tbuckley/cabot-search huggingface dataset:
Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.
Authors: W C Hsueh, B D Mitchell, R Aburomia, T Pollin, H Sakul, M Gelder Ehm, B K Michelsen, M J Wagner, P L St Jean, W C Knowler, D K Burns, C J Bell, A R Shuldiner
Journal: Diabetes Care (2000)

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to &amp;lt;0.0001). CONCLUSIONS: Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.
Decrease in glomerular filtration rate in Japanese patients with type 2 diabetes is linked to atherosclerosis.
Authors: H Taniwaki, Y Nishizawa, T Kawagishi, E Ishimura, M Emoto, T Okamura, Y Okuno, H Morii
Journal: Diabetes Care (1998)

We assessed the effects of atherosclerosis on the glomerular filtration rate (GFR) in patients with type 2 diabetes and who had micro- or normoalbuminuria.A total of 61 Japanese patients with type 2 diabetes were recruited from inpatients of Osaka City University Hospital. They ranged in age from 40 to 69 years (28 men and 33 women). Each subject collected a 24-h urine sample for quantitative analysis of albumin. Absence of albuminuria was defined as a urinary albumin excretion level of <30 mg/24 h (n = 36) and microalbuminuria as a level of 30-300 mg/24 h. The GFR was estimated using 99mTc diethylenetriamine pentaacetic renogram method. As indexes of atherosclerosis, we measured the intimal-medial thickness (IMT) and distensibility of the carotid artery using high-resolution B-mode ultrasonagraphy and an echo-tracking system. We measured the resistance index (RI) of the renal interlobar arteries by pulsed Doppler sonography.The clinical characteristics of type 2 diabetic patients with and without microalbuminuria did not differ except for duration of diabetes, which was longer in the patients with microalbuminuria. GFR also did not differ between the patients with and without microalbuminuria. GFR was significantly correlated with the patient's age (r = -0.256, P < 0.05), carotid IMT (r = -0.326, P < 0.05), carotid stiffness beta (r = -0.449, P < 0.001), and renal arterial RI (r = -0.365, P < 0.05). In multiple regression analysis, independent factors associated with GFR were carotid IMT (R2 = 0.108, P = 0.0102), carotid stiffness beta (R2 = 0.208, P = 0.0003), and renal artery RI (R2 = 0.130, P = 0.0043).The decline in GFR in type 2 diabetic patients in the early stages of nephropathy may be due in part to atherosclerosis.
Survival and Neurologic Recovery in Patients With ST-Segment Elevation Myocardial Infarction Resuscitated From Cardiac Arrest
Authors: Vinay R. Hosmane, Nowwar G. Mustafa, Vivek K. Reddy, Charles L. Reese, Angela DiSabatino, Paul Kolm, James T. Hopkins, William S. Weintraub, Ehsanur Rahman
Journal: Journal of the American College of Cardiology (2009)
Thrombophilia and the Risk of Recurrent Venous Thromboembolism—Reply
Authors: Francis Couturaud, Guy Meyer, Dominique Mottier
Journal: JAMA (2015)

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Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non–Small Cell Lung Cancer
Authors: Bruce E. Johnson, David Jackman, Pasi A. Jänne
Journal: Clinical Cancer Research (2007)

Abstract Background and Rationale: Only 10% of patients with relapsed non–small cell lung cancer (NSCLC) treated with chemotherapy or erlotinib have a partial response to treatment, and nearly all eventually recur and die from their NSCLC. Agents that can block other pathways in addition to the epidermal growth factor receptor signals may improve the therapeutic efficacy of erlotinib. Everolimus (RAD001) is an inhibitor of the mammalian target of rapamycin, which is downstream of initial epidermal growth factor receptor signaling. A trial combining erlotinib with everolimus has been undertaken for patients with relapsed NSCLC. Materials and Methods: Subjects with previously treated NSCLC are treated with increasing doses of daily erlotinib and everolimus given either daily or once weekly. The study's objectives in phase I are to assess the feasibility of combining daily erlotinib and either daily or weekly everolimus, to assess toxicity, and to determine the appropriate dose for subsequent trials. Results: The protocol calls for patients to be treated with escalating daily or weekly everolimus in combination with erlotinib given at doses of 100 mg daily to escalate to 150 mg daily. The dose escalation with both daily and weekly everolimus and erlotinib is ongoing. Conclusions: Everolimus has an appropriate rationale for therapeutic use in combination with erlotinib for patients with NSCLC. This manuscript will review the preclinical rationale for undertaking a study of erlotinib combined with everolimus for patients with relapsed NSCLC.
Mechanisms underlying regional differences in lipolysis in human adipose tissue.
Authors: H Wahrenberg, F Lönnqvist, P Arner
Journal: Journal of Clinical Investigation (1989)

Catecholamine-induced lipolysis was investigated in nonobese females and males. Isolated subcutaneous adipocytes were obtained from the abdominal and gluteal regions. The lipolytic effect of noradrenaline was four to fivefold more marked in abdominal adipocytes than in gluteal fat cells. This regional difference was more apparent in females than in males. No site differences were observed when lipolysis was stimulated with agents acting at different postreceptor levels. The beta-adrenergic lipolytic sensitivity was 10-20 times greater in abdominal adipocytes from both sexes than in gluteal adipocytes. Abdominal adipocytes from females showed a 40 times lower alpha 2-adrenergic antilipolytic sensitivity than did gluteal adipocytes, but the adenosine receptor sensitivity was similar in both sites. Beta-receptor affinity for agonists displayed no site or sex variation. Abdominal adipocytes showed a twofold increased beta-adrenoceptor density than did gluteal cells from both sexes. The alpha 2-adrenoceptor density was similar in all regions, but in females the affinity of clonidine for these sites was 10-15 times lower in the abdominal fat cells compared with gluteal cells. In conclusion, regional differences in catecholamine-induced lipolysis are regulated at the adrenoceptor level, chiefly because of site variations in beta-adrenoceptor density. Further variations in the affinity properties of alpha 2-adrenergic receptor in females may explain why the regional differences in catecholamine-induced lipolysis are more pronounced in women than in men.
Rapid diagnosis of gram negative pneumonia by assay of endotoxin in bronchoalveolar lavage fluid.
Authors: J Pugin, R Auckenthaler, O Delaspre, E van Gessel, P M Suter
Journal: Thorax (1992)

<h3>AIM</h3> To determine the sex of individual cells in paraffin sections of the human eye by fluorescence in situ hybridisation (FISH) of the X and Y chromosomes. <h3>METHODS</h3> The authors developed a protocol for FISH of the X and Y chromosomes in paraffin sections of human eyes. <h3>RESULTS</h3> In all the specimens that had been fixed in 10% formalin and with a fixation time of up to 3 days sex determination of individual cells was achieved. The percentage of cells with clearly identifiable signals was up to 98% for corneal epithelium, keratocytes, corneal endothelium, trabecular meshwork, lens epithelium, retina, and optic nerve. <h3>CONCLUSIONS</h3> FISH allows the determination of the sex of single cells in paraffin sections of human eyes without destruction of the tissue structure. Its main application is the histological analysis of sex mismatched corneal, RPE, or neuroretinal transplants to distinguish host and donor cells.
Contribution of Cerebrovascular Health to the Diagnosis of Alzheimer Disease
Authors: Karen M. Rodrigue
Journal: JAMA Neurology (2013)

Sporadic alzheimer disease (ad) is a multifaceted neurodegenerative syndrome with complicated and unclear etiology that results in debilitating cognitive decline in old age.Although several decades of AD research resulted in major scientific advancements in identifying and tracking the disease, as well as discovering many salient genetic and environmental factors, considerably less progress in the development of efficacious therapies has been made.A major challenge for the field has been identifying sensitive and specific markers for detection in early stages of the disease, because by the time clinical symptoms are present, neuropathology is already quite advanced. 1Understanding the cascade of events that is unique to AD is complicated by the fact that AD exhibits a diverse clinical presentation and is often concomitant with other types of brain injury and dementia.A common example of this comorbidity is vascular disease, which can act as a risk factor for AD 2 but also contributes to cognitive decline in its own right. 3Understanding the nature of the contributions of vascular pathology to AD is an important (and open) area of current research.Knowing if cerebrovascular disease plays an early and initiating role in the formation of AD neuropathology may have a significant impact on strategies to treat or even prevent the disease since vascular diseases are often highly responsive to treatment.However, cerebrovascular disease may simply occur in parallel to the development of AD pathology as a correlate and by-product of the aging process.Research examining the impact of various vascular health risk factors and specific neurovascular changes that can be measured in the human brain in vivo, along with biomarkers for AD (eg, β-amyloid [Aβ] positron emission tomography imaging of aggregated fibrillar amyloid plaque), are needed to elucidate this question.
Comment on: Alssema et al. One Risk Assessment Tool for Cardiovascular Disease, Type 2 Diabetes, and Chronic Kidney Disease. Diabetes Care 2012; 35:741–748
Authors: Jason L. Vassy
Journal: Diabetes Care (2012)

Alssema et al. (1) recently reported a novel prediction score for cardiometabolic risk among white European adults. Unlike the many available validated models that separately predict cardiovascular disease, type 2 diabetes, or chronic kidney disease, their model predicts the occurrence of any of these three outcomes. This approach acknowledges one of the challenges faced by all primary care providers: how to screen for the risk for multiple conditions in a time-limited setting (2). Moreover, …
Retinal disease in patients with systemic lupus erythematosus
Authors: O. Ushiyama
Journal: Annals of the Rheumatic Diseases (2000)

To investigate the incidence of retinopathy in systemic lupus erythematosus (SLE) and to clarify its significance in relation to other clinical manifestations.A cross sectional study on lupus retinopathy was made in 69 patients with SLE. One expert ophthalmologist examined the ocular fundi of the lupus patients without any information of their disease state. Clinical and laboratory findings in the patients with retinopathy and those without were compared.Retinopathy was found in 7/69 (10%) patients. The findings included haemorrhages, vasculitis, cotton wool spots, and hard exudates, all of which were considered to reflect vascular damage. Retinopathy was found to be associated with the presence of anticardiolipin antibody (p<0.05) and with central nervous system lupus (p<0.01). The patients with retinopathy had higher levels of serum creatinine than the patients without retinopathy (p<0.01). The disease activity of lupus, as assessed by the maximum SLE disease activity index (SLEDAI) score of the patients, was also significantly higher in the patients with retinopathy (p<0.03).Incidence of retinopathy in SLE was similar to that in previous reports and it may reflect tissue microangiopathy, particularly associated with vasculitis or anticardiolipin antibodies, or both.
Journal impact factors for 2000: Thorax flying yet higher
Authors: A J KNOX
Journal: Thorax (2001)

The journal impact factors for 2000 have recently been released and the good news for Thorax is that it has again increased its impact factor from 3.44 in 19991 to 3.98, and it has narrowed the gap considerably on its main two competitors—the American Thoracic Society publications. The position of Thorax in terms …
Targeted therapies: summary clinical trials working group
Authors: M E Weinblatt, P L C M van Riel
Journal: Annals of the Rheumatic Diseases (2006)

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3<i>R</i>(+)-<i>N</i>-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1<i>H</i>-1,4-benzodiazepin-3-yl)-<i>N</i>′-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(l<i>H</i>-indol-3-yl)-2-methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4-oxo-[l<i>S</i>-la.2[<i>S</i><sup>*</sup>(<i>S</i><sup>*</sup>)]4<i>a</i>]}-butanoate <i>N</i>-methyl-d-glucamine (PD135,158), and (<i>R</i>)-1-naphthalenepropanoic acid, <i>b</i>-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2-oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(<i>R</i>)-2,3-dihydro-1-(2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1<i>H</i>-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, <i>N</i>-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1<i>H</i>-1,5-benzodiazepin-3-yl]-<i>N</i>′-phenylurea (GV150,013X) and ([(<i>N</i>-[methoxy-3 phenyl] <i>N</i>-[<i>N</i>-methyl <i>N</i>-phenyl carbamoylmethyl], carbomoyl-methyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation.
Intrarectal Treatment of 100 Cases of Ulcerative Colitis with Prednisolone-21-phosphate Enemata
Authors: S. G. F. Matts
Journal: BMJ (1961)

MEDICAL JOURNALshowed active inflammation, as indicated by the presence of polymorphs in the mucosa.In patients who had been without symptoms for six or less months, the great majority, 14 out of 17, had an abnormal mucosa.histologically, and in 13 of these it also appeared abnormal on sigmoidoscopy.However, the patients without symptoms for more than six months were different.About one-half showed a normal appear- ance by sigmoidoscopy and the other half abnormal, but of the 15 cases whose appearances were normal eight had an abnormal mucosa microscopically.This
The risk of subsequent primary cancers after colorectal cancer in southeast England
Authors: H S Evans
Journal: Gut (2002)

Multiple cancers may occur in an individual because of a genetic predisposition, environmental exposure, cancer therapy, or immunological deficiency. Colorectal cancer is one of the most commonly diagnosed cancers, and inherited factors play an important role in its aetiology.To characterise the occurrence of multiple primary cancers in patients diagnosed with colorectal cancer and explore the possibility of a common aetiology for different cancer sites.The Thames Cancer Registry database was used to identify patients with a first colorectal cancer, resident in the North or South Thames region, diagnosed between 1 January 1961 and 31 December 1995. A total of 127 281 patients were included, 61 433 men and 65 848 women.Observed numbers of cancers occurring after the diagnosis of colorectal cancer were compared with expected numbers, calculated using appropriate age, sex, and period specific rates, to obtain standardised incidence ratios. The occurrence of colorectal cancers subsequent to cancers at other sites was also examined.Small intestinal cancer was significantly increased in men diagnosed with colorectal cancer before the age of 60 years and in women diagnosed with colorectal cancer after the age of 65 years. Colorectal cancer was also significantly increased after a first diagnosis of cancer of the small intestine. Other cancer sites with a significant increase after colorectal cancer included the cervix uteri, corpus uteri, and ovary.Patients with colorectal cancer are at increased risk of developing cancer at a number of other sites. Some of these associations are consistent with the effects of known inherited cancer susceptibility genes.
Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein
Authors: D Thomas
Journal: Cardiovascular Research (2003)

Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress. Previous studies have revealed that activation of the beta-adrenergic system and consecutive elevation of the intracellular cAMP concentration regulate HERG channels via protein kinase A-mediated phosphorylation of the channel protein and via direct interaction with the cAMP binding site of HERG. In contrast, the influence of the alpha-adrenergic signal transduction cascade on HERG currents as suggested by recent reports is less well understood. The aim of the present study was to elucidate the biochemical pathways of the protein kinase C (PKC)-dependent regulation of HERG currents.HERG channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique.Application of the phorbol ester PMA, an unspecific protein kinase activator, shifted the voltage dependence of HERG activation towards more positive potentials. This effect could be mimicked by activation of conventional PKC isoforms with thymeleatoxin. Coexpression of HERG with the beta-subunits minK or hMiRP1 did not alter the effect of PMA. Specific inhibition of PKC abolished the PMA-induced activation shift, suggesting that PKC is required within the regulatory mechanism. The PMA-induced effect could still be observed when the PKC-dependent phosphorylation sites in HERG were deleted by mutagenesis. Cytoskeletal proteins such as actin filaments or microtubules did not affect the HERG activation shift.In addition to the known effects of PKA and cAMP, HERG channels are also modulated by PKC. The molecular mechanisms of this PKC-dependent process are not completely understood but do not depend on direct PKC-dependent phosphorylation of the channel.
A Plasmodium falciparum Histone Deacetylase Regulates Antigenic Variation and Gametocyte Conversion
Authors: Bradley I. Coleman, Kristen M. Skillman, Rays H.Y. Jiang, Lauren M. Childs, Lindsey M. Altenhofen, Markus Ganter, Yvette Leung, Ilana Goldowitz, Björn F.C. Kafsack, Matthias Marti, Manuel Llinás, Caroline O. Buckee, Manoj T. Duraisingh
Journal: Cell Host & Microbe (2014)