was evaluated to predictors by conducting survival analysis (using a Cox proportional hazards model).  Results: Of 298 recruited MDR-TB patients, 171 patients were male and 178 patients were Iranian. The median age was 41years. 60% of patients had the history of TB treatment. The median time to sputum conversion was 51 days. Diabetes mellitus, co-disease, adverse drugs reaction and male sex delayed sputum conversion.  Conclusion: Most MDR-TB patients achieved sputum smear conversion within 51 days. DM, adverse effects, male gender and co-disease were predictors of delay conversion.
EFFECT OF ENZYME INHIBITORS AND ACTIVATORS ON THE MULTIPLICATION OF TYPHUS RICKETTSIAE
Authors: Donald Greiff, Henry Pinkerton, Vicente Moragues
Journal: The Journal of Experimental Medicine (1944)

By injection into typhus-infected yolk sacs, a number of agents were tested for possible inhibition or acceleration of rickettsial growth. The previously reported rickettsiostatic activity of penicillin was further confirmed. Para-aminobenzoic acid, in single injections of 6.6 mg. and 3.3 mg. giving initial concentrations of approximately 1:6000 and 1:12,000 was found to have rickettsiostatic activity approximately equal to that of penicillin. No conclusion could be drawn regarding the possibility of a synergistic action of para-aminobenzoic acid and penicillin. Para-aminobenzoic acid neutralized with sodium hydroxide was found to be as effective as the acid itself, when given in single injections of 6.6 mg. Sodium benzoate, as Well as the ortho and meta forms of aminobenzoic acid were found to be ineffective when given in similar amounts. Para-aminobenzoic acid, when added to the food in a concentration of 3 per cent, was shown to have a remarkably effective chemotherapeutic action on murine typhus infection in mice. Sodium fluoride was found at times to accelerate the growth of rickettsiae in the yolk sac, and to cause heavy infection under conditions such that the controls showed practically no multiplication of the organism. When rickettsiostatic substances (penicillin and para-aminobenzoic acid) were combined with sodium fluoride, their rickettsiostatic activity was not demonstrably changed. Other agents studied and found not to affect rickettsial multiplication are listed. The possible mechanisms involved in the observed inhibition and stimulation of rickettsial growth under these conditions are discussed.
Clinical Determinants of Ventricular Sympathetic Reinnervation After Orthotopic Heart Transplantation
Authors: Frank M. Bengel, Peter Ueberfuhr, Thomas Hesse, Nina Schiepel, Sibylle I. Ziegler, Siegfried Scholz, Stephan G. Nekolla, Bruno Reichart, Markus Schwaiger
Journal: Circulation (2002)

It has been demonstrated that ventricular sympathetic reinnervation after cardiac transplantation improves exercise performance. The extent of reinnervation increases with time but is variable. Little is known about other influencing factors.Seventy-seven nonrejecting transplant recipients were cross-sectionally studied by PET with the catecholamine analogue C-11 hydroxyephedrine at 4.8+/-3.5 years after transplantation. Results were compared with history-derived parameters related to recipient's clinical course before, during, and after surgery; donor characteristics; and immunogenetics. Partial reinnervation was observed in 52 patients (extent, 21+/-16% of left ventricle). Complete denervation was found in 25 patients at various times after transplantation. Reinnervation extent correlated with time after surgery (r=0.387; P<0.001) but also inversely with donor age (r=-0.309, P=0.006) and recipient age (r=-0.243, P=0.032). Maximal hydroxyephedrine retention correlated inversely with frequency of rejection episodes (r=-0.267, P=0.019), was reduced when aortic complications occurred perioperatively (9 patients), and correlated inversely with aortic cross-clamp time (r=-0.331, P=0.006). Other parameters were not associated with reinnervation. Patients were surveyed for clinical complications over >12 months after PET (until 7.3+/-4.2 years after transplantation), but significant effects of reinnervation on outcome were not observed.The present data suggest that sympathetic reinnervation after cardiac transplantation is not simply a function of time. Reinnervation is more likely with young age, fast and uncomplicated surgery, and low rejection frequency. Despite few effects on prognosis in otherwise healthy recipients, improved understanding of clinical determinants may contribute to enhance allograft reinnervation and thereby augment exercise capacity in the future.
Interaction of the chemoreflex and the pulmonary inflation reflex in the regulation of coronary circulation in conscious dogs.
Authors: S F Vatner, R J McRitchie
Journal: Circulation Research (1975)

The interaction of chemoreflex and pulmonary inflation reflex control of the coronary circulation was examined in conscious dogs by comparing the responses to chemoreflex stimulation (intracarotid injection of nicotine) when ventilation was allowed to increase with those when ventilation was controlled. The responses were also compared with those elicited by both forced mechanical and spontaneous hyperinflation. When the heart rate was constant, intracarotidly administered nicotine induced an increase in the depth of respiration followed closely by an increase in late diastolic coronary flow from 48 +/- 2 to 106 +/- 8 ml/min and a reduction in late diastolic coronary resistance from 1.62 +/- 0.08 to 0.78 +/- 0.06 mm Hg/ml min-1. After beta-receptor and cholinergic blockade, a similar coronary dilation in response to nicotine occurred only when ventilation was allowed to increase. However, when ventilation was controlled, intracarotidly administered nicotine increased coronary resistance after combined beta-receptor and cholinergic blockade. The reflex coronary dilation was not observed after carotid sinus nerve section or after alpha-receptor blockade. Thus, nicotine stimulation of the carotid chemoreflex results in a striking coronary dilation that has two components. The minor component involves a chemoreflex with its efferent pathway in tthe vagi. The major component of coronary dilation follows an increase in the depth of respiration, and its efferent component appears to involve withdrawal of alpha-adrenergic constrictor tone. An almost identical period of reflex coronary dilation followed either forced mechanical or spontaneous hyperinflation in the conscious dog.
A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life
Authors: Yik Andy Yeung, Xiumin Wu, Arthur E. Reyes, Jean-Michel Vernes, Samantha Lien, John Lowe, Mauricio Maia, William F. Forrest, Y. Gloria Meng, Lisa A. Damico, Napoleone Ferrara, Henry B. Lowman
Journal: Cancer Research (2010)

Abstract Bevacizumab [Avastin; anti–vascular endothelial growth factor (VEGF) antibody] is an antiangiogenic IgG approved for treating patients with certain types of colon, breast, and lung cancer. In these indications, bevacizumab is administered every 2 to 3 weeks, prompting us to study ways to reduce the frequency of administration. Increasing affinity to neonatal Fc receptor (FcRn) may extend the pharmacokinetic half-life of an antibody, but the quantitative effect of FcRn affinity on clearance has not been clearly elucidated. To gain further insight into this relationship, we engineered a series of anti-VEGF antibody variants with minimal amino acid substitutions and showed a range of half-life improvements in primates. These results suggest that, if proven clinically safe and effective, a modified version of bevacizumab could potentially provide clinical benefit to patients on long-term anti-VEGF therapy through less-frequent dosing and improved compliance with drug therapy. Moreover, despite having half-life similar to that of wild-type in mice due to the species-specific FcRn binding effects, the variant T307Q/N434A exhibited superior in vivo potency in slowing the growth of certain human tumor lines in mouse xenograft models. These results further suggest that FcRn variants may achieve increased potency through unidentified mechanisms in addition to increased systemic exposure. Cancer Res; 70(8); 3269–77. ©2010 AACR.