tbuckley/cabot-search huggingface dataset:
Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo
Authors: Stephanie E. Wölfle, Volker J. Schmidt, Joachim Hoyer, Ralf Köhler, Cor de Wit
Journal: Cardiovascular Research (2009)

The activation of endothelial Ca2+-dependent K+-channels, KCa3.1 (IKCa), and KCa2.3 (SKCa) has been proposed to be a prerequisite for endothelial hyperpolarization, which subsequently hyperpolarizes and relaxes smooth muscle [endothelium-derived hyperpolarizing factor (EDHF)-type dilation] and initiates conducted dilations. Although EDHF is the main mediator of acetylcholine (ACh)-induced dilation in the murine skeletal microcirculation, the differential contribution of KCa3.1 and KCa2.3 is not known.We assessed agonist-induced and conducted dilations as well as endothelial hyperpolarization in the cremaster microcirculation of KCa3.1-deficient (KCa3.1-/-) and wild-type mice (wt) in vivo after blockade of NO and prostaglandins. Compared with wt, resting tone was enhanced by approximately 25% in arterioles of KCa3.1-/- mice. ACh-induced dilations in KCa3.1-/- mice were virtually abolished at low and intermediate concentrations and a remaining dilation at 10 micromol/L ACh was abrogated by blockade of KCa2.3 with UCL1684. Sodium nitroprusside- and adenosine-induced dilations were similar in wt and KCa3.1-/-. Focal application of ACh induced dilations at the local site in both genotypes, which conducted along the vessel. However, the amplitude of the dilation decreased with distance only in KCa3.1-/-. Blockade of KCa2.3 in wt did not affect conducted dilations. A KCa3.1 opener induced a conducting dilation in wt but not in KCa3.1-/-. Membrane potential recordings in vivo demonstrated endothelial hyperpolarization in response to ACh in both genotypes; however, the hyperpolarization was severely impaired in KCa3.1-/- (Delta membrane potential: -3 +/- 1 vs. -14 +/- 2 mV).We conclude that KCa3.1 is of major importance for endothelial hyperpolarization and EDHF-type responses in skeletal muscle arterioles, and its deficiency is not compensated by KCa2.3. Sole activation of KCa3.1 is capable of initiating conducted responses, and KCa3.1 may contribute to the propagation of the signal, although its presence is not mandatory.
The spine in sport and veteran military parachutists
Authors: C. F. Murray-Leslie, D. J. Lintott, V. Wright
Journal: Annals of the Rheumatic Diseases (1977)

Spinal injuries and symptoms were studied in 109 ex-military parachutists and 112 sport (free fall) parachutists by means of postal questionnaires. 46 ex-military parachutists aged 50 years or over had a radiological examination of the lumbar spine and 58 sport parachutists had a radiological examination of the cervical spine as part of the survey. A history of back pain was significantly (P<0.01) associated with body weight in sport parachutists but not with the number of descents or with the subject's age. In the older ex-military group neither age, weight, nor the number of descents was significantly associated with backache. Of those ex-military parachutists x-rayed, 10 (21.7%) were found to have vertebral body fractures (most frequently at D12), and 8 of these were unaware of these lesions. Vertebral fractures caused no disability and did not permanently curtail parachuting activities in either the sport or ex-military group. Of the ex-military parachutists x-rayed, 84.7% had lumbar disc degeneration of all grades of severity, 17.4% had moderate changes, and 10.8% had severe changes. The frequency of moderate and severe disc degeneration was significantly related to age but not to body weight or to the number of descents. Spondylolysis was found in 2 subjects (4.3%) and spondylolisthesis unassociated with spondylolysis in 4 (8.7%). Spondylolisthesis was always associated with a history of back pain.A low prevalence of radiological cervical intervertebral disc degeneration of all grades of severity of 8.7% was found among the free fall parachutists (mean age 33 years). 2 cases of cervical vertebral body fracture were seen, one related to a parachute landing injury and the other to a parachute opening injury. This study does not implicate parachuting as a cause of intervertebral disc degeneration, either cervical or lumbar, nor as a cause of spondylolysis or spondylolisthesis. Serious long-term disability from pain appears to be uncommon among parachutists despite the frequency of the spinal trauma they sustain.
Local Effects of Sodium, Calcium and Magnesium Upon Small and Large Blood Vessels of the Dog Forelimb
Authors: FRANCIS J. HADDY
Journal: Circulation Research (1960)

Resistance to blood flow through the small vessels of the dog foreleg decreased following local elevation of serum sodium and magnesium concentrations. Small vessel resistance increased following elevation of calcium concentration. Associated with the former changes was decreased responsiveness to levarterenol and methacholine. These changes likely result from effects of the cations upon the smooth muscle cell of the arteriole.
The effect of cellular retinoic acid binding protein-I expression on the CYP26-mediated catabolism of all-trans retinoic acid and cell proliferation in head and neck squamous cell carcinoma
Authors: Jun Yeon Won, Eui-Cheol Nam, Seung Joo Yoo, Hyun Ja Kwon, Soo Jong Um, Hye Sook Han, Sun Hee Kim, Youngro Byun, Sang Yoon Kim
Journal: Metabolism (2004)
Inorganic phosphate homeostasis. Renal adaptation to the dietary intake in intact and thyroparathyroidectomized rats.
Authors: U Tröhler, J P Bonjour, H Fleisch
Journal: Journal of Clinical Investigation (1976)

The possibility of renal tubular adaptation to variations in dietary inorganic phosphate (Pi) was investigated in intact and thyroparathyroidectomized (TPTX) rats pair-fed diets containing low, normal, and high amounts of Pi for periods up to 10 days. Clearances were measured before and during active i.v. infusions with Pi in conscious animals. Thus tubular reabsorption of phosphate (TRPi) could be assessed over a wide range of plasma phosphate concentrations ([Pi]P1). It was found that the renal tubule could adapt its capacity to transport Pi according to the dietary Pi: TRPi was always higher, for a given [Pi]P1, in the animals fed low than in those fed higher Pi diets. This diet-induced modification also occurred in the absence of thyroparathyroid glands, in the presence of the same calcemia and urinary pH, and during marked extracellular volume expansion. A time-course study in rats TPTX both before and during the administration of the experimental diets showed that a difference in the tubular handling of Pi was detectable as early as 3 days after switching the animals from a normal to low- or high-Pi diets. These results indicate that factors other than parathyroid hormone are implicated in the tubular response to variations in the dietary intake of inorganic phosphate.
Rhinovirus bronchiolitis and recurrent wheezing: 1-year follow-up
Authors: F Midulla, A Pierangeli, G Cangiano, E Bonci, S Salvadei, C Scagnolari, C Moretti, G Antonelli, V Ferro, P Papoff
Journal: European Respiratory Journal (2011)

The association between bronchiolitis and recurrent wheezing remains controversial. In this prospective study, we assessed risk factors for recurrent wheezing during a 12-month follow-up in 313 infants aged &lt;12 months hospitalised for their first episode of bronchiolitis. Demographic, clinical and laboratory data were obtained with a questionnaire and from medical files. A total of 14 respiratory viruses were concurrently assayed in nasal washings. Parents were interviewed 12 months after hospitalisation to check whether their infants experienced recurrent wheezing. The rate of recurrent wheezing was higher in infants with bronchiolitis than in controls (52.7 versus 10.3%; p&lt;0.001). Multivariate analysis identified rhinovirus (RV) infection (OR 3.3, 95% CI 1.0–11.1) followed by a positive family history for asthma (OR 2.5, 95% CI 1.2–4.9) as major independent risk factors for recurrent wheezing. In conclusion, the virus most likely to be associated with recurrent wheezing at 12 months after initial bronchiolitis is RV, a viral agent that could predict infants prone to the development of recurrent wheezing.
A Genomic Portrait of Human Microsatellite Variation
Authors: B. A. Payseur, P. Jing, R. J. Haasl
Journal: Molecular Biology and Evolution (2010)

Rapid advances in DNA sequencing and genotyping technologies are beginning to reveal the scope and pattern of human genomic variation. Although single nucleotide polymorphisms (SNPs) have been intensively studied, the extent and form of variation at other types of molecular variants remain poorly understood. Polymorphism at the most variable loci in the human genome, microsatellites, has rarely been examined on a genomic scale without the ascertainment biases that attend typical genotyping studies. We conducted a genomic survey of variation at microsatellites with at least three perfect repeats by comparing two complete genome sequences, the Human Genome Reference sequence and the sequence of J. Craig Venter. The genomic proportion of polymorphic loci was 2.7%, much higher than the rate of SNP variation, with marked heterogeneity among classes of loci. The proportion of variable loci increased substantially with repeat number. Repeat lengths differed in levels of variation, with longer repeat lengths generally showing higher polymorphism at the same repeat number. Microsatellite variation was weakly correlated with regional SNP number, indicating modest effects of shared genealogical history. Reductions in variation were detected at microsatellites located in introns, in untranslated regions, in coding exons, and just upstream of transcription start sites, suggesting the presence of selective constraints. Our results provide new insights into microsatellite mutational processes and yield a preview of patterns of variation that will be obtained in genomic surveys of larger numbers of individuals.
Confirmation of first person to person transmission of swine flu in UK expected soon
Authors: A. O'Dowd
Journal: BMJ (2009)

The first human to human transmission of swine influenza in the United Kingdom is expected to be confirmed today, as the number of confirmed cases has risen to eight.

Worldwide, there are now 331 confirmed cases of influenza A (H1N1) and 10 confirmed deaths in Mexico and the US, although Mexican health officials believe it may have caused 168 deaths in their country. The World Health Organization says that the flu has been detected in 11 different countries. 

The Scottish government will reveal today whether or not a honeymoon couple who returned from Mexico and were confirmed to have the disease has passed it on to a friend …
Treatment With Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents
Authors: Athanase Benetos, Carlos Labat, Patrick Rossignol, Renaud Fay, Yves Rolland, Filippo Valbusa, Paolo Salvi, Mauro Zamboni, Patrick Manckoundia, Olivier Hanon, Sylvie Gautier
Journal: JAMA Internal Medicine (2015)

IMPORTANCEClinical evidence supports the beneficial effects of lowering blood pressure (BP) levels in community-living, robust, hypertensive individuals older than 80 years.However, observational studies in frail elderly patients have shown no or even an inverse relationship between BP and morbidity and mortality.OBJECTIVE To assess all-cause mortality in institutionalized individuals older than 80 years according to systolic BP (SBP) levels and number of antihypertensive drugs. DESIGN, SETTING, AND PARTICIPANTSThis longitudinal study included elderly residents of nursing homes.The interaction between low (<130 mm Hg) SBP and the presence of combination antihypertensive treatment on 2-year all-cause mortality was analyzed.A total of 1127 women and men older than 80 years (mean, 87.6 years; 78.1% women) living in nursing homes in France and Italy were recruited, examined, and monitored for 2 years.Blood pressure was measured with assisted self-measurements in the nursing home during 3 consecutive days (mean, 18 measurements).Patients with an SBP less than 130 mm Hg who were receiving combination antihypertensive treatment were compared with all other participants.MAIN OUTCOMES AND MEASURES All-cause mortality over a 2-year follow-up period.RESULTS A significant interaction was found between low SBP and treatment with 2 or more BP-lowering agents, resulting in a higher risk of mortality (unadjusted hazard ratio [HR], 1.81; 95% CI, 1.36-2.41);adjusted HR, 1.78; 95% CI, 1.34-2.37;both P < .001) in patients with low SBP who were receiving multiple BP medicines compared with the other participants.Three sensitivity analyses confirmed the significant excess of risk: propensity score-matched subsets (unadjusted HR, 1.97; 95% CI, 1.32-2.93;P < .001;adjusted HR, 2.05; 95% CI, 1.37-3.06;P < .001),adjustment for cardiovascular comorbidities (HR, 1.73; 95% CI, 1.29-2.32;P < .001),and exclusion of patients without a history of hypertension who were receiving BP-lowering agents (unadjusted HR, 1.82; 95% CI, 1.33-2.48;P < .001;adjusted HR, 1.76; 95% CI, 1.28-2.41;P < .001). CONCLUSIONS AND RELEVANCEThe findings of this study raise a cautionary note regarding the safety of using combination antihypertensive therapy in frail elderly patients with low SBP (<130 mm Hg).Dedicated, controlled interventional studies are warranted to assess the corresponding benefit to risk ratio in this growing population.
Isoform-specific roles of protein phosphatase 1 catalytic subunits in sarcoplasmic reticulum-mediated Ca2+ cycling
Authors: Hidekazu Aoyama, Yasuhiro Ikeda, Yosuke Miyazaki, Koichi Yoshimura, Shizuka Nishino, Takeshi Yamamoto, Masafumi Yano, Makoto Inui, Hiroki Aoki, Masunori Matsuzaki
Journal: Cardiovascular Research (2010)

Protein phosphatase 1 (PP1) is the major isotype of serine/threonine phosphatase in cardiomyocytes, and its activity has been thought to be important for heart failure progression. The PP1 catalytic subunits consist of three distinct genes, PP1α, PP1β/δ, and PP1γ. To date, the function of each PP1 isoform is not well characterized in cardiomyocytes. We sought to determine the functional contribution of each PP1 isoform to sarcoplasmic reticulum (SR)-mediated Ca2+ cycling in isolated adult rat cardiomyocytes. Adenoviral vectors encoding short hairpin RNA for each PP1 isoform were transfected into isolated rat cardiomyocytes, and this was followed by analysis of cell shortening, Ca2+ transients, and the phosphorylation levels of Ca2+ regulatory proteins. Physical interactions between each PP1 isoform and SR Ca2+ regulatory proteins were characterized in isolated cardiomyocytes expressing green fluorescent protein (GFP)-tagged PP1 catalytic subunits, and also in canine junctional and longitudinal SR preparations. Successful PP1 isoform knockdown was achieved for each isoform without affecting the expression of the other isoforms. PP1β knockdown most significantly enhanced the Ca2+ transient and cell shortening by augmenting phospholamban (PLN) phosphorylation at baseline and with low-dose isoproterenol stimulation (10 nM). Interestingly, PP1β was preferentially associated with sarco-endoplasmic ATPase and PLN in GFP-PP1-transfected cardiomyocytes, as well as in canine longitudinal SR preparations. These findings indicate that PP1β is the most significant PP1 isoform involved in regulating SR Ca2+ cycling in rat cardiomyocytes.
Archery, mathematics, and conceptualizing inaccuracies in medicine in 13th century Iraq and Syria
Authors: N Peter Joosse, Peter E Pormann
Journal: Journal of the Royal Society of Medicine (2008)

in his grandfather's house in a street called Darb al-Faludhaj in Baghdad.He died there on 9 November 1231, and was buried in the Wardiyah cemetery next to his father,
MCL-1 Promoter Insertions Dial-Up Aggressiveness of Chronic Leukemia
Authors: S. Kitada, J. C. Reed
Journal: JNCI Journal of the National Cancer Institute (2004)

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western world, accounting for approximately 12 000 new cases annually, and a prevalence of about 50 000 to 60 000 patients in the United States alone. CLL is a quintessential example of a human malignancy caused predominantly by defective apoptosis, as opposed to accelerated cell division. The malignant lymphocytes that accumulate in patients with CLL are largely quiescent, noncycling cells that display prolonged lifespans due to failed programmed cell death (1). Normally, a delicate balance of anti-apoptotic and pro-apoptotic genes keeps cell lifespan in check, functioning analogous to an electrical rheostat to carefully adjust the body’s cell flux dial that ensures the daily production of approximately 50 –70 billion cells in humans that is offset by a commensurate amount of cell death. Imbalances in the activities of these apoptosis-regulatory gene networks create a fertile soil in which the seeds of carcinogenesis can take root. In this issue of the Journal, Moshynska et al. (2) describe somatic mutations in the promoter region of MCL-1, an anti-apoptotic gene. The findings provide new insights into the mechanisms responsible for dysregulation of apoptosis in CLL. MCL-1 is a member of the BCL-2 gene family, which includes 25 known members in humans [see (3) for review]. Bcl-2-family proteins include both anti-apoptotic and proapoptotic members. Imbalances in the levels or activities of these proteins are commonly associated with malignancy, including lymphocytic malignancies such as non-Hodgkin lymphoma, in which the founding member of the family, Bcl-2, was first discovered nearly two decades ago by virtue of the involvement of its encoding gene in chromosomal translocations (4). Analogously, transgenic mice overexpressing Mcl-1 protein in lymphocytes frequently develop lymphomas (5), attesting to the in vivo importance of this anti-apoptotic protein for B-cell neoplasia. The clinical course of CLL is highly heterogeneous, with time to progression varying from months to many years. Responses to chemotherapy also vary widely. This heterogeneity has prompted searches for biomarkers that might be predictive of prognosis. Previous studies documented high levels of antiapoptotic Bcl-2 relative to pro-apoptotic Bax protein in CLLs,
The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma
Authors: E Derenzini, M Lemoine, D Buglio, H Katayama, Y Ji, R E Davis, S Sen, A Younes
Journal: Blood Cancer Journal (2011)

Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1-1 μ) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μ) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL.
Comprehensive Foot Examination and Risk Assessment
Authors: Andrew J.M. Boulton, David G. Armstrong, Stephen F. Albert, Robert G. Frykberg, Richard Hellman, M. Sue Kirkman, Lawrence A. Lavery, Joseph W. LeMaster, Joseph L. Mills, Michael J. Mueller, Peter Sheehan, Dane K. Wukich
Journal: Diabetes Care (2008)

It is now 10 years since the last technical review on preventative foot care was published (1), which was followed by an American Diabetes Association (ADA) position statement on preventive foot care in diabetes (2). Many studies have been published proposing a range of tests that might usefully identify patients at risk of foot ulceration, creating confusion among practitioners as to which screening tests should be adopted in clinical practice. A task force was therefore assembled by the ADA to address and concisely summarize recent literature in this area and then recommend what should be included in the comprehensive foot exam for adult patients with diabetes. The committee was cochaired by the immediate past and current chairs of the ADA Foot Care Interest Group (A.J.M.B. and D.G.A.), with other panel members representing primary care, orthopedic and vascular surgery, physical therapy, podiatric medicine and surgery, and the American Association of Clinical Endocrinologists.

The lifetime risk of a person with diabetes developing a foot ulcer may be as high as 25%, whereas the annual incidence of foot ulcers is ∼2% (3–7). Up to 50% of older patients with type 2 diabetes have one or more risk factors for foot ulceration (3,6). A number of component causes, most importantly peripheral neuropathy, interact to complete the causal pathway to foot ulceration (1,3–5). A list of the principal contributory factors that might result in foot ulcer development is provided in Table 1.

View this table:

 Table 1—  
Risk factors for foot ulcers



The most common triad of causes that interact and ultimately result in ulceration has been identified as neuropathy, deformity, and trauma (5). As identification of those patients at risk of foot problems is the first step in preventing such complications, this report will focus on key components of the …
Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity
Authors: Rima Chakaroun, Matthias Raschpichler, Nora Klöting, Andreas Oberbach, Gesine Flehmig, Matthias Kern, Michael R. Schön, Edward Shang, Tobias Lohmann, Miriam Dreßler, Mathias Fasshauer, Michael Stumvoll, Matthias Blüher
Journal: Metabolism (2011)