tbuckley/cabot-search huggingface dataset:
The pH of spontaneously beating cultured rat heart cells is regulated by an ATP-calmodulin-dependent Na+/H+ antiport.
Authors: P L Weissberg, P J Little, E J Cragoe, A Bobik
Journal: Circulation Research (1989)

We investigated the mechanisms by which spontaneously beating cultured rat ventricular cells regulate intracellular pH (pHi). Specifically, the relative contributions of the Na+/H+ antiport, Cl-/HCO3- exchange, ATP, and calmodulin-dependent processes in regulating the pHi of cells loaded with the intracellular fluorescent pH indicator BCECF were investigated. The pHi of ventricular cells bathed in HEPES-buffered medium averaged 7.30 +/- 0.02. Subsequent exposure of the cells to CO2-HCO3- -buffered medium resulted in intracellular acidification followed by recovery to pHi levels approximately 0.1 pH units lower than in controls. Recovery was inhibited by the Na+/H+ antiport inhibitor 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The recovery from intracellular acidification, induced by a 15-mM ammonium chloride prepulse, was also dependent solely upon activation of the Na+/H+ antiport. Recovery was dependent upon extracellular sodium, was completely inhibited by EIPA, and could be modulated by changes in extracellular pH (pHo). At low pHo values (6.3) the recovery of pHi was greatly attenuated, while at high pHo (8.0) the recovery process was accelerated. The final pHi to which the cells recovered was also dependent upon pHo. Preincubation of the cells with 2-deoxy-D-glucose to deplete cellular ATP levels reduced pHi by approximately 0.2 pH units and greatly impaired the cells' ability to recover from 15-mM ammonium chloride-induced acid load. Similarly, preincubation of cells with the calmodulin inhibitors W-7 and trifluoperazine also impaired their ability to recover from the acid load. The Cl- -HCO3- exchange played no role in the cells' ability to recover from intracellular acidosis. However, the presence of HCO3- significantly increased the resistance of myocardial cells to changes in pHi by approximately doubling their buffer capacity. These results demonstrated that a Na+/H+ antiport is the major pHi-regulating system in spontaneously beating rat ventricular cells. The ability of the Na+/H+ antiport to regulate myocardial pHi is dependent upon the cells' ability to maintain adequate levels of ATP. The antiport's dependency on ATP, in conjunction with its dependency on calmodulin, suggests that activation of the antiport in ventricular cells involves phosphorylation processes.
Lower oesophageal sphincter hypersensitivity to opioid receptor stimulation in patients with idiopathic achalasia.
Authors: R Penagini, B Bartesaghi, P Zannini, G Negri, P A Bianchi
Journal: Gut (1993)

Impairment of non-cholinergic innervation of the lower oesophageal sphincter has been suggested in idiopathic achalasia. As opioid nerves are present in the lower oesophageal sphincter and opioid peptides affect lower oesophageal sphincter motility, the effect of an opioid agonist, morphine (100 micrograms/kg iv), and an opioid blocker, naloxone (80 micrograms/kg iv), on lower oesophageal sphincter motor function was assessed in 10 healthy subjects and in 10 patients with untreated idiopathic achalasia on separate days and in randomised order. In addition, in six of the patients, naloxone 0.8 mg iv was injected 60 minutes after morphine and recordings continued for a further five minutes. Lower oesophageal sphincter pressure was monitored by a sleeve device. In the healthy subjects morphine decreased (p &lt; 0.01) resting lower oesophageal sphincter pressure by 4 (1) mm Hg (23 (8)%). In the achalasia patients the effect was more marked, lower oesophageal sphincter pressure being reduced (p &lt; 0.01) by 11 (2) mm Hg (46 (8)%). Naloxone reversed lower oesophageal sphincter pressure to basal. Both absolute and percentage decreases after morphine were significantly greater (p &lt; 0.05) in the achalasia patients than in the healthy subjects. Swallow induced lower oesophageal sphincter relaxation was significantly decreased (p &lt; 0.05) by morphine in the healthy subjects but not in the achalasia patients. Naloxone had no effect on resting lower oesophageal sphincter pressure or swallow induced relaxation in either healthy subjects or achalasia patients. In conclusion achalasia patients are hypersensitive to the effect of morphine on resting lower oesophageal sphincter pressure. This finding is unlikely to be the result of a denervation process involving opioid nerves.
Excess Iodine from an Unexpected Source
Authors: Seth M. Arum, Xuemei He, Lewis E. Braverman
Journal: New England Journal of Medicine (2009)

Although embryonal carcinomas express little or no retinoblastoma protein (pRB), 3 mature teratomas express high levels of pRB.Normally, cyclindependent kinase 4/6 (CDK4/6) stimulates cell growth by phosphorylating pRB.The development of selective CDK inhibitors, 4 including PD0332991 (Pfizer), which selectively inhibits CDK4/6, suggests a new treatment for growing teratoma syndrome.We report on the clinical course of three men, 22 to 37 years of age, with growing teratoma syndrome who were treated in a phase 1 trial of PD0332991 for refractory solid tumors (ClinicalTrials.govnumber, NCT00141297). 5This trial was sponsored and funded by Pfizer.The patients initially presented with metastatic nonseminomatous germ-cell tumors.They received four cycles of cisplatin-based chemotherapy, with normalization of serum tumor markers.Each patient underwent two or more operations for growing teratoma syndrome after chemotherapy.Subsequently, progressive disease that was not amenable to further surgery developed in all the patients.Written informed consent was obtained from the patients in this protocol, which was approved by the institutional review board of the University of Pennsylvania.There was a strong nuclear expression of pRB in the epithelial component of the teratomas in all three patients (Fig. 1A, 1B, and 1C).At enrollment, all patients had radiologic evidence of disease progression (Fig. 1D).Patient 1 received oral PD0332991, 150 mg daily, for 21 days on an every-28-days cycle.The dose was decreased to 100 mg because of neutropenia.He had stable disease for 18 months.Patient 2 initiated treatment with PD0332991, 200 mg daily, for 14 days on an every-21-days cycle.The dose was decreased to 150 mg because of headaches and vomiting.Neutropenia also developed.He had a partial response (according to the Response Evaluation Criteria in Solid Tumors) for 22 months and continued to receive treatment.Patient 3 initiated treatment with PD0332991 at a dose of 125 mg daily for 21 days on an every-28-days cycle.He also had neutropenia.He had stable disease for 24 months and continued to receive treatment.These preliminary data suggest that PD0332991 has therapeutic benefit in patients with growing teratoma syndrome in whom the tumor is inoperable.We suggest further evaluation of CDK inhibitors in pRB-expressing teratomas.
UK doctors' body criticises plans for patient feedback
Authors: R. Coombes
Journal: BMJ (2009)

The Medical Protection Society has criticised government plans to encourage patients to post feedback about their GP on a publicly funded health website.

NHS Choices (www.nhs.uk), a multimillion pound government website, already allows patients to rate hospitals. 

Stephanie Brown, director of policy and communications at the Medical Protection Society, a non-profit making organisation that provides legal advice to healthcare professionals, said the plan to extend the NHS Choices service to primary care could lead to “extremely inappropriate” comments being posted online about individual GPs, remarks which may unfairly reflect on a doctor’s clinical competence.

“Patients base their judgments of doctor’s ability on many …
STUDIES ON IMMUNITY IN A TYPE OF HUMAN ALLERGY (HAY FEVER): SEROLOGIC RESPONSE OF NON-SENSITIVE INDIVIDUALS TO POLLEN INJECTIONS
Authors: Robert A. Cooke, Mary Loveless, Arthur Stull
Journal: The Journal of Experimental Medicine (1937)

Large injections of ragweed pollen extract into normal non-sensitive volunteers did not produce a sensitization to ragweed. Group 1 volunteers in whose skin many reactions were induced by injections of ragweed extract mixed with ragweed sensitive serum failed to show any serological changes. The theory that the immune substance found in the serum of treated ragweed sensitive cases was due to the reaction or to some substance created by it and not to the ragweed per se was not upheld. On the contrary in group 2, volunteers who received larger amounts of ragweed but no sensitive serum, serological changes were induced resembling those previously observed to occur in ragweed sensitive patients after treatment. They were demonstrable by an inhibition of the immediate reaction and by interference with the neutralization of sensitive serum by its antigen. These serological changes are therefore independent of the specific reaction characteristic of this type of allergy. The inhibiting factor was found to be related to the pseudoglobulin fraction of the serum and was shown to be specific.
Steroid sparing effects of intranasal corticosteroids in asthma and allergic rhinitis
Authors: A. Nair, S. Vaidyanathan, K. Clearie, P. Williamson, K. Meldrum, B. J. Lipworth
Journal: Allergy (2009)

Treating allergic rhinitis may have a downstream anti-inflammatory effect on the lower airways. We conducted a dose ranging study in asthma and persistent allergic rhinitis to evaluate if intranasal corticosteroids exhibit a sparing effect on the dose of inhaled corticosteroid.Twenty five participants were randomized to receive two weeks of 100 microg/day (Low dose) or 500 microg/day (High dose) of inhaled fluticasone propionate both with intranasal placebo; or inhaled fluticasone 100 microg/day with intranasal fluticasone 200 microg/day (Combined) in a double-blind cross-over fashion.Low dose fluticasone produced a shift of 1.20 doubling-dilutions (95% CI, 0.63, 1.77); Combined fluticasone, 1.79 doubling-dilutions (95% CI, 0.77, 2.80) and high dose fluticasone, 2.01 doubling-dilutions (95% CI, 1.42, 2.61) in methacholine PC(20) from respective baselines. There was a significant difference between high and low doses: 0.82 doubling dilutions (95%CI, 0.12, 1.50) but not between combined and low dose 0.58 doubling dilutions (95% CI, -0.78, 1.95). Combined treatment alone produced improvements in peak nasal inspiratory flow (P < 0.001), rhinitis quality of life (P = 0.004) and nasal NO (P = 0.01); reduced blood eosinophil count (P = 0.03), and serum eosinophil cationic protein (P = 0.02). All treatments significantly improved tidal NO, FEV(1) and asthma quality of life.High-dose fluticasone was superior to low dose fluticasone for methacholine PC20, demonstrating room for further improvement. Combined treatment was not significantly different from low dose fluticasone and we could not demonstrate a steroid sparing effect on methacholine PC20. Combined treatment alone produced improvements in upper airway outcomes and suppressed systemic inflammation but not adrenal function.
Comparison of residential and nursing home care before and after the 1993 community care policy
Authors: V. L S Crawford, T R O Beringer, R W Stout
Journal: BMJ (1999)

The NHS and Community Care Act 1990 moved responsibility for supplementing those in residential and nursing home care from social security to local authorities and was accompanied by a transfer of funds.1 This system was implemented on 1 April 1993 with the aim that care should be provided and funded in accordance with the person's need for care.

For the first time the level of dependency and need would influence financial support for admission to an institutional care facility. If the aim was achieved and care is now better targeted a clearer differentiation in levels of dependency between residential and nursing care would be expected after 1 April 1993, with a higher level of dependency in nursing homes.

View this table:

Mean (SE) scores for each measure of dependency by type of care and period of admission. Increasing dependency is indicated by increase in physical dependency or behavioural rating score or decrease in abbreviated mental score, Barthel index, information or …
Protease nexin-2/amyloid beta protein precursor. A tight-binding inhibitor of coagulation factor IXa.
Authors: A H Schmaier, L D Dahl, A J Rozemuller, R A Roos, S L Wagner, R Chung, W E Van Nostrand
Journal: Journal of Clinical Investigation (1993)

Protease nexin-2/amyloid 6 protein precursor (PN-2/A#PP) is an abundant, secreted platelet protein which is a potent inhibi- tor of coagulation Factor XIa.We examined other potential anticoagulant activities of PN-2/Ai8PP.Purified Kunitz pro- tease inhibitor domain of PN-2/A8PP and PN-2/ABPP itself were found to prolong the coagulation time of plasma and pure Factor IXa.The Kunitz protease inhibitor domain also inhib- ited the ability of Factor IXa to activate Factor X. PN-2/AAPP inhibited Factor IXa with a K1 of 7.9 to 3.9 X 10-1 M in the absence and presence of heparin, respectively.When the sec- ond-order rate constant of PN-2/AO8PP's inhibition of Factor IXa (2.7 X 108 M-'min-') was compared to that of antithrom- bin III (3.8 X 106 M-'min-'), PN-2/AfiPP was at least a 71-fold more potent inhibitor of Factor IXa than antithrombin III.PN-2/AfiPP formed a complex with Factor IXa as de- tected by gel filtration and ELISA.The finding that PN-2/ AfiPP is a potent inhibitor of Factor IXa could help to explain the spontaneous intracerebral hemorrhages seen in patients with hereditary cerebral hemorrhage with amyloidosis Dutch- type where there is an extensive accumulation of PN-2 /A46PP in their cerebral blood vessels.
Compensatory Change of Interacting Amino Acids in the Coevolution of Transcriptional Coactivator MBF1 and TATA-Box–Binding Protein
Authors: Qing-Xin Liu, Naomi Nakashima-Kamimura, Kazuho Ikeo, Susumu Hirose, Takashi Gojobori
Journal: Molecular Biology and Evolution (2007)

To elucidate the transcriptional regulation in eukaryotic genome network, it is important to understand coevolution of transcription factors, transcriptional coactivators, and TATA-box–binding protein (TBP). In this study, coevolution of transcriptional coactivator multiprotein-bridging factor 1 and its interacting target TBP was first evaluated experimentally by examining if compensatory amino acid changes took place at interacting sites of both proteins. The experiments were conducted by identifying interaction sites and comparing the amino acids at these sites among different organisms. Here, we provide evidence for compensatory changes of transcription coactivator and its interacting target, presenting the 1st report that transcription coactivator may have undergone coevolution with TBP.
Expression of IP-10 and its receptor CXCR3 in hepatic stellate cells identifies a novel autocrine and paracrine system
Authors: A. Bonacchi, P. Romagnani, R.G. Romanelli, E. Efsen, G. Galli, F. Annunziato, C. Mavilia, E. Laffi, P. Gentilini, F. Marra
Journal: Journal of Hepatology (2000)
SPOROTRICHOSIS IN AMERICA
Authors: RICHARD L. SUTTON
Journal: JAMA (1910)

Since the publication of my recent article on sporotrichosis,<sup>1</sup>I have received communications from several physicians regarding similar cases which they have encountered in their work. Although cultures were made in only a few instances, the clinical manifestations in the majority of the cases were such that there can be little doubt regarding the nature of the causative agent. Four other American cases have been reported since my article was written, one by Stelwagon,<sup>2</sup>one by Pusey,<sup>3</sup>and one by Hyde and Davis<sup>4</sup>(who refer to a third Chicago case under the care of Dr. Zuraski). Pusey has suggested that the affection probably occurs much more frequently than statistics would indicate, and my experience certainly tends to prove the correctness of this supposition. The lesions often resemble those of tertiary lues, and as they heal promptly under antisyphilitic treatment it is very probable that many cases
Movement of criticall ill patients within hospital.
Authors: G Waddell
Journal: BMJ (1975)

Critically ill patients were observed during routine movement inside the hospital to and from the intensive therapy unit. One patient a month suffered major cardiorespiratory collapse or death as a direct result of movement. Renewed bleeding of a pelvic fracture, cardiac arrhythmia, cardiac embarrassment due to a haemothorax, and cardiovascular decompensation were seen. It was difficult to continue treatment during movement, especially maintaining an airway or providing adequate intermittent positive pressure ventilation. Seventy postoperative patients suffered few ill effects on being moved. Greater awareness of the dangers of moving critically ill patients within hospital is needed. Thorough preparation for the move and adequate maintenance of treatment during movement requires the skill of experienced medical staff.
Corrective GUSB Transfer to the Canine Mucopolysaccharidosis VII Brain
Authors: Aurelie Cubizolle, Nicolas Serratrice, Nadia Skander, Marie-Anne Colle, Sandy Ibanes, Aurelie Gennetier, Neus Bayo-Puxan, Khalil Mazouni, Franck Mennechet, Beatrice Joussemet, Yan Cherel, Yaouen Lajat, Charles Vite, Florence Bernex, Vasiliki Kalatzis, Mark E Haskins, Eric J Kremer
Journal: Molecular Therapy (2013)

Severe deficiency in lysosomal β-glucuronidase (β-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in β-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the first study attempting the correction of the >200-fold larger and challenging canine MPS VII brain. Here, the efficacy of a helper-dependent (HD) canine adenovirus (CAV-2) vector harboring a human GUSB expression cassette (HD-RIGIE) in the MPS VII dog brain was tested. Vector genomes, β-glu activity, GAG content, lysosome morphology and neuropathology were analyzed and quantified. Our data demonstrated that CAV-2 vectors preferentially transduced neurons and axonal retrograde transport from the injection site to efferent regions was efficient. HD-RIGIE injections, associated with mild and transient immunosuppression, corrected neuropathology in injected and noninjected structures throughout the cerebrum. These data support the clinical evaluation of HD CAV-2 vectors to treat the neurological defects associated with MPS VII and possibly other neuropathic lysosomal storage diseases.
In Vitro and In Vivo Inhibition of Neuroblastoma Tumor Cell Growth by AKT Inhibitor Perifosine
Authors: Z. Li, F. Tan, D. J. Liewehr, S. M. Steinberg, C. J. Thiele
Journal: JNCI Journal of the National Cancer Institute (2010)

Activated AKT is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. The aim of this study was to investigate the effect of perifosine, a nontoxic AKT inhibitor, as a single agent on NB cell growth in vitro and in vivo. Four human NB cell lines (AS, NGP, BE2, and KCNR) were treated with increasing concentrations of perifosine, and a quantitative analysis of cell death (apoptosis) was performed by using MTS and caspase-3/7 activity assays. Survival of mice carrying xenograft NB tumors that were treated with perifosine (n = 6–7 mice per group) was compared with that of untreated mice (n = 7 mice per group) using Kaplan–Meier analysis. Tumor volumes were calculated to determine the effect of perifosine on NB tumor growth. Phosphorylation of AKT and expression of cleaved caspase-3 were measured in proteins from the tumors. All statistical tests were two-sided. Perifosine, at 30 μM concentration, decreased AKT phosphorylation and increased apoptosis in all four NB cell lines in vitro. Perifosine-treated mice bearing xenograft NB tumors had longer survival than untreated mice (untreated vs treated, median survival: AS, 13 days, 95% confidence interval [CI] = 11 to 16 days vs not reached, P = .003; NGP, 22 days, 95% CI = 20 to 26 days vs not reached, P = .013; BE2, 24 days, 95% CI = 21 to 27 days vs not reached, P < .001; and KCNR, 18 days, 95% CI = 18 to 21 days vs not reached, P < .001). Perifosine treatment induced regression in AS tumors, growth inhibition in BE2 tumors, and slower growth in NGP and KCNR tumors. Inhibition of AKT phosphorylation and induction of caspase-dependent apoptosis were noted in tumors of perifosine-treated mice in all four in vivo NB tumor models. Perifosine inhibited the activation of AKT and was an effective cytotoxic agent in NB cells in vitro and in vivo. Our study supports the future clinical evaluation of perifosine for the treatment of NB tumors.
Leukocyte adhesion-deficient neutrophils fail to amplify phagocytic function in response to stimulation. Evidence for CD11b/CD18-dependent and -independent mechanisms of phagocytosis.
Authors: H D Gresham, I L Graham, D C Anderson, E J Brown
Journal: Journal of Clinical Investigation (1991)

Stimulation of PMN with inflammatory mediators markedly augments Fc and CR1 receptor-mediated ingestion. However, CD11/CD18-deficient PMN from three patients with complete leukocyte adhesion deficiency (LAD) failed to recruit phagocytic function in response to phorbol esters, cytokine, or Arg-Gly-Asp-containing ligand stimulation. Because stimulated ingestion is protein kinase C (PKC)-dependent, our data indicate that LAD PMN exhibit only PKC-independent phagocytosis. The defect in PKC-dependent ingestion is specific for CD11b/CD18 and not secondary to the chronic or recurrent infections which occur in this disease. The LAD phenotype for phagocytic function can be reproduced in normal PMN by the anti-CD11b MAbs OKM1 and OKM10. In contrast, MAb Mo1 (anti-CD11b) and MAb IB4 (anti-CD18) inhibit both CD11b/CD18-dependent and -independent mechanisms of ingestion by normal PMN. Their ability to inhibit CD11b/CD18-independent ingestion may be mediated by cAMP, as shown by experiments with a protein kinase A inhibitor HA1004 and by direct measurement of cAMP levels in immune complex- and FMLP-stimulated PMN. These data indicate that CD11b/CD18-independent and -dependent mechanisms of phagocytosis exist and that some effects of anti-CD11b/CD18 MAbs may be mediated by alterations in cAMP levels.
Symptomatic Atrial Septal Defect in Infancy
Authors: CARL E. HUNT, RUSSELL V. LUCAS
Journal: Circulation (1973)

Atrial septal defect of the ostium secundum variety (ASD) is uncommonly diagnosed in infancy and rarely results in congestive heart failure (CHF). Eleven patients with uncomplicated ASD who developed CHF between 6 days and 13 months of age are presented. The diagnosis of ASD was documented by cardiac catheterization in all 11 patients. Left-to-right shunt ranged from 52 to 80%. Right ventricular pressure was near systemic levels in two patients and at least somewhat elevated in the other nine. Total pulmonary resistance (TPR) was within normal limits in all 11. No left ventricular obstructive lesions were found. Although one patient had unusual thickening of the left ventricular myocardium, and the left ventricular cavity was enlarged in two other cases, no specific abnormality in left or right ventricular function could be defined. Spontaneous closure of the ASD did not occur in any of our patients. Since spontaneous closure even of a large ASD can occur, however, it seems advisable to defer elective surgical closure until after 2 years of age if successful medical management can be achieved. In those patients in whom early surgery is not necessary, the clinical course usually becomes that of a typical ASD by age 2 years.