tbuckley/cabot-search huggingface dataset:
Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN
Authors: Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Ying Huang, Hyoungbin Oh, Robert M. Hughes, Mara E. Klein, Shoichi Takikita, Kunio Nagashima, Laura S. Schmidt, W. Marston Linehan
Journal: JNCI Journal of the National Cancer Institute (2012)

Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood.Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) -Cre or myogenin (MYOG) -Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)- Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided.Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN ( f/f ) vs FLCN ( f/f ) /CKM-Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < .001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney.FLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation.
Toxic Response of Rats to Cyclamates in Chow and Semisynthetic Diets
Authors: Leonard Friedman, Howard L. Richardson, Mary E. Richardson, Elizabeth J. Lethco, Wendell C. Wallace, Frances M. Sauro
Journal: JNCI Journal of the National Cancer Institute (1972)

Cyclamates were fed to rats in 2 independently conducted studies. In study one, sodium and calcium cyclamate in commercial chow diets were fed, at dietary levels from 0.4–10%, to male and female weanling Osborne-Mendel rats for 101 weeks; in study two, 1 and 2% calcium cyclamate in semisynthetic diets containing 10 and 20% casein were fed to male weanling Holtzman rats for 75 weeks. In both studies, adverse reactions were noted. With the semisynthetic diet, growth rate was depressed, soft stools were produced, and the rate of kidney and urinary bladder lesions was increased. These adverse reactions did not appear to be affected by the protein content of the diet. No observed cytogenetic damage was produced by calcium cyclamate ingestion. With the chow diet, survival decreased and urinary bladder and kidney lesions increased; this increase was much more marked in severity and incidence than that with the semi-synthetic diets. The lesions noted with the highest frequency in the kidneys were nephrocalcinosis and calyceal polyposis, and in the urinary bladder, epithelial hyperplasia, thickening or edema of the urinary bladder wall, and mucosal papilloma. Transitional cell carcinoma with varying degrees of invasion was detected in the urinary bladders of 3 of the 23 rats receiving calcium cyclamate in the chow diets. Two of these carcinomas were in rats fed diets containing only 0.4% of this compound. Bladder calculi were also occasionally present and were in 2 of the bladders with carcinomas. These lesions were not seen in any rats fed control diets.
Pathogenesis of Osteoarthritis
Authors: F. D. Hart
Journal: BMJ (1970)

The prevalence of hip OA was higher than described in radiographic surveys, with 29.5%, 32.8% and 43.7% in right, left and ''any'' hip, respectively.Males had a non-significant trend towards higher prevalence of hip OA, (p ¼ 0.2, 2).Generalised OA was defined as hand OA plus knee and/or hip OA.Ultrasound evidence of generalised OA (48%) and isolated hand OA (31%) were common, compared to isolated hip or knee OA (5%) and both hip and knee OA (3%).Conclusions: This is the first study to look at the prevalence of ultrasound defined OA in the community.The higher prevalence of OA in the hands and hips in this study, when compared to previous radiographic studies, adds evidence to the idea that ultrasound is more sensitive than radiographs in detecting OA, particularly for the presence of osteophytes.The high prevalence of isolated hand OA suggests that ultrasound defined hand OA may be a predictor of the development of generalised OA.A study of longitudinal risk factors for OA obtained prospectively in this cohort is underway.
Response to Comment on: Chakkera et al. Pretransplant Risk Score for New-Onset Diabetes After Kidney Transplantation. Diabetes Care 2011;34:2141–2145
Authors: Harini A. Chakkera, William C. Knowler
Journal: Diabetes Care (2012)

Responding to our recent article in Diabetes Care (1), Valderhaug et al. (2) wrote that we underestimated the prevalence of pretransplant diabetes and the incidence of new-onset diabetes after kidney transplantation (NODAT) because of our diagnostic methods. We diagnosed diabetes pre- and posttransplant using the data available in our practice—prescribed therapy, fasting plasma glucose (FPG), and HbA1c—rather than the 2003 consensus criteria that include an oral glucose tolerance test (OGTT) but not HbA1c (3).

This criticism reflects a controversy about diagnostic criteria that exists even in the absence of kidney …
The cellular infiltrate of the jejunum in adult coeliac disease and dermatitis herpetiformis following the reintroduction of dietary gluten.
Authors: M Lancaster-Smith, P J Kumar, A M Dawson
Journal: Gut (1975)

The cellular infiltrate of the jejunal mucosa has been studied in patients with both treated and untreated adult coeliac disease and dermatitis herpetiformis and serially in treated patients before and after the reintroduction of gluten to the diet. In adult coeliac disease and dermatitis herpetiformis the jejunal mucosa showed similar abnormalities of the cellular infiltrate which was characterized by an increase in intraepithelial lymphocytes and lamina propria plasma cells and eosinophils, with the greatest numbers of cells occurring in untreated patients. At 24-48 hours following a single 25-g gluten challenge there was an increase in lamina propria plasma cells, lymphocytes and eosinophils and intraepithelial lymphocytes. This rise was sustained after seven days on a gluten-containing diet for all of these cell groups except lamina propria lymphocytes. These responses were essentially similar in both adult coeliac disease and in those dermatitis herpetiformis patients who had jejunal lesions before treatment. In dermatitis herpetiformis patients with normal jejunal morphology on a normal diet there was an upward trend in lamina propria plasma cells and intraepithelial lymphocytes within one to three weeks of taking extra dietary gluten. These results are compatible with the view that more than one immunological mechanism may be responsible for the pathogenesis of the jejunal lesion of coeliac disease and dermatitis herpetiformis.
Anti-Mac-1 selectively inhibits the mouse and human type three complement receptor.
Authors: D I Beller, T A Springer, R D Schreiber
Journal: The Journal of Experimental Medicine (1982)

Anti-Mac-1 (M1/70), a rat monoclonal antibody that reacts with mouse and human macrophages, polymorphonuclear leukocytes (PMNL), and natural killer cells, selectively inhibited complement receptor-mediated rosetting by murine macrophages and human PMNL. Preincubation of macrophages with anti-Mac-1 inhibited formation of rosettes with sheep erythrocytes bearing IgM antibody and murine C3 fragments. No inhibition was observed when other monoclonal antibodies that react with macrophages (such as anti-Ly5, anti-H-2, or anti-pan-leukocyte) were tested at 10-fold higher concentrations. Anti-Mac-1 did not affect macrophage Fc receptor-mediated rosetting. Erythrocytes bearing homogeneous human C3 fragments C3b (EC3b) or C3bi (EC3bi) were used to test the specificity of the murine macrophage and human PMNL complement receptor inhibited by anti-Mac-1. In both cases, anti-Mac-1 inhibited CR3-mediated rosetting of EC3bi but not CR1-dependent rosetting of EC3b. The results show that Mac-1 is either identical to CR3 or closely associated with CR3 function. This is one of the first cases in which a monoclonal antibody-defined differentiation antigen has been associated with a specific cell surface function.
New regimen for eccentric calf-muscle training in patients with chronic insertional Achilles tendinopathy: results of a pilot study
Authors: P Jonsson, H Alfredson, K Sunding, M Fahlström, J Cook
Journal: British Journal of Sports Medicine (2008)

Chronic painful insertional Achilles tendinopathy is seen in both physically active and non-active individuals. Painful eccentric training, where the patients load the Achilles tendon into full dorsiflexion, has shown good results in patients with mid-portion Achilles tendinosis. However, only 32% of patients with insertional Achilles tendinopathy had good clinical results with that type of eccentric training regimen.To investigate whether a new model of painful eccentric training had an effect on chronic painful insertional Achilles tendinopathy.27 patients (12 men, 15 women, mean age 53 years) with a total of 34 painful Achilles tendons with a long duration of pain (mean 26 months), diagnosed as insertional Achilles tendinopathy, were included. The patients performed a new model of painful eccentric training regimen without loading into dorsiflexion. This was done as 3x15 reps, twice a day, 7 days/week, for 12 weeks. Pain during Achilles-tendon-loading activity (VAS) and patient's satisfaction (back to previous activity) were evaluated.At follow-up (mean 4 months) 18 patients (67%, 23/34 tendons) were satisfied and back to their previous tendon-loading activity. Their mean VAS had decreased from 69.9 (SD 18.9) to 21 (SD 20.6) (p<0.001). Nine patients (11 tendons) were not satisfied with the treatment, although their VAS was significantly reduced from 77.5 (8.6) to 58.1 (14.8) (p<0.01).In this short-term pilot study this new model of painful eccentric calf-muscle training showed promising clinical results in 67% of the patients.
Prognostic value of intra-left ventricular electromechanical asynchrony in patients with mild hypertrophic cardiomyopathy compared with power athletes
Authors: A D’Andrea, P Caso, S Cuomo, G Salerno, R Scarafile, C Mita, G De Corato, B Sarubbi, M Scherillo, R Calabrò
Journal: British Journal of Sports Medicine (2006)

Objectives: We sought to assess the indexes of myocardial activation delay, using Doppler myocardial imaging (DMI), as potential diagnostic tools and predictors of cardiac events in patients with hypertrophic cardiomyopathy (HCM) compared with power athletes. Background: the distribution and magnitude of left ventricular (LV) hypertrophy are not uniform in patients with HCM, which results in heterogeneity of regional LV systolic function. Methods: The study population comprised 70 young patients with HCM (mean (SD) age 29.4 (5.9) years) with mild septal hypertrophy (15–19 mm) and 85 age and sex matched athletes with septal thickness &gt;12 mm, followed up for 44.4 (10.8) months. Using pulsed DMI, myocardial peak velocities, systolic time intervals, and myocardial intraventricular and interventricular systolic delays were measured in six different basal myocardial segments. Results: DMI analysis showed in HCM lower myocardial both systolic and early diastolic peak velocities of all the segments. Patients with HCM also showed significant interventricular and intraventricular delay (p&lt;0.0001), whereas athletes showed homogeneous systolic activation of the ventricular walls. During the follow up, seven sudden deaths occurred in the HCM group, while no cardiovascular event was observed in the group of athletes. In patients with HCM, intraventricular delay on DMI was the most powerful independent predictor of sudden cardiac death (p&lt;0.0001). An intraventricular delay &gt;45 ms identified with high sensitivity and specificity patients with HCM at higher risk of ventricular tachycardia and cardiac events (test accuracy 90.6%). Conclusions: DMI may be a valid supporting tool for the differential diagnosis between HCM and “athlete’s heart”. In patients with HCM, DMI indexes of intraventricular delay may provide additional information for selecting subgroups of patients with HCM at increased risk of ventricular arrhythmias and sudden cardiac death at follow up. Accordingly, such patients may benefit from early intensive treatment and survey. Miniabstract: Doppler myocardial imaging may represent a valid supporting tool for the differential diagnosis between mild hypertrophic cardiomyopathy (HCM) and “athlete’s heart”. In patients with HCM, DMI indexes of intraventricular delay may provide additional information for selecting subgroups of patients with HCM at increased risk of ventricular arrhythmias and sudden cardiac death at follow up.
Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients
Authors: S Danese
Journal: Gut (2003)

<h3>ABSTRACT</h3> <h3>Background</h3> Paragangliomas (PGLs) are rare neuroendocrine tumors that can arise from any autonomic ganglion of the body. Most PGLs do not metastasize. Here, we present a rare case of metastatic PGL of the spine in a patient with a germline pathogenic succinate dehydrogenase subunit B (<i>SDHB</i>) mutation. <h3>Methods</h3> In addition to a case report we provide a literature review of metastatic spinal PGL to highlight the importance of genetic testing and long-term surveillance of these patients. <h3>Results</h3> A 45-year-old woman with history of spinal nerve root PGL, 17 years prior, presented with back pain of several months9 duration. Imaging revealed multilevel lytic lesions throughout the cervical, thoracic, and lumbar spine as well as involvement of the right mandibular condyle and clavicle. Percutaneous biopsy of the L1 spinal lesion confirmed metastatic PGL and the patient underwent posterior tumor resection and instrumented fusion of T7–T11. Postoperatively the patient was found to have a pathogenic <i>SDHB</i> deletion. <h3>Conclusions</h3> Patients with <i>SDHx</i> mutation, particularly <i>SDHB,</i> have increased risk of developing metastatic PGLs. Consequently, these individuals require long-term surveillance given the risk for developing new tumors or disease recurrence, even years to decades after primary tumor resection. Surgical management of spinal metastatic PGL involves correcting spinal instability, minimizing tumor burden, and alleviating epidural cord compression. In patients with metastatic PGL of the spine, genetic testing should be considered.
Load-insensitive relaxation caused by hypoxia in mammalian cardiac muscle.
Authors: L H Chuck, M A Goethals, W W Parmley, D L Brutsaert
Journal: Circulation Research (1981)

The relaxation of isolated cardiac muscles from mammals was recently shown to be sensitive to the loading conditions because the time course of relaxation could be changed by changing the load.This effect apparently is related to the amount and functional status of the sarcoplasmic reticulum.The purpose of this study was to determine whether hypoxia affected the load sensitivity of papillary muscles isolated from both rats and cats.We used three mechanical tests to establish the presence of load-sensitive relaxation.First, we superimposed records of isotonic contractions at increasing afterloads up to isometric contraction.From these records we measured the ratio (tRi) which was the time from the initiation of the contraction to the initial decay of force at each isotonic afterload, divided by the time it took for the force of an isometric contraction to relax to that same afterload.If the tRi was less than 1.0, then the muscle was load sensitive.Hypoxia caused the loss of load-sensitive relaxation in isotonically contracting rat papillary muscles since the tRi ratios were not significantly different from 1.0 at all afterloads.Both hypoxia and caffeine were required to make cat papillary muscles load insensitive.Second, during hypoxia, loads added in midcontraction did not induce early relaxation in rat papillary muscles, but still did so in cat muscles.Hypoxia plus caffeine eliminated this load-induced early relaxation in cat papillary muscles.Third, physiologically contracting muscles made hypoxic did not lengthen earlier in response to an additional load.This decrease of load sensitivity under hypoxic conditions could contribute to the relaxation abnormalities observed during regional wall motion studies.
Can Nasal ECP Help to Predict Clinical Outcome of Specific Immunotherapy in Mite-allergic Rhinitis Patients
Authors: M.A.R. Branco-Ferreira, A. Spinola-Santos, M. Pereira-Santos, M. Palma-Carlos, M.A. Pereira-Barbosa, A.G. Palma-Carlos
Journal: Journal of Allergy and Clinical Immunology (2006)
Heparin-Induced Thrombocytopenia
Authors: Gowthami M. Arepally, Thomas L. Ortel
Journal: New England Journal of Medicine (2006)

A 63-year-old man with coronary artery disease who has recently undergone bypass surgery presents with dyspnea. Laboratory testing reveals a platelet count of 86,000 per cubic millimeter, as compared with 225,000 per cubic millimeter at the time of discharge nine days earlier. Findings on chest radiography are unremarkable; spiral computed tomography of the chest shows a pulmonary embolism. Heparin-induced thrombocytopenia is suspected. What diagnostic studies are warranted, and how should this patient be treated?
Alan Usher David Walter Hugh Barnes Henry Herbert Evans Batten Thomas Roy Farrimond John Ferrington Donald Kellock Thomas William Aitken McKay Basil Elystan Miles Amiya Pada Mukherjee Arpan Mukherjee
Authors: A. Usher, M. Weatherall, S. H Gould, B. C Zoob, A. Bartlam, S. Milner, S Cronin, A W Craft, J. Ross, S. C O Taggart, H. Ahmad
Journal: BMJ (1998)

# Alan Usher {#article-title-2}

Professor of forensic pathology Sheffield, 1978-90 ( b Chester le Street, Co Durham, 1930; q Newcastle 1954; FRCPath, DMJ; OBE), d 31 June 1998. He was born in a workhouse, where his father was the master, and this—together with almost losing a leg from osteomyelitis when he was a teenager—gave him a lifelong sympathy with disadvantaged people. After house jobs he started as a lecturer in 1961, but just beforehand spent 18 months as a ship's doctor with the Blue Funnel line, going to the Far East and 1000 miles up the Amazon. In 1964 he became head of the department of forensic pathology and consultant to both the Home Office and the South Yorkshire police force.

Usher's experience was vast. He performed up to 1000 necropsies a year, amounting to over 27 500 during his life time. Nearly 800 of these were murder investigations, and they included the Helen Smith case in Jeddah, one of the Yorkshire Ripper deaths, the Cannock Chase murder, the Confait case, the Perera dismemberment, and many others. He also played a major part in the investigations on the victims of the Flixborough explosion in 1974 and of the calamity at the Hillsborough football ground in 1989. As a result of his involvement in Regina v Leonard Arthur (in which a paediatrician was accused of euthanasia of a baby with Down's syndrome), the law was changed so that technical evidence had to be treated like alibi defence and disclosed to the court beforehand. His manner in court was always cool and unflappable. He was formidable to crossexamine, because he was fair. As a result judges, juries, and the bar all trusted him. Humour was never far from the surface, moreover, and he was a well known raconteur and much sought after as after dinner speaker and lecturer.

A major contribution was raising the facilities for forensic medicine …
A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer
Authors: Shane Stegeman, Ernest Amankwah, Kerenaftali Klein, Tracy A. O'Mara, Donghwa Kim, Hui-Yi Lin, Jennifer Permuth-Wey, Thomas A. Sellers, Srilakshmi Srinivasan, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A. Haiman, Johanna Schleutker, Børge G. Nordestgaard, Ruth C. Travis, David Neal, Paul Pharoah, Kay-Tee Khaw, Janet L. Stanford, William J. Blot, Stephen Thibodeau, Christiane Maier, Adam S. Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Radka Kaneva, Manuel R. Teixeira, Amanda B. Spurdle, Judith A. Clements, Jong Y. Park, Jyotsna Batra
Journal: Cancer Discovery (2015)

Abstract Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3′ untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P &amp;lt; 2.3 × 10−5) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. Significance: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk. Cancer Discov; 5(4); 368–79. ©2015 AACR. See related commentary by Yousef, p. 351 This article is highlighted in the In This Issue feature, p. 333
Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses
Authors: Persis J. Amrolia, Giada Muccioli-Casadei, Eric Yvon, Helen Huls, Uluhan Sili, Eric D. Wieder, Catherine Bollard, Jaroslav Michalek, Victor Ghetie, Helen E. Heslop, Jeffrey J. Molldrem, Cliona M. Rooney, John Schlinder, Ellen Vitetta, Malcolm K. Brenner
Journal: Blood (2003)
On the encompassing of the behaviour of man
Authors: Morten Overgaard, Soeren Willert
Journal: Behavioral and Brain Sciences (2003)

One supposition underlying the Anderson &amp; Lebiere (A&amp;L) target article is that the maximally broad “encompassing of its subject matter – the behavior of man” (cf. sect. 6, last para.) is regarded as an unquestioned quality criterion for guiding cognitive research. One might argue for an explicit specification of the limitations of a given paradigm, rather than extending it to apply to as many domains as possible.
Essential Role of the Apoptotic Cell Engulfment Genes draper and ced-6 in Programmed Axon Pruning during Drosophila Metamorphosis
Authors: Takeshi Awasaki, Ryoko Tatsumi, Kuniaki Takahashi, Kunizo Arai, Yoshinobu Nakanishi, Ryu Ueda, Kei Ito
Journal: Neuron (2006)