tbuckley/cabot-search huggingface dataset:
Reduced Vascular Endothelial Growth Factor Expression and Intra-Epidermal Nerve Fiber Loss in Human Diabetic Neuropathy
Authors: Cristian Quattrini, Maria Jeziorska, Andrew J.M. Boulton, Rayaz A. Malik
Journal: Diabetes Care (2007)

OBJECTIVE—To assess the relevance of vascular endothelial growth factor (VEGF) in the maintenance of peripheral nerve integrity in diabetic neuropathy we have assessed the expression of VEGF and intra-epidermal nerve fiber density (IENFD) in skin biopsy samples from diabetic patients. RESEARCH DESIGN AND METHODS—Fifty-three diabetic patients and 12 nondiabetic control subjects underwent neurological evaluation, electrophysiology, quantitative sensory, and autonomic function testing. Dermal blood flow responses were evaluated with laser Doppler flowmetry. Skin biopsies were performed on the dorsum of the foot, and IENFD was quantified and compared with the expression of vascular endothelial growth factor A (VEGF-A), its receptor vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1α (HIF-1α), and microvessel density. RESULTS—IENFD decreased progressively with increasing severity of diabetic neuropathy (P &amp;lt; 0.001). The dermal blood flow response to acetylcholine was reduced in diabetic patients with mild and moderate neuropathy (P &amp;lt; 0.01), and the intensity of staining for epidermal VEGF-A was significantly reduced in diabetic patients compared with control subjects (P &amp;lt; 0.01). Epidermal HIF-1α and VEGFR-2 expression did not differ between groups. CONCLUSIONS—Progressive endothelial dysfunction, a reduction in VEGF expression, and loss of intra-epidermal nerve fibers occurs in the foot skin of diabetic patients with increasing neuropathic severity.
LIP expression is regulated by IGF-1R signaling and participates in suppression of anoikis
Authors: Huili Li, Brenda R Baldwin, Cynthia A Zahnow
Journal: Molecular Cancer (2011)

Abstract Background The transcription factor, CCAAT enhancer binding protein-β (C/EBPβ), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation. Increases in the ratio of LIP/LAP are associated with aggressive, metastatic breast cancer; however, little is known regarding the molecular mechanisms that regulate LIP expression or the biological actions of an increase in the LIP/LAP ratio. Metastasis is highly dependent upon the suppression of anoikis and the role of C/EBPβ and LIP in this anchorage-independent, survival process is currently not known in mammary epithelial cells. IGF-1R signaling is important for the survival of breast cancer cells and crosstalk between IGF-1R and EGFR signaling pathways have been implicated in the development of more aggressive disease. We therefore evaluated in mammary epithelial cells whether IGF-1R signaling regulates the LIP/LAP ratio, analyzed the potential interplay between EGFR and IGF-1R signaling and addressed the biological significance of increased LIP expression in cellular survival and suppression of anoikis. Results Our data provide the first evidence that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. Although crosstalk between IGF-1R signaling and EGFR signaling is detectable in MCF10A cells, this crosstalk is not required for the IGF-1 mediated regulation of LIP expression. Rather, the critical regulator of IGF-1 induced LIP expression appears to be EGFR-independent, Akt activity. Our data also demonstrate that increases in LIP expression promote cell survival via suppression of anoikis. Likewise, knockdown of total C/EBPβ leads to increased cell death and suggest that C/EBPβ expression is important for survival and resistance to anoikis. IGF-1 treatment can partially rescue vector control cells from anoikis; however, cells with reduced C/EBPβ expression do not survive anoikis. Conclusions Taken together, our data demonstrate that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. C/EBPβ expression and elevations in LIP play an important role in regulating cellular survival via suppression of anoikis, in an IGF-1R mediated context or in a manner independent of IGF-1R signaling.
Concurrent infection with Schistosoma mansoni attenuates inflammation induced changes in colonic morphology, cytokine levels, and smooth muscle contractility of trinitrobenzene sulphonic acid induced colitis in rats
Authors: T G Moreels
Journal: Gut (2003)

<b>Background and aims:</b> Crohn's disease, characterised by chronic T helper 1 (Th1) inflammation and dysmotility of the gut, is most prevalent in developed countries. Parasitic infections are most prevalent in developing countries and induce a T helper 2 (Th2) immune response. We hypothesised that this Th2 immune response protects against Th1 gut inflammation. <b>Methods:</b> The parasite <i>Schistosoma mansoni</i> induces a transient Th2 immune response in the semipermissive rat host. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis is an experimental model of Th1-like gut inflammation. The effect of concurrent infection with <i>S mansoni</i> on the course of TNBS induced colitis was assessed using macroscopic and microscopic damage scores, histology, myeloperoxidase (MPO) activity assay, cytokine production assay, and by studying in vitro contractility of longitudinal and circular colonic muscle strips. <b>Results:</b> TNBS induced colitis that spontaneously healed after four weeks. Concurrent infection with <i>S mansoni</i> significantly reduced the duration of TNBS induced colitis to two weeks, as shown by macroscopic and microscopic damage scores and by a faster decrease in colonic MPO activity. TNBS increased colonic interleukin 2 (IL-2) production whereas <i>S mansoni</i> increased splenic IL-4 and IL-2 levels. Contractility of longitudinal and circular muscle strips was maximally inhibited one week after TNBS and normalised after three weeks. After four weeks, longitudinal muscle strip contractility was significantly increased. Concurrent infection with <i>S mansoni</i> normalised longitudinal muscle contractility after one week whereas circular muscle contractility remained inhibited. <b>Conclusions:</b> Concurrent infection with <i>S mansoni</i> significantly attenuates TNBS induced colitis in the rat. Inflammation induced disturbances in contractility of longitudinal and circular colonic muscle strips may outlast the inflammatory reaction.
Varicocele and male infertility: Part II: Varicocele: effect on sperm functions
Authors: R. Hauser
Journal: Human Reproduction Update (2001)

Despite the numerous studies published over the past decade, the role of varicocele in male infertility is still controversial. Although more frequent in infertile men, its influence on sperm production or function has not, as yet, been determined. Moreover, the exact mechanism of varicocele action is not clear. We have surveyed the literature, the correlation of varicocele to sperm parameters and to sperm function tests, such as binding capacity, hypo-osmotic swelling test, presence of reactive oxygen species, and in particular, the correlation to fertility potential. Almost every subject examined had contradictory results. Larger control studies may possibly elucidate and clarify the cases in which varicocele is associated to sperm function, and where treatment may improve fertility.
Long-Term Follow-Up After Percutaneous Transluminal Coronary Angioplasty Was Not Performed Based on Intravascular Ultrasound Findings
Authors: Andrea S. Abizaid, Gary S. Mintz, Roxana Mehran, Alexandre Abizaid, Alexandra J. Lansky, Augusto D. Pichard, Lowell F. Satler, Hongsheng Wu, Chrysoula Pappas, Kenneth M. Kent, Martin B. Leon
Journal: Circulation (1999)

Background —Angiography is limited in determining the anatomic severity of coronary artery stenoses. Clinical decision-making in patients with symptoms and intermediate lesions remains challenging. Methods and Results —The current analysis included 300 patients (357 intermediate native artery lesions) in whom intervention was deferred based on intravascular ultrasound (IVUS) findings. Standard clinical, angiographic, and IVUS parameters were collected. Patients were followed for &gt;1 year. Events occurred in 24 patients (8%). They included 2 cardiac deaths, 4 myocardial infarctions, and 18 target-lesion revascularizations (TLR; 12 percutaneous transluminal coronary angiographies and 6 coronary artery bypass grafts; only 3 TLRs occurred within 6 months after the IVUS study). All significant univariate clinical, angiographic, and IVUS parameters ( P &lt;0.05) were tested in multivariate models. These included diabetes mellitus, IVUS lesion lumen area, maximum lumen diameter, minimum lumen diameter, plaque area, plaque burden, and area stenosis (AS). No angiographic measurement was significant at P &lt;0.05. The only independent predictors of an event (death, myocardial infarction, or TLR) were IVUS minimum lumen area and AS. The only independent predictors of TLR were diabetes mellitus, IVUS minimum lumen area, and AS. In 248 lesions with a minimum lumen area ≥4.0 mm 2 , the event rate was only 4.4% and the TLR rate 2.8%. Conclusions —Long-term follow-up after IVUS-guided deferred interventions in patients with de novo intermediate native artery lesions showed a low event rate. In patients with a minimum lumen area ≥4.0 mm 2 , the event rate was especially low. IVUS imaging is an acceptable alternative to physiological assessment in these patients.
Ventricular and Periventricular Structural Volumes in First- Versus Multiple-Episode Bipolar Disorder
Authors: Stephen M. Strakowski, Melissa P. DelBello, Molly E. Zimmerman, Glen E. Getz, Neil P. Mills, Jennifer Ret, Paula Shear, Caleb M. Adler
Journal: American Journal of Psychiatry (2002)

Ventriculomegaly has been reported in bipolar disorder, although whether it occurs at illness onset or progresses during the course of the disorder is unknown. In addition, it is unknown whether ventriculomegaly in bipolar disorder reflects acquired volume loss or underdevelopment of periventricular structures.Magnetic resonance imaging was used to measure the volumes of the lateral and third ventricles and periventricular structures (caudate, putamen, thalamus, hippocampus). Patients with DSM-IV bipolar disorder, 18 who were having a first episode and 17 with multiple episodes, were compared with 32 healthy subjects.The lateral ventricles were significantly larger in the patients with multiple-episode bipolar disorder than in the first-episode patients or the healthy subjects, even after periventricular and total cerebral volumes were taken into account. Having larger lateral ventricles was associated with a higher number of prior manic episodes. The multiple-episode patients had a smaller total cerebral volume than the healthy subjects but not the first-episode patients. The putamen was significantly larger in the first-episode patients (and nearly so in the multiple-episode patients) than in the healthy subjects, although there was no difference between patient groups.Lateral ventriculomegaly was greater in bipolar disorder patients who had had repeated manic episodes, but it does not appear to be secondary to small critical periventricular structures. A larger than normal striatum, which has been reported in previous studies, was observed in first-episode patients. These results support the importance of prospectively studying neuroanatomic changes in bipolar disorder.
Childhood Levels of Serum Apolipoproteins B and A-I Predict Carotid Intima-Media Thickness and Brachial Endothelial Function in Adulthood
Authors: Markus Juonala, Jorma S.A. Viikari, Mika Kähönen, Tiina Solakivi, Hans Helenius, Antti Jula, Jukka Marniemi, Leena Taittonen, Tomi Laitinen, Tapio Nikkari, Olli T. Raitakari
Journal: Journal of the American College of Cardiology (2008)
The `dnet’ approach promotes emerging research on cancer patient survival
Authors: Hai Fang, Julian Gough
Journal: Genome Medicine (2014)

We present the `dnet' package and apply it to the `TCGA' mutation and clinical data of >3,000 patients. We uncover the existence of an underlying gene network that at least partially controls cancer `survivalness', with mutations that are significantly correlated with patient survival, yet independent of tumour origin and type. The survivalness network has natural community structure corresponding to tumour hallmarks, and contains genes that are potentially druggable in the clinic. This network has evolutionary roots in Deuterostomia identifying PTK2 and VAV1 as under-valued relative to more studied genes from that era. The `dnet' R package is available at http://cran.r-project.org/package=dnet .
A Shining Light in the Darkness for the Treatment of Pancreatic Neuroendocrine Tumors
Authors: Jaume Capdevila, Josep Tabernero
Journal: Cancer Discovery (2011)

Abstract Gastroenteropancreatic neuroendocrine tumors are rare neoplasms; past decades have seen limited research channeled into this area. Recently, 2 placebo-controlled phase III trials using 2 drugs—everolimus and sunitinib—with distinct molecular rationales achieved their principal objective of increasing survival in patients with advanced pancreatic neuroendocrine tumors (PNET). Nonetheless, several questions remain unanswered, notably defining the optimal schedule for integrating these targeted agents with conventional cytotoxics and other treatment options, and identifying appropriate biomarkers for patients with the potential to derive greater benefit. In this article, we analyze the results of the 2 largest studies ever completed in patients with PNETs and discuss the challenges for future drug development in this setting. Summary: Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies. Cancer Discovery; 1(3); 213–21. © 2011 AACR.
Increased Plasma Arginine Vasopressin in Clinical Adrenocortical Insufficiency and Its Inhibition By Glucosteroids*
Authors: Abdul B. J. Ahmed, Barbara C. George, Carlos Gonzalez-Auvert, Joseph F. Dingman
Journal: Journal of Clinical Investigation (1967)

Trichloroacetic acid extracts of plasma were fractionated on a CG-50 resin column and the 50% acetic acid eluents chromatographed on silicic acid-impregnated glass paper in butanol-acetic acid-water. The specific arginine vasopressin (AVP) zone was eluted and assayed for antidiuretic activity in the diuretic rat. Thioglycolate inactivation was used to confirm AVP activity. Recovery of as little as 4 muU AVP per ml plasma ranged between 80 and 90%. In normal subjects after an overnight fast, plasma AVP ranged between 2.5 and 10.0 muU per ml. AVP secretion was inhibited by hemodilution and stimulated with nicotine and hypertonic saline. Plasma AVP was absent in patients with diabetes insipidus even after neurohypophyseal stimulation. Plasma AVP was abnormally elevated during mild dehydration and remained above the normal range despite hemodilution in patients with untreated adrenocortical insufficiency demonstrating a delayed water diuresis. Glucosteroid therapy lowered plasma AVP to normal in dehydrated patients. A normal diuretic response to hydration was accompanied by a fall in plasma AVP to zero in steroid-treated patients. These findings suggest that hypersecretion of AVP may play an important role in the abnormal water metabolism of adrenocortical insufficiency and that the glucosteroids promote normal water diuresis by inhibiting the secretion of AVP from the neurohypophysis.
Successful delivery of clinical gastroenterology studies in the UK
Authors: Mark A Hull, John T McLaughlin
Journal: Gut (2014)

Recent publications in Gut 1 ,2 have highlighted the beneficial role of the National Institute for Health Research (NIHR) Clinical Research Network in supporting clinical gastroenterology research in the UK.3 On an European level, the European Clinical Research Infrastructures Network provides integrated support to multinational clinical research projects in partner countries. The overarching aim of the NIHR Clinical Research Network is to maximise clinical research delivery by providing the infrastructure that allows high-quality studies to be undertaken in the NHS. The support available encompasses many aspects of the study life-cycle, including study set-up, researcher training and aiding study delivery, for example by providing protected clinician research time and research nurse support at individual study sites in NHS institutions. All clinical gastroenterology research studies entered onto the NIHR Clinical Research Network Portfolio are eligible for support.3 

The performance of the NIHR Clinical Research Network Portfolio is closely monitored using several High Level Objectives, one of which is increasing the proportion of studies that deliver in line with their planned delivery time and patient recruitment targets. The progress of each study during the recruitment phase is rated on a BRAG (black/red/amber/green) system, with studies deemed to be on target (‘green’) if recruitment is running at least 80% of that expected according to each study's self-determined recruitment schedule.4 Upon closure, studies which successfully recruited to their …
Induced sputum eosinophils and neutrophils and bronchiectasis severity in allergic bronchopulmonary aspergillosis
Authors: P.A.B. Wark, N. Saltos, J. Simpson, S. Slater, M.j Hensley, P.G. Gibson
Journal: European Respiratory Journal (2000)

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus that may progress to bronchiectasis. The aim of the present study was to characterize airway inflammation in patients with clinically stable ABPA and asthma, and to correlate this with bronchiectasis severity. Subjects with ABPA and central bronchiectasis (ABPA-CB; n=16) and ABPA with serological evidence alone (ABPA-S; n=10) were studied. Comparison groups were A. fumigatus-sensitized asthma (n=19), non-A. fumigatus-sensitized asthma (n=15) and healthy controls (n=8). Hypertonic saline challenge, sputum induction and high-resolution computed tomography (HRCT) of the chest were performed. Sputum eosinophil numbers were markedly elevated in ABPA-CB (median 8.4%) compared to ABPA-S (2.4%), A. fumigatus-sensitized asthma (1.8%), asthma (1.8%) and controls (0.3%) (p&lt;0.01); sputum eosinophil cationic protein levels were higher in ABPA-CB (median 13,706 ng.mL(-1)), compared to ABPA-S (1,633.5 ng.mL(-1)), A. fumigatus-sensitized asthma (1,550.7 ng.mL(-1)), asthma (309.2 ng.mL(-1)), and controls (110 ng.mL(-1)) (p&lt;0.001). ABPA-CB also showed increased sputum neutrophil number (median 60.3%) compared to the other groups (controls 29.3%) (p=0.01). The severity of bronchiectasis on HRCT correlated with sputum neutrophil (r=0.6) and eosinophil number (r=0.5) but not serum immunoglobulin-E levels. In conclusion, clinically stable allergic bronchopulmonary aspergillosis with bronchiectasis is characterized by an intense heterogenous inflammatory infiltrate consisting of eosinophils and neutrophils, which correlates closely with the severity of bronchiectasis on high-resolution computed tomography. Sputum analysis may be useful in monitoring the course of allergic bronchopulmonary aspergillosis.
Mechanism of exercise-induced hypoglycemia in depancreatized dogs maintained on long-acting insulin.
Authors: R Kawamori, M Vranic
Journal: Journal of Clinical Investigation (1977)

Human diabetics on intermediate and long-acting insulin occasionaly become hypoglycemic during exercise. We have shown previously that during exercise, hypoglycemia did not occur in depancreatized insulin-infused dogs because the increments in glucose production and utilization were proportional and of the same magnitude as in normal dogs. Therefore, to elucidate the mechanism of the glucose-lowering effect of strenuous exercise, we measured glucose production and utilization, metabolic clearance of glucose, and serum immunoreactive insulin in postabsorptive depancreatized dogs 8 h after a subcutaneous injection of protamine zinc and crystalline insulin. During rest, plasma glucose was stable, but ranged between hypoglycemia and hyperglycemia. Hyperglycemia was associated with overproduction of glucose, indicating insulin deficiency despite normal or elevated serum immunoreactive insulin. Glucose clearance, as in normal dogs, increased threefold but glucose production increased only marginally (50%) and, consequently, glucose decreased in plasma. The decrease of plasma glucose was directly proportional to the preexercise concentration and production of glucose. The magnitude of inhibition glucose production was not correlated with the serum immunoreactive insulin indicating either that some released insluin was not active or that a moderate immunoreactive insulin increment induced a near-maximal inhibition. It is concluded that in depancreatized dogs injected with protamine zinc insulin, exercise accelerates mobilization of insulin from its injection site presumably because of increased blood and lymph flow. Glucose utilization did not exceed that in normal dogs, but hepatic glucose production failed to increase sufficiently to meet the needs of muscle in exercise.
Association of the Infant Gastrointestinal Microbiome with Nocturnal Symptoms in Children with Asthma
Authors: Albert M. Levin, Suzanne Havstad, Alexandra R. Sitarik, Christine L.M. Joseph, Kei Fujimura, Ganesa R. Wegienka, Edward M. Zoratti, Haejin Kim, Christine Cole Johnson, Homer A. Boushey, Susan V. Lynch, Dennis R. Ownby
Journal: Journal of Allergy and Clinical Immunology (2015)
From sick notes to fit notes
Authors: J. Verbeek, I. Madan
Journal: BMJ (2009)

Doctors need better support in dealing with work related medical problems

Dame Carol Black’s report Working for a Healthier Tomorrow strongly advocates changes in the arrangements for sickness certification to promote better health of the working age population in the United Kingdom.1 The report states that current social security systems encourage people to stay off work until they are fully medically fit to return to their job. This policy increases the risk of long term disability and subsequent loss of employment.

General practitioners are usually the first healthcare professionals that employees encounter when they are off sick from work. After seven days of absence from work because of illness, employers can request a sick note from the employee, so they can claim statutory sick pay. Employees will usually seek advice from their general practitioner regarding their fitness to return to work. Herein lies the problem. General practitioners feel that they are the patients’ advocates and thus have to follow their patients’ wishes. Few general practitioners think that …