tbuckley/cabot-search huggingface dataset:
Urinary organic anion excretion in response to dietary acid and base loading.
Authors: R K Packer, C A Curry, K M Brown
Journal: Journal of the American Society of Nephrology (1995)

Animals eating a base-loaded or base-forming diet excrete urine containing large amounts of organic anions (OA). Although citrate is the only OA previously identified as being excreted in appreciable amounts during base loading, citrate excretion accounts for only part of total OA excretion. The objectives of this study were to identify other OA excreted by rats and to see how their excretion changed in response to moderate (8 micro Eq/g per day) and heavy (30 micro Eq/g per day) loads of NaHCO3 and NH4Cl. Urinary OA were identified by high-performance liquid chromatography and were measured by enzymatic techniques as well. It was found that, in addition to citrate, significant quantities of alpha-ketoglutarate (alpha-KG) were excreted by base-loaded rats and that the excretion of citrate, alpha-KG, and succinate increased with base loading and decreased with acid loading. Citrate plus alpha-KG excretion rates were, respectively, two-thirds and one-third the rate of HCO3- excretion in rats given moderate and heavy base loads. The excretion of creatinine, glutamine, and hippurate showed no clear pattern in response to acid or base loading. It was concluded that, especially in animals experiencing moderate base loads, increases in the excretion of citrate and alpha-KG represent a much more significant component of base excretion than has been recognized previously.
Demonstration of Selective Protein Kinase C–Dependent Activation of Src and Lck Tyrosine Kinases During Ischemic Preconditioning in Conscious Rabbits
Authors: Peipei Ping, Jun Zhang, Yu-Ting Zheng, Richard C. X. Li, Buddhabeb Dawn, Xian-Liang Tang, Hitoshi Takano, Zarema Balafanova, Roberto Bolli
Journal: Circulation Research (1999)

Src tyrosine kinases have been shown to mediate cellular responses to stress in noncardiac cells. However, the effect of myocardial ischemia on Src tyrosine kinases is unknown. Furthermore, the identity of the tyrosine kinase(s) involved in the genesis of ischemic preconditioning (PC) remains obscure. Here, we present the first evidence that ischemic PC (6 cycles of 4-minute coronary occlusion and 4-minute reperfusion) induces selective activation of 2 members of the Src family of tyrosine kinases, Src and Lck, in the heart of conscious rabbits. The activation of Src in the particulate fraction was not evident at 5 minutes after ischemic PC but became apparent at 30 minutes (+119% versus control), whereas the activation of Lck in the particulate fraction was apparent both at 5 minutes (+103% versus control) and at 30 minutes (+89%) after ischemic PC. The activity of the other 5 members of the Src tyrosine kinases expressed in the rabbit heart (Fyn, Fgr, Yes, Lyn, and Blk) was not affected by ischemic PC. Ischemic PC had no effect on the activity of epidermal growth factor receptor kinases, either at 5 or at 30 minutes. The activation of Src and Lck was completely abrogated by the tyrosine kinase inhibitor lavendustin A, given at doses that have previously been shown to block the protective effect of ischemic PC in this same conscious rabbit model, suggesting that Src and Lck kinases are essential for the development of ischemic PC. The activity of the epsilon isoform of protein kinase C (PKC) in the particulate fraction increased at 5 minutes (+72%) and at 30 minutes (+67%) after ischemic PC. Pretreatment with lavendustin A had no effect on the activation of PKCepsilon, whereas pretreatment with the PKC inhibitor chelerythrine (given at doses that have previously been shown to block ischemic PC) blocked not only the activation of PKCepsilon but also that of Src and Lck, indicating that Src and Lck are downstream of PKCepsilon in the signaling cascade of ischemic PC. This study identifies a new component of the signaling mechanism of ischemic PC. The results support the concept that, in conscious rabbits, 2 specific members of the Src family of tyrosine kinases, Src and Lck, play an important role in the genesis of late PC by serving as downstream elements of PKC-mediated signal transduction.
Pathophysiological classification of Raynaud's phenomenon
Authors: K. HAAVIK NILSEN
Journal: British Journal of Dermatology (1980)

The main types of underlying mechanism in Raynaud's phenomenon were tested separately in thirty-six patients. Within each of three groups of patients who were clinically classified according to strict definitions as having primary Raynaud's disease, systemic sclerosis or rheumatoid arthritis, there was pathophysiological heterogeneity. It is therefore suggested that in studies of treatment, at least when it is aimed primarily at one pathophysiological mechanism, the patients should be selected according to the mechanism rather than what is commonly done now, according to the associated disorder.
Research priorities in sarcomeric cardiomyopathies
Authors: J. van der Velden, C. Y. Ho, J. C. Tardiff, I. Olivotto, B. C. Knollmann, L. Carrier
Journal: Cardiovascular Research (2015)

The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is harmless in a family member. Moreover, the clinical phenotype varies ranging from asymmetric hypertrophy to severe dilatation of the heart. Identification of a single phenotype-associated disease mechanism would facilitate the design of targeted treatments for patient groups with different clinical phenotypes. However, evidence from both the clinic and basic knowledge of functional and structural properties of the sarcomere argues against a 'one size fits all' therapy for treatment of one clinical phenotype. Meticulous clinical and basic studies are needed to unravel the initial and progressive changes initiated by sarcomere mutations to better understand why mutations in the same gene can lead to such opposing phenotypes. Ultimately, we need to design an 'integrative physiology' approach to fully realize patient/gene-tailored therapy. Expertise within different research fields (cardiology, genetics, cellular biology, physiology, and pharmacology) must be joined to link longitudinal clinical studies with mechanistic insights obtained from molecular and functional studies in novel cardiac muscle systems. New animal models, which reflect both initial and more advanced stages of sarcomeric cardiomyopathy, will also aid in achieving these goals. Here, we discuss current priorities in clinical and preclinical investigation aimed at increasing our understanding of pathophysiological mechanisms leading from mutation to disease. Such information will provide the basis to improve risk stratification and to develop therapies to prevent/rescue cardiac dysfunction and remodelling caused by sarcomere mutations.
URINARY ALPHA-KETOLIC STEROID METABOLITES OF CORTICAL HORMONES ADMINISTERED TO SUBJECTS WITH ADRENAL CORTICAL INSUFFICIENCY 1
Authors: E. M. Richardson, J. C. Touchstone, F. C. Dohan, Helen Bulaschenko, Irmgard Landolt, Walter Applin
Journal: Journal of Clinical Investigation (1955)

The analysis of urinary excretory products following the administration of known compounds is one of the classical methods for the study of their metabolism. The developments inpaper chromatographic (1) and micro-analytic (2) technics and the use of glucuronidase hydrolysis (3) have considerably decreased the difficulties of investigating steroid metabolism by this method. Using these newer technics, we have studied the urinary excretion pattern of the major alpha-ketolic steroids after the administration of the six active adrenal cortical steroids to individuals with severe adrenal cortical insufficiency. We have found, as has been demonstrated for other steroids (4), that the major alpha-ketolic metabolites result from the reduction in ring A of the steroid nucleus to the 3-alpha-hydroxy pregnane derivatives (the socalled tetrahydro form) and that the hydroxyl and ketone groups on carbon atom 11 are interconvertible for corticosterone and 1 1-dehydrocorticosterone as well as for hydrocortisone and cortisone.
Modern mammography screening and breast cancer mortality: population study
Authors: H. Weedon-Fekjaer, P. R. Romundstad, L. J. Vatten
Journal: BMJ (2014)

<b>Objective</b> To evaluate the effectiveness of contemporary mammography screening using individual information about screening history and breast cancer mortality from public screening programmes. <b>Design</b> Prospective cohort study of Norwegian women who were followed between 1986 and 2009. Within that period (1995-2005), a national mammography screening programme was gradually implemented, with biennial invitations sent to women aged 50-69 years. <b>Participants</b> All Norwegian women aged 50-79 between 1986 and 2009. <b>Main outcome measures</b> Multiple Poisson regression analysis was used to estimate breast cancer mortality rate ratios comparing women who were invited to screening (intention to screen) with women who were not invited, with a clear distinction between cases of breast cancer diagnosed before (without potential for screening effect) and after (with potential for screening effect) the first invitation for screening. We took competing causes of death into account by censoring women from further follow-up who died from other causes. Based on the observed mortality reduction combined with the all cause and breast cancer specific mortality in Norway in 2009, we used the CISNET (Cancer Intervention and Surveillance Modeling Network) Stanford simulation model to estimate how many women would need to be invited to biennial mammography screening in the age group 50-69 years to prevent one breast cancer death during their lifetime. <b>Results</b> During 15 193 034 person years of observation (1986-2009), deaths from breast cancer occurred in 1175 women with a diagnosis after being invited to screening and 8996 women who had not been invited before diagnosis. After adjustment for age, birth cohort, county of residence, and national trends in deaths from breast cancer, the mortality rate ratio associated with being invited to mammography screening was 0.72 (95% confidence interval 0.64 to 0.79). To prevent one death from breast cancer, 368 (95% confidence interval 266 to 508) women would need to be invited to screening. <b>Conclusion</b> Invitation to modern mammography screening may reduce deaths from breast cancer by about 28%.
Significant Prevalence of Histologic Disease in Patients With Chronic Hepatitis B and Mildly Elevated Serum Alanine Aminotransferase Levels
Authors: Philip S.Y. Tsang, Huy Trinh, Ruel T. Garcia, Jeanine T. Phan, Nghiem B. Ha, Huy Nguyen, Khanh Nguyen, Emmet B. Keeffe, Mindie H. Nguyen
Journal: Clinical Gastroenterology and Hepatology (2008)
Homogeneity of Metabolic Control in New South Wales and the Australian Capital Territory, Australia
Authors: Penny Handelsman, Maria E. Craig, Kim C. Donaghue, Albert Chan, Barbara Blades, Rosetta Laina, Darna Bradford, Angela Middlehurst, Geoffrey Ambler, Charles F. Verge, Patricia Crock, Patrick Moore, Martin Silink
Journal: Diabetes Care (2001)

Decreased insulin sensitivity in offspring whose parents
Update on the ongoing outbreak of haemolytic uraemic syndrome due to Shiga toxin-producing Escherichia coli (STEC) serotype O104, Germany, May 2011
Authors: M Askar, M S Faber, C Frank, H Bernard, A Gilsdorf, A Fruth, R Prager, M Höhle, T Suess, M Wadl, G Krause, K Stark, D Werber
Journal: Eurosurveillance (2011)

Since early May 2011, a large outbreak of haemolytic uraemic syndrome (HUS) and bloody diarrhoea related to infections with Shiga toxin-producing Escherichia coli (STEC) has been observed in Germany. The outbreak is focused in the north, but cases have been reported from all German states and other countries. Since our report last week, the number of HUS cases has increased to 470 and STEC serotype O104 has been confirmed in many cases.
Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma
Authors: Menno D. de Jong, Bach Van Cam, Phan Tu Qui, Vo Minh Hien, Tran Tan Thanh, Nguyen Bach Hue, Marcel Beld, Le Thi Phuong, Truong Huu Khanh, Nguyen Van Vinh Chau, Tran Tinh Hien, Do Quang Ha, Jeremy Farrar
Journal: New England Journal of Medicine (2005)

In southern Vietnam, a four-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter). The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's nine-year-old sister had died from a similar syndrome two weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis. Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought.
PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease
Authors: Elahe Taherzadeh-Fard, Carsten Saft, Denis A Akkad, Stefan Wieczorek, Aiden Haghikia, Andrew Chan, Jörg T Epplen, Larissa Arning
Journal: Molecular Neurodegeneration (2011)

Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.
Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma
Authors: Michael D. Prados, Susan M. Chang, Nicholas Butowski, Rebecca DeBoer, Rupa Parvataneni, Hannah Carliner, Paul Kabuubi, Jennifer Ayers-Ringler, Jane Rabbitt, Margaretta Page, Anne Fedoroff, Penny K. Sneed, Mitchel S. Berger, Michael W. McDermott, Andrew T. Parsa, Scott Vandenberg, C. David James, Kathleen R. Lamborn, David Stokoe, Daphne A. Haas-Kogan
Journal: Journal of Clinical Oncology (2008)

This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response.Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials.Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival.Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.
Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial
Authors: D. Klingbiel, Z. Saridaki, A.D. Roth, F.T. Bosman, M. Delorenzi, S. Tejpar
Journal: Annals of Oncology (2014)
Cost-Effectiveness of Second-Generation Antipsychotics and Perphenazine in a Randomized Trial of Treatment for Chronic Schizophrenia
Authors: Robert A. Rosenheck, Douglas L. Leslie, Jody Sindelar, Edward A. Miller, Haiqun Lin, T. Scott Stroup, Joseph McEvoy, Sonia M. Davis, Richard S.E. Keefe, Marvin Swartz, Diana O. Perkins, John K. Hsiao, Jeffrey Lieberman
Journal: American Journal of Psychiatry (2006)

BACKGROUND: Second-generation antipsychotics have largely replaced first-generation antipsychotics for the treatment of schizophrenia, but a large-scale cost/effectiveness analysis has not been attempted. Method: Patients with schizophrenia (N=1,493) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetia-pine, risperidone, or ziprasidone) and followed for up to 18 months. Patients with tardive dyskinesia were prohibited from assignment to perphenazine. Patients could be reassigned at any time to another second-generation drug, including clozapine, but not to perphenazine. The cost analysis included medications plus health services use. Quality-adjusted life year (QALY) ratings were assessed on the basis of Positive and Negative Syndrome Scale (PANSS) subscale scores and side effects. An intention-to-treat analysis included all available observations, classified by initial drug assignment, and costs of reassignment of most patients to another second-generation drug. The analysis was repeated considering only treatment on initially assigned medications. Results: Although QALY ratings, PANSS scores, and other quality of life measures indicated modest improvement over 18 months, there were no significant differences between perphenazine and any second-generation medication. Average total monthly health care costs were $300–$600 (20%–30%) lower for perphenazine than for second-generation antipsychotics because of lower drug cost. Differences in costs remained when maximally discounted drug prices were used for all patients and when only observations during treatment with the first medication were included. Conclusions: Treatment with perphenazine was less costly than treatment with second-generation antipsychotics with no significant differences in measures of effectiveness. However, the trial was limited by a high dropout rate, and longer-term neurological and metabolic side effects require further study.
Risk factors associated with lower extremity stress fractures in runners: a systematic review with meta-analysis
Authors: Alexis A Wright, Jeffrey B Taylor, Kevin R Ford, Lindsey Siska, James M Smoliga
Journal: British Journal of Sports Medicine (2015)

Background Stress fractures are common overuse injuries with up to 95% occurring in the lower extremities. Among runners, stress fractures account for 15–20% of all musculoskeletal injuries. Purpose We systematically reviewed and critiqued the evidence regarding risk factors associated with increased risk of lower extremity stress fractures in runners. Study design Systematic review. Methods A systematic, computerised literature search of Medline, Embase, PubMed, SPORTDiscus, and CINAHL databases (from database inception through 9 January 2014) using keywords related to risk factors and stress fractures. This systematic review with meta-analysis utilised the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for the search and reporting phases of the study. Inverse variance meta-analyses, using a random effects model were used to summarise ORs. Results 8 articles met the inclusion criteria; 7 were considered low risk. 4 articles qualified for meta-analysis. Results of the meta-analysis identified previous history of stress fracture and female sex as the primary risk factors for future stress fracture with a pooled OR of 4.99 (95% CI 2.91 to 8.56; p&lt;0.001; I 2 =0%) and 2.31 (95% CI 1.24 to 4.29; p&lt;0.01; I 2 =0%), respectively. Conclusions Currently, only previous history of stress fracture and female sex are risk factors for lower extremity stress fractures strongly supported by the data.
Downregulating Hedgehog Signaling Reduces Renal Cystogenic Potential of Mouse Models
Authors: Pamela V. Tran, George C. Talbott, Annick Turbe-Doan, Damon T. Jacobs, Michael P. Schonfeld, Luciane M. Silva, Anindita Chatterjee, Mary Prysak, Bailey A. Allard, David R. Beier
Journal: Journal of the American Society of Nephrology (2014)

Renal cystic diseases are a leading cause of renal failure. Mutations associated with renal cystic diseases reside in genes encoding proteins that localize to primary cilia. These cystoproteins can disrupt ciliary structure or cilia-mediated signaling, although molecular mechanisms connecting cilia function to renal cystogenesis remain unclear. The ciliary gene, Thm1(Ttc21b), negatively regulates Hedgehog signaling and is most commonly mutated in ciliopathies. We report that loss of murine Thm1 causes cystic kidney disease, with persistent proliferation of renal cells, elevated cAMP levels, and enhanced expression of Hedgehog signaling genes. Notably, the cAMP-mediated cystogenic potential of Thm1-null kidney explants was reduced by genetically deleting Gli2, a major transcriptional activator of the Hedgehog pathway, or by culturing with small molecule Hedgehog inhibitors. These Hedgehog inhibitors acted independently of protein kinase A and Wnt inhibitors. Furthermore, simultaneous deletion of Gli2 attenuated the renal cystic disease associated with deletion of Thm1. Finally, transcripts of Hedgehog target genes increased in cystic kidneys of two other orthologous mouse mutants, jck and Pkd1, and Hedgehog inhibitors reduced cystogenesis in jck and Pkd1 cultured kidneys. Thus, enhanced Hedgehog activity may have a general role in renal cystogenesis and thereby present a novel therapeutic target.