tbuckley/cabot-search huggingface dataset:
Severe Hypoglycemia and Cardiovascular Disease Incidence in Type 1 Diabetes
Authors: Gabriella Gruden, Federica Barutta, Nish Chaturvedi, Casper Schalkwijk, Coen D. Stehouwer, Daniel R. Witte, John H. Fuller, Paolo Cavallo Perin, Graziella Bruno
Journal: Diabetes Care (2012)

Frequent episodes of severe hypoglycemia may increase the risk of cardiovascular disease (CVD) in people with diabetes. Our aim was to study the relationship between severe hypoglycemic episodes and CVD incidence in subjects with type 1 diabetes, and further, to assess if markers of inflammation/endothelial injury were enhanced in individuals who experienced hypoglycemic episodes.The prospective study included 2,181 type 1 diabetic patients from the EURODIAB Prospective Complications Study. At baseline, frequency of self-reported severe hypoglycemia, defined as episodes serious enough to require the help of another person, was assessed based on responses to a patient questionnaire. Both fatal/nonfatal CVD was assessed 7.3 years after baseline examination. At the follow-up visit, data on both severe and nonsevere hypoglycemic episodes in the previous year were collected through a questionnaire and markers of inflammation/stress response/endothelial injury measured by enzyme-linked immunosorbent assays in the 531 subjects of the nested case-control study, including 363 case subjects with one or more complications of diabetes and 168 control subjects with no evidence of any complication.During the follow-up period, 176 patients had incident CVD. Logistic regression analysis showed that severe hypoglycemia at the baseline examination was not associated with incidence of CVD (adjusted odds ratios [95% CI]: one to two episodes, 0.87 [0.55-1.37]; three or more episodes, 1.09 [0.68-1.75]). Furthermore, follow-up serum levels of markers of endothelial damage/inflammation were not cross-sectionally associated with the frequency of hypoglycemic episodes.Taken together our data do not support the hypothesis that in type 1 diabetes, severe hypoglycemia increases the risk of CVD.
P105 Complications of incisional hernia repair after orthotopic liver transplantation
Authors: M Hoare, C Callaghan, P Gibbs
Journal: Gut (2010)

Introduction  Incisional hernia is common after liver transplantation (LT) affecting between 5–23% of recipients. Operative repair is feasible but complications may be increased given co-morbidity in LT recipients. Hernia recurrence rates after repair range between 16–50% in other series.  Method  A retrospective review of incisional herniorrhaphy identified from our institutional LT database was conducted to determine post-operative complication and recurrence rates. Complications were categorised into chest: PE, chest sepsis, re-intubation; Renal: acute renal failure defined by RIFLE criteria, requirement for RRT and one year follow-up renal function; Wound: wound infection by clinical or microbiological diagnosis. Hernia recurrence was defined by clinical or radiological diagnosis.  Results  Sixty-nine herniorrhaphy procedures were identified in 59 individuals (38 male (64%); mean age 59.3 (range (25.9–77.6)); 16 (23%) diabetics) performed at a median 1053 days (range 130–6932) after LT Median length of in-hospital stay was 7 days (range 1–33). There were no liver-related complications. Chest sepsis occurred in 13 of 69 (19%) cases; 12 settled with antibiotics; 1 patient with cystic fibrosis required mechanical ventilation. There were no pulmonary emboli. There was a significant rise in creatinine from pre-operative median of 102 μM (57–545 μM) to post-operative of 125 μM (75–575 μM) (p  C. difficile -diarrhoea and wound seroma. After each repair subjects were followed for a median 928 days (range 18–3323). 18/69 (26%) procedures were complicated by recurrent hernia at a median of 407 days (6–1572) of which 2 were incarcerated. Kaplan-Meier analysis determined a 1, 2 and 3 year hernia-free survival of 87%, 74% and 72% respectively.  Conclusion  There were significant rates of chest and renal complications following incisional herniorrhaphy in liver transplant recipients, but few long-term sequelae. Incisional hernia repair was complicated by a 26% 2-year recurrence rate.
Complementation of a pathogenic <i>IFNGR2</i> misfolding mutation with modifiers of N-glycosylation
Authors: Guillaume Vogt, Jacinta Bustamante, Ariane Chapgier, Jacqueline Feinberg, Stephanie Boisson Dupuis, Capucine Picard, Nizar Mahlaoui, Laure Gineau, Alexandre Alcaïs, Christophe Lamaze, Jennifer M. Puck, Geneviève de Saint Basile, Claudia Djambas Khayat, Raymond Mikhael, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2008)

Germline mutations may cause human disease by various mechanisms. Missense and other in-frame mutations may be deleterious because the mutant proteins are not correctly targeted, do not function correctly, or both. We studied a child with mycobacterial disease caused by homozygosity for a novel in-frame microinsertion in IFNGR2. In cells transfected with the mutant allele, most of the interferon γ receptor 2 (IFN-γR2) protein was retained within the cell, and that expressed on the cell surface had an abnormally high molecular weight (MW). The misfolding mutation was not gain-of-glycosylation, as it created no new N-glycosylation site. The mutant IFNGR2 allele was null, as the patient's cells did not respond to IFN-γ. Based on the well-established relationship between protein N-glycosylation and protein quality control processes, we tested 29 compounds affecting maturation by N-glycosylation in the secretory pathway. Remarkably, up to 13 of these compounds reduced the MW of surface-expressed mutant IFN-γR2 molecules and restored cellular responsiveness to IFN-γ. Modifiers of N-glycosylation may therefore complement human cells carrying in-frame and misfolding, but not necessarily gain-of-glycosylation, mutations in genes encoding proteins subject to trafficking via the secretory pathway. Some of these compounds are available for clinical use, paving the way for clinical trials of chemical complementation for various human genetic traits.
Entecavir versus Lamivudine for Patients with HBeAg-Negative Chronic Hepatitis B
Authors: Ching-Lung Lai, Daniel Shouval, Anna S. Lok, Ting-Tsung Chang, Hugo Cheinquer, Zachary Goodman, Deborah DeHertogh, Richard Wilber, Richard C. Zink, Anne Cross, Richard Colonno, Lori Fernandes
Journal: New England Journal of Medicine (2006)

Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B.In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis).Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P=0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups.Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).
β-Catenin Up-Regulates the Expression of the Urokinase Plasminogen Activator in Human Colorectal Tumors
Authors: Elke Hiendlmeyer, Susanne Regus, Stella Wassermann, Falk Hlubek, Angela Haynl, Arno Dimmler, Claudia Koch, Claudia Knoll, Moniek van Beest, Ute Reuning, Thomas Brabletz, Thomas Kirchner, Andreas Jung
Journal: Cancer Research (2004)

Abstract Expression of the urokinase plasminogen activator (uPA) increases during the progression of colorectal tumors from adenomas to carcinomas. The highest amounts of uPA are found at the invasion front of carcinomas, which also displays a strong expression of nuclear β-catenin and is therefore a region expressing β-catenin target genes at high levels. Here we show that β-catenin contributes to the transactivation of uPA. Therefore, β-catenin might have an impact on the capacity of colorectal tumors for invasion and metastasis, as well as dormancy, which are hallmarks of cancer.
Cerebral Structural Changes in Diabetic Kidney Disease: African American–Diabetes Heart Study MIND
Authors: Kaycee M. Sink, Jasmin Divers, Christopher T. Whitlow, Nicholette D. Palmer, S. Carrie Smith, Jianzhao Xu, Christina E. Hugenschmidt, Benjamin C. Wagner, Jeff D. Williamson, Donald W. Bowden, Joseph A. Maldjian, Barry I. Freedman
Journal: Diabetes Care (2014)

OBJECTIVE Albuminuria and reduced kidney function are associated with cognitive impairment. Relationships between nephropathy and cerebral structural changes remain poorly defined, particularly in African Americans (AAs), a population at higher risk for both cognitive impairment and diabetes than European Americans. We examined the relationship between urine albumin:creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and cerebral MRI volumes in 263 AAs with type 2 diabetes. RESEARCH DESIGN AND METHODS Cross-sectional associations between renal parameters and white matter (WM), gray matter (GM), hippocampal, and WM lesion (WML) volumes were assessed using generalized linear models adjusted for age, education, sex, BMI, hemoglobin A1c (HbA1c) level, and hypertension. RESULTS Participants had a mean (SD) age of 60.2 years (9.7 years), and 62.7% were female. Mean diabetes duration was 14.3 years (8.9 years), HbA1c level was 8.2% (2.2%; 66 mmol/mol), eGFR was 86.0 mL/min/1.73 m2 (23.2 mL/min/1.73 m2), and UACR was 155.8 mg/g (542.1 mg/g; median 8.1 mg/g). Those with chronic kidney disease (CKD) (eGFR &amp;lt;60 mL/min/1.73 m2 or UACR &amp;gt;30 mg/g) had smaller GM and higher WML volumes. Higher UACR was significantly associated with higher WML volume and greater atrophy (larger cerebrospinal fluid volumes), and smaller GM and hippocampal WM volumes. A higher eGFR was associated with larger hippocampal WM volumes. Consistent with higher WML volumes, participants with CKD had significantly poorer processing speed and working memory. These findings were independent of glycemic control. CONCLUSIONS We found albuminuria to be a better marker of cerebral structural changes than eGFR in AAs with type 2 diabetes. Relationships between albuminuria and brain pathology may contribute to poorer cognitive performance in patients with mild CKD.
Protection from Rapamycin-Induced Apoptosis by Insulin-Like Growth Factor-I Is Partially Dependent on Protein Kinase C Signaling
Authors: Kuntebommanahalli N. Thimmaiah, John B. Easton, Peter J. Houghton
Journal: Cancer Research (2010)

Rapamycin-induced apoptosis in sarcoma cells is inhibited by insulin-like growth factor-I (IGF-I) through a signaling pathway independent of Ras-extracellular signal-regulated kinase 1/2 and Akt. IGF-I induces Bad phosphorylation (Ser112, Ser136, and Ser155) in a pathway involving phosphoinositide 3' kinase (PI3K) and protein kinase C (PKC; mu, epsilon, or theta) resulting in sequestering Bad from mitochondria and subsequently interacting with 14-3-3gamma in the cytosol. Gene knockdown of Bad, Bid, Akt1, Akt2, PKC-mu, PKC-epsilon, or PKC-theta was achieved by transient transfection using small interfering RNAs. Results indicate that IGF-I signaling to Bad requires activation of PI3K and PKC (mu, theta, epsilon) but not mTOR, Ras-extracellular signal-regulated kinase 1/2, protein kinase A, or p90(RSK). Wortmannin blocked the phosphorylation of PKC-mu (Ser744/Ser748), suggesting that PI3K is required for the activation of PKCs. PKCs phosphorylate Bad under in vitro conditions, and the association of phosphorylated Bad with PKC-mu or PKC-epsilon, as shown by immunoprecipitation, indicated direct involvement of PKCs in Bad phosphorylation. To confirm these results, cells overexpressing pEGFP-N1, wt-Bad, or Bad with a single site mutated (Ser112Ala; Ser136Ala; Ser155Ala), two sites mutated (Ser(112/136)Ala; Ser(112/155)Ala; Ser(136/155)Ala), or the triple mutant were tested. IGF-I protected completely against rapamycin-induced apoptosis in cells overexpressing wt-Bad and mutants having either one or two sites of phosphorylation mutated. Knockdown of Bid using small interfering RNA showed that Bid is not required for rapamycin-induced cell death. Collectively, these data suggest that IGF-I-induced phosphorylation of Bad at multiple sites via a pathway involving PI3K and PKCs is important for protecting sarcoma cells from rapamycin-induced apoptosis.
Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction
Authors: L. Moleda, J. Trebicka, P. Dietrich, E. Gabele, C. Hellerbrand, R. H. Straub, T. Sauerbruch, J. Schoelmerich, R. Wiest
Journal: Gut (2011)

<h3>Background</h3> Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved. <h3>Methods</h3> All experiments were performed in CCl<sub>4</sub>-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to α<sub>1</sub>-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries. <h3>Results</h3> NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries. <h3>Conclusions</h3> NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.
Oral Phosphodiesterase-5 Inhibitors and Hormonal Treatments for Erectile Dysfunction: A Systematic Review and Meta-analysis
Authors: Alexander Tsertsvadze, Howard A. Fink, Fatemeh Yazdi, Roderick MacDonald, Anthony J. Bella, Mohammed T. Ansari, Chantelle Garritty, Karla Soares-Weiser, Raymond Daniel, Margaret Sampson, Steven Fox, David Moher, Timothy J. Wilt
Journal: Annals of Internal Medicine (2009)

Background: Erectile dysfunction (ED) is a common male sexual disorder. The relative benefits and harms of pharmacologic therapies for ED, as well as the value of hormonal testing in men with ED, are uncertain. Purpose: To evaluate the efficacy and harms of oral phosphodiesterase-5 (PDE-5) inhibitors and hormonal treatments for ED and assess the effect of measuring serum hormone levels on treatment outcomes for ED. Data Sources: English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, AMED, and SCOPUS through April 2009. Trial reference lists also were scanned. Study Selection: Randomized, controlled trials (RCTs) of oral PDE-5 inhibitors and hormonal treatment for ED, and observational studies reporting measurement of serum hormone levels, prevalence of hormonal abnormalities, or both in men with ED. Data Extraction: Two independent reviewers abstracted data on study, participant, and treatment characteristics; efficacy and harms outcomes; and prevalence of hormonal abnormalities. Data Synthesis: Data, primarily from short-term trials (≤12 weeks), indicate that PDE-5 inhibitors were more effective than placebo in improving sexual intercourse success (69.0% vs. 35.0%). The proportion of men with improved erections was significantly greater among those treated with PDE-5 inhibitors (range, 67.0% to 89.0%) than with placebo (range, 27.0% to 35.0%). The PDE-5 inhibitors were associated with increased risk for any adverse events compared with placebo (for example, relative risk with sildenafil, 1.72 [95% CI, 1.53 to 1.93]). In 4 head-to-head RCTs comparing sildenafil, vardenafil, and tadalafil, improvement of ED and adverse events did not differ among treatments. Results from 15 RCTs evaluating hormonal treatment of ED were inconsistent on whether treatment improved outcomes. Evidence was insufficient regarding whether men with ED had a higher prevalence of hypogonadism than men without ED. Limitations: Many RCTs were of low methodological and reporting quality, particularly those involving hormonal treatments or directly comparing different PDE-5 inhibitors. Most RCTs provided only short-term efficacy and harms data. Conclusion: Oral PDE-5 inhibitors improved erectile functioning and had similar efficacy and safety profiles. Results on the efficacy of hormonal treatments and the value of hormone testing in men with ED were inconclusive. Primary Funding Source: Agency for Healthcare Research and Quality.
Measurement of Pressures in Man by Cardiac Catheters
Authors: EARL H. WOOD, ISIDOOR R. LEUSEN, HOMER R. WARNER, J. LEO WRIGHT
Journal: Circulation Research (1954)

Relationships between artefacts in recorded intracardiac pulses and the dynamic response and susceptibility of catheter-manometer systems to artefacts caused by motion of the catheter were investigated. Sine-wave motions of the catheter, resembling motion frequently seen when the catheter is in the pulmonary artery, produce sine-wave pressure variations with peak-to-peak amplitudes of 10 mm. Hg. Square-wave motions (impacts) produce high-frequency pressure variations, greatest (10 to 200 mm. Hg) when directed along the axis and much less when perpendicular to the axis of the catheter. High-fidelity records of pressure by conventional cardiac catheter-manometer systems are most unlikely when such catheters are threaded through the beating heart.
Pentagastrin induced motility pattern in the human upper gastrointestinal tract is reversed by proglumide.
Authors: J F Erckenbrecht, J Caspari, M Wienbeck
Journal: Gut (1984)

The effects of pentagastrin and the putative gastrin antagonist proglumide on interdigestive motility of the upper small bowel were studied in a randomised double blind study in 10 healthy human volunteers. Intraluminal pressures were recorded manometrically in the duodenum and jejunum for five hours. Sixty minutes after starting a pentagastrin infusion (0.15 micrograms/kg/h) either placebo or proglumide was infused intravenously. Pentagastrin converted the normal interdigestive motility to irregular motor activity, while proglumide restored the periodic fasted pattern. We conclude that gastrin is a likely candidate involved in the conversion of the fasted to the fed motility pattern in the human upper gut.
Choosing the Best Strategy to Prevent Childhood Iron Deficiency
Authors: Alan R. Cohen
Journal: JAMA (1999)

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SOMATO-PSYCHIC DISORDERS OF OLD AGE
Authors: HAROLD D. PALMER, FRANCIS J. BRACELAND, DONALD W. HASTINGS
Journal: American Journal of Psychiatry (1943)

1. Increase in the number of patients admitted to mental hospitals with senile psychoses was believed to indicate the need of studying such cases with a view to their prevention and amelioration. One hundred twenty-three cases admitted to the Pennsylvania Hospital from 1930 to 1939 inclusive, and diagnosed at staff conferences after three or four weeks of hospital treatment and observation as senile dementia or arteriosclerotic psychoses, were studied. 2. In this group of long-standing cases treated 25 per cent made social recoveries and were able to return to normal life. 3. Prodromal symptomatology beginning at least six months to one year before hospitalization is usual in such cases. Points aiding in early recognition of the prodromal stage have been stressed. 4. Multiplicity of causation is almost universal, with definite somatic disorders heavily preponderant. 5. General treatment consisting of elimination of foci of infection, correction of toxemias, constipation, avitaminosis, malnutrition, dehydration, fatigue and circulatory deficiencies is essential. Special treatment may be given as indicated. 6. In general accurate prognosis is not possible, but is somewhat more favorable in cases showing correctible somatic disorders. 7. There is reason to believe that the recovery rate of 25 per cent can be duplicated and improved upon, and preventive measures made more effective, as the traditional medical attitude of hopelessness towards the mental disorders of old age gives place to one of scientific inquiry and painstaking clinical effort. 8. Organization of a nation-wide system of preventive treatment for preserving somato-psychic health in the old age group would be, both medically and economically, a richly repaying undertaking.