tbuckley/cabot-search huggingface dataset:
Therapy in the Early Stage: Incretins
Authors: Simona Cernea, Itamar Raz
Journal: Diabetes Care (2011)

The complex pathological mechanisms responsible for development of type 2 diabetes are not fully addressed by conventional drugs, which are also associated with inconvenient side effects such as weight gain or hypoglycemia. Two types of incretin-based therapies are now in use: incretin mimetics (glucagon-like peptide-1 [GLP-1] receptor agonists that bind specific receptors and mimic the action of natural GLP-1) and incretin enhancers (inhibitors of the enzyme that degrade the incretin hormones and thus prolong their activity). Both offer important advantages over previous agents. In addition to the proven glucose-lowering efficacy, they promote weight loss (or are weight neutral) by slowing gastric emptying and inducing satiety, inhibit glucagon secretion with maintenance of counterregulatory mechanisms, and exhibit cardiovascular benefits, while having a low risk profile. Importantly, short-term studies have shown that incretins/incretin-based therapies protect β-cells (by enhancing cell proliferation and differentiation and inhibiting apoptosis) and stimulate their function (by recruiting β-cells to the secretory process and increasing insulin biosynthesis/secretion). These therapies have the opportunity to interfere with the disease progression if used as an early intervention, when enough β-cell mass/function can still be preserved or restored.
No further increase in asthma, hay fever and atopic sensitisation in adolescents living in Switzerland
Authors: C. Braun-Fahrländer, M. Gassner, L. Grize, K. Takken-Sahli, U. Neu, T. Stricker, H.S. Varonier, B. Wüthrich, F.H. Sennhauser
Journal: European Respiratory Journal (2004)

Prevalence rates of childhood asthma and allergy have been on the increase for several decades. The present study investigated whether this trend continued during the 1990s in adolescents living in Switzerland. Between 1992 and 2000, the change in prevalence of specific immunoglobulin E to aeroallergens, asthma symptoms and hay fever symptoms assessed by parents' and students' answers to the International Study of Asthma and Allergies in Childhood questions was investigated using three cross-sectional surveys. In total 1,324 (74.9%), 1,668 (80.6%) and 1,250 (73.9%) adolescents participated. Prevalence rates of asthma and current asthmatic symptoms remained constant, irrespective of whether the assessment was based on parental questionnaires or the student's self-completed written or video questionnaires (students' report of current wheeze 8.8, 7.3, and 8.3%). Similarly, no further increase was observed for reported hay fever rates and allergic sensitisation rates (positive multiscreen allergy test, SX1-test: 34.6, 38.9, and 35.6%, respectively). Although time trends in the occurrence of a series of known risk factors were recorded, none of these factors had a significant impact on asthma and allergy prevalence over time. No further increase in asthma and allergy rates occurred during the 1990s in adolescents living in Switzerland. However, to adequately assess the trend a longer period of observation is needed.
Lipins: Multifunctional Lipid Metabolism Proteins
Authors: Lauren S. Csaki, Karen Reue
Journal: Annual Review of Nutrition (2010)

The lipin proteins are evolutionarily conserved proteins with roles in lipid metabolism and disease. There are three lipin protein family members in mammals and one or two orthologs in plants, invertebrates, and single-celled eukaryotes. Studies in yeast and mouse led to the identification of two distinct molecular functions of lipin proteins. Lipin proteins have phosphatidate phosphatase activity and catalyze the formation of diacylglycerol in the glycerol-3-phosphate pathway, implicating them in the regulation of triglyceride and phospholipid biosynthesis. Mammalian lipin proteins also possess transcriptional coactivator activity and have been implicated in the regulation of metabolic gene expression. Here we review key findings in the field that demonstrate roles for lipin family members in metabolic homeostasis and in rare human diseases, and we examine evidence implicating genetic variations in lipin genes in common metabolic dysregulation such as obesity, hyperinsulinemia, hypertension, and type 2 diabetes.
Prevalence of Chronic Kidney Disease and Survival among Aboriginal People
Authors: Song Gao, Braden J. Manns, Bruce F. Culleton, Marcello Tonelli, Hude Quan, Lynden Crowshoe, William A. Ghali, Lawrence W. Svenson, Brenda R. Hemmelgarn
Journal: Journal of the American Society of Nephrology (2007)

Globally, it is known that the incidence of end-stage renal disease is higher among Aboriginals, but it is unknown whether this is due to an increased prevalence of chronic kidney disease or other unidentified factors. We studied 658,664 people of non–First Nations and 14,989 people of First Nations and found that the age- and sex-adjusted prevalence of chronic kidney disease was significantly higher among those of non–First Nations compared to those of First Nations (67.5 versus 59.5 per 1000 population; P < 0.0001). However, severe chronic kidney disease (estimated glomerular filtration rate <30 ml/min per 1.73 m2) was almost two-fold higher among people of First Nations (P < 0.0001). Cox proportional hazards models suggested that compared to people of non–First Nations, those of First Nations with chronic kidney disease had a 77% increased risk of death after adjusting for age, gender, diabetes and baseline eGFR. In conclusion, whether the higher incidence of end-stage renal disease among people of First Nations is due to suboptimal management of chronic kidney disease and its associated comorbidities, more rapid loss of kidney function, or other unidentified factors remains to be determined.
The SPGP gene, encoding the canalicular bile acid transporting protein SPGP/cBST, is not expressed in a subgroup of patients with progressive familial intrahepatic cholestasis (PFIC-2)
Authors: Peter Jansen, Guido Hooiveld, Hans Koning, Harrie van Goor, Annette Gouw, Folkert Kuipers, Charles Bijleveld, Maarten Slooff, Michael Müller
Journal: Journal of Hepatology (1998)
Impaired SHP2-Mediated Extracellular Signal-Regulated Kinase Activation Contributes to Gefitinib Sensitivity of Lung Cancer Cells with Epidermal Growth Factor Receptor–Activating Mutations
Authors: Matthew J. Lazzara, Keara Lane, Richard Chan, Paul J. Jasper, Michael B. Yaffe, Peter K. Sorger, Tyler Jacks, Benjamin G. Neel, Douglas A. Lauffenburger
Journal: Cancer Research (2010)

Abstract Most non–small cell lung cancers (NSCLC) display elevated expression of epidermal growth factor receptor (EGFR), but response to EGFR kinase inhibitors is predominantly limited to NSCLC harboring EGFR-activating mutations. These mutations are associated with increased activity of survival pathways, including phosphatidylinositol 3-kinase/AKT and signal transducer and activator of transcription 3/5. We report that EGFR-activating mutations also surprisingly lead to decreased ability to activate extracellular signal-regulated kinase (ERK) compared with wild-type EGFR. In NSCLC cells and mouse embryonic fibroblasts expressing mutant EGFR, this effect on ERK correlates with decreased EGFR internalization and reduced phosphorylation of SHP2, a tyrosine phosphatase required for the full activation of ERK. We further show that ERK activation levels affect cellular response to gefitinib. NSCLC cells with EGFR mutation display reduced gefitinib sensitivity when ERK activation is augmented by expression of constitutively active mutants of mitogen-activated protein kinase/ERK kinase (MEK). Conversely, in a NSCLC cell line expressing wild-type EGFR, gefitinib treatment along with or following MEK inhibition increases death response compared with treatment with gefitinib alone. Our results show that EGFR-activating mutations may promote some survival pathways but simultaneously impair others. This multivariate alteration of the network governing cellular response to gefitinib, which we term “oncogene imbalance,” portends a potentially broader ability to treat gefitinib-resistant NSCLC. Cancer Res; 70(9); 3843–50. ©2010 AACR.
Abstract 4576: IMGN853, an anti-Folate Receptor I antibody-maytansinoid conjugate for targeted cancer therapy
Authors: Olga Ab, Laura M. Bartle, Lingyun Rui, Jennifer Coccia, Holly A. Johnson, Kathleen R. Whiteman, Brenda Kellogg, Lauren Clancy, Xiuxia Sun, Victor S. Goldmacher
Journal: Cancer Research (2011)

Abstract Previously we reported (O. Ab; EORTC, 2010) that an antibody-maytansinoid conjugate (AMC) composed of an anti-FOLR1 antibody conjugated to the cytotoxic maytansinoid, DM4, via the disulfide-containing linker, SPDB, was potent in killing FOLR1-expressing cancer cells in vitro and in vivo. In light of the favorable results noted, we assessed the optimal antibody, linker, and maytansinoid agent for an AMC targeting FOLR1, as reported here. Antibody selection. Anti-FOLR1 antibodies were generated by immunizing mice with human FOLR1-expressing cells, and a panel of FOLR1-specific antibodies was identified by flow cytometry binding assay. Several FOLR1-antibodies with high binding affinity to both human and monkey FOLR1 were chosen for further evaluation and were humanized using ImmunoGen's resurfacing technology. Antibodies were conjugated to DM1 via the non-cleavable SMCC linker and the conjugates tested for activity against FOLR1-positive KB cells in vitro and in vivo. All conjugates had comparable cytotoxic potencies in vitro. However, the in vivo anti-tumor activity of one conjugate, M9346A-SMCC-DM1, was significantly better than that of SMCC-DM1 conjugates of other FOLR1 antibodies. Based on this finding, the M9346A antibody was chosen for further development. Linker/maytansinoid selection. The M9346A antibody was linked to DM1 or DM4 via the disulfide-containing cleavable linkers SPP, SPDB or sulfo-SPDB, or via the non-cleavable SMCC linker. We compared the in vitro cytotoxic activities of these conjugates on KB, Igrov-1 and Jeg-3 cell lines. The conjugates with cleavable linkers displayed markedly greater in vitro activities than the SMCC conjugate. We then examined the in vivo activities of the conjugates in FOLR1-positive KB- and Ovcar 3-tumor models. Again, we found that the conjugates with cleavable linkers were more active in vivo than the noncleavable conjugate. Among the conjugates with cleavable linkers, the sulfo-SPDB-DM4 conjugate was the most active conjugate against the Ovcar-3 model, it had activity comparable to that of the SPDB-DM4 conjugate against KB tumors, and both were more active than the SPP-DM1 conjugate in the two xenograft models. Taking into consideration that sulfo-SPDB-DM4 was the most efficacious design in vivo and the potential of the hydrophilic sulfo-SPDB-linker to enable better activity against PgP-expressing cells (previously reported data), M9346A-sulfo-SPDB-DM4 was selected to be the candidate for development and designated IMGN853. IMGN853 is a promising candidate for the treatment of FOLR1-expressing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4576. doi:10.1158/1538-7445.AM2011-4576
Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use
Authors: Bertil B. Fredholm, Karl Bättig, Janet Holmén, Astrid Nehlig, Edwin E. Zvartau
Journal: Pharmacological Reviews (1999)

Caffeine is the most widely consumed behaviorally active substance in the world. Almost all caffeine comes from dietary sources (beverages and food), most of it from coffee and tea. Acute and, especially, chronic caffeine intake appear to have only minor negative consequences on health. For this
Control over Conflict during Movement Preparation: Role of Posterior Parietal Cortex
Authors: Elizabeth J. Coulthard, Parashkev Nachev, Masud Husain
Journal: Neuron (2008)

Flexible behavior in humans often requires that rapid choices be made between conflicting action plans. Although much attention has focused on prefrontal regions, little is understood about the contribution of parietal cortex under situations of response conflict. Here we show that right parietal damage associated with spatial neglect leads to paradoxical facilitation (speeding) of rightward movements in the presence of conflicting leftward response plans. These findings indicate a critical role for parietal regions in action planning when there is response competition. In contrast, patients with prefrontal damage have an augmented cost of conflict for both leftward and rightward movements. The results suggest involvement of two independent systems in situations of response conflict, with right parietal cortex being a crucial site for automatic activation of competing motor plans and prefrontal regions acting independently to inhibit action plans irrelevant to current task goals.
Illness and Treatment Perceptions Are Associated With Adherence to Medications, Diet, and Exercise in Diabetic Patients
Authors: Elizabeth Broadbent, Liesje Donkin, Julia C. Stroh
Journal: Diabetes Care (2011)

To investigate diabetic patients' perceptions of illness and treatments, and explore relationships to adherence and blood glucose control.Forty-nine type 1 and one hundred and eight type 2 diabetic patients completed questionnaires assessing illness perceptions, treatment beliefs, and adherence to medications, diet, and exercise. Blood glucose control was assessed from blood tests.Patients rated medication more important than diet and exercise, and reported higher adherence to medications. Insulin was perceived as more helpful for diabetes, while antihypertensives and cholesterol medication were perceived more helpful for preventing heart problems. Perceptions were associated with adherence to insulin, cholesterol and antihypertensive medications, exercise, and diet. Blood glucose control in type 1 diabetic patients was associated with insulin adherence and perceived personal control, and in type 2 diabetic patients to being prescribed insulin or antihypertensives, and perceived personal control.Patients hold specific mental models about diabetes treatments, which are associated with adherence.
A Direct-Interview Family Study of Generalized Social Phobia
Authors: Murray B. Stein, Mariette J. Chartier, Andrea L. Hazen, Maria V. Kozak, Manuel E. Tancer, Sheila Lander, Patricia Furer, Donna Chubaty, John R. Walker
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The goal of this direct-interview family study was to replicate and extend an earlier finding of a familial liability for social phobia. The authors hypothesized that there would be higher rates of the generalized type of social phobia—but not the nongeneralized (or "discrete") type—among relatives of probands with generalized social phobia. They also hypothesized that rates of avoidant personality disorder, a frequent comorbid condition, would be higher in relatives of probands with generalized social phobia. METHOD: The authors examined rates of three social phobia subtypes defined a priori—discrete, nongeneralized, and generalized—as well as rates of avoidant personality disorder by direct interview of 106 first-degree relatives of 23 patients with generalized social phobia and 74 first-degree relatives of 24 comparison subjects without social phobia. RESULTS: Relative risks for generalized social phobia and avoidant personality disorder were markedly higher (approximately 10-fold) among first-degree relatives of probands with generalized social phobia than among first-degree relatives of comparison probands. In contrast, relative risks for discrete social phobia and nongeneralized social phobia were not significantly different between the two groups of first-degree relatives. CONCLUSIONS: These results confirm earlier findings of a higher rate of social phobia among relatives of probands with generalized social phobia and extend these findings by specifically indicating that it is only the generalized type (and its probable axis II counterpart, avoidant personality disorder) that occurs more often among the families of probands with generalized social phobia. Implications for subsequent genetic studies are discussed. (Am J Psychiatry 1998; 155:90–97)
Brain Natriuretic Peptide Is Produced in Cardiac Fibroblasts and Induces Matrix Metalloproteinases
Authors: Toshihiro Tsuruda, Guido Boerrigter, Brenda K. Huntley, Josh A. Noser, Alessandro Cataliotti, Lisa C. Costello-Boerrigter, Horng H. Chen, John C. Burnett
Journal: Circulation Research (2002)

Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart. It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs). BNP mRNA was detected in CFs, and a specific radioimmunoassay demonstrated that BNP 1-32 was secreted into the media at a rate of 11.2±1.0 pg/10 5 cells per 48 hours (mean±SEM). The amount of BNP secretion was significantly ( P &lt;0.01) augmented by 10 −7 mol/L tumor necrosis factor-α in a time-dependent manner. BNP significantly ( P &lt;0.01) inhibited de novo collagen synthesis as assessed by [ 3 H]proline incorporation, whereas zymographic MMP-2 (gelatinase) abundance was significantly ( P &lt;0.05) stimulated by BNP between 10 −7 and 10 −6 mol/L. In addition, protein expression of MMP-1, -2, and -3 and membranous type-1 MMP was significantly increased by 10 −6 mol/L BNP. The cGMP analogue 8-bromo-cGMP (10 −4 mol/L) mimicked the BNP effect, whereas inhibition of protein kinase G by KT5823 (10 −6 mol/L) significantly ( P &lt;0.05) attenuated BNP-induced zymographic MMP-2 abundance. In summary, this study reports that BNP is present in cultured CFs and that BNP decreases collagen synthesis and increases MMPs via cGMP–protein kinase G signaling. These in vitro findings support a role for BNP as a regulator of myocardial structure via control of cardiac fibroblast function.
Comparison of long term evolution of adult onset and juvenile onset Still's disease, both followed up for more than 10 years.
Authors: J Cabane, A Michon, J M Ziza, P Bourgeois, O Bletry, P Godeau, M F Kahn
Journal: Annals of the Rheumatic Diseases (1990)

Still9s disease is a clinical entity of unknown origin, which can appear before 15 years of age (juvenile onset Still9s disease) or later (adult onset Still9s disease). There are few reported data about the long term prognosis of Still9s disease and no study compares the long term evolution of adult onset and juvenile onset Still9s disease. Eighteen patients fulfilling the American Rheumatism Association criteria for Still9s disease were followed up for more than 10 years. Ten (group 1) had juvenile onset Still9s disease and eight (group 2) adult onset Still9s disease. A comparison of the groups showed no significant differences in the initial systemic manifestations of Still9s disease, or in the joint lesions. Both groups had severe sequelae, which appeared between six and 10 years after the initial flare up of Still9s disease. Nine patients had articular damage and nine had only arthritis without apparent x ray abnormalities. Nine patients had bilateral hip destruction in less than four years. Of these nine, seven required 13 total hip replacements before the age of 45. In the whole group of 18 patients bilateral involvement of the following joints was also seen: carpus (seven patients), knee (four), tarsus (four), ankle (three); three patients had ankylosis of the cervical spine. The occurrence of amyloidosis (three cases, two deaths) was restricted to group 2. This was the only difference between the groups, as the treatments were identical. It is concluded that the articular prognosis of Still9s disease is poor, be it adult onset or juvenile onset, with severe joint destruction in half of the patients.
Longitudinal cohort study of childhood IQ and survival up to age 76
Authors: Lawrence Jeffrey Whalley, I. J. Deary
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To test the association between childhood IQ and mortality over the normal human lifespan. <b>Design:</b> Longitudinal cohort study. <b>Setting:</b> Aberdeen. <b>Subjects:</b> All 2792 children in Aberdeen born in 1921 and attending school on 1 June 1932 who sat a mental ability test as part of the Scottish mental survey 1932. <b>Main outcome measure:</b> Survival at 1 January 1997. <b>Results:</b> 79.9% (2230) of the sample was traced. Childhood mental ability was positively related to survival to age 76 years in women (P&lt;0.0001) and men (P&lt;0.0001). A 15 point disadvantage in mental ability at age 11 conferred a relative risk of 0.79 of being alive 65 years later (95% confidence interval 0.75 to 0.84); a 30 point disadvantage reduced this to 0.63 (0.56 to 0.71). However, men who died during active service in the second world war had a relatively high IQ. Overcrowding in the school catchment area was weakly related to death. Controlling for this factor did not alter the association between mental ability and mortality. <b>Conclusion:</b> Childhood mental ability is a significant factor among the variables that predict age at death. <h3>What is already known on this topic</h3> People in deprived conditions tend to have more illness and die younger The reasons for this inequality in health are not fully established <h3>What this study adds</h3> IQ at age 11 years was significantly associated with survival up to 76 years in an Aberdeen cohort The association was unaffected by adjustment for overcrowding Men with high IQ were more likely to die in active service in the second world war
Influence of antimicrobial chemotherapy on spirometric parameters and pro-inflammatory indices in severe pulmonary tuberculosis
Authors: ML Plit, R Anderson, CE Van Rensburg, L Page-Shipp, JA Blott, JL Fresen, C Feldman
Journal: European Respiratory Journal (1998)

Patients who have completed a treatment for severe pulmonary tuberculosis (TB) are often left with severe respiratory disability. There have been few prospective studies assessing the effect of treatment on lung function in such patients. The influence of antimicrobial chemotherapy on lung function was investigated over a six month period in patients with newly diagnosed pulmonary TB to test the hypothesis that treatment improves lung function, as well as to identify factors that may influence lung function outcome. Seventy-six patients were recruited into the study, of whom 74 completed the treatment programme. Forty-two were current smokers and 13 seropositive for the human immunodeficiency virus. Improvement in lung function occurred in 54% of patients, but residual airflow limitation or a restrictive pattern was evident in 28% and 24% of patients, respectively. The extent of lung infiltration (radiographic score) both at the outset and after chemotherapy was significantly and negatively related to forced expiratory volume in one second (FEV1) (% pred) (r=-0.41, and r=-0.46, respectively). The post-treatment serum C-reactive protein and alpha1-protease inhibitor levels were negatively associated with FEV1 (% pred) (r=-0.30 and r=-0.35, respectively). These findings demonstrate that, while antimicrobial chemotherapy may lead to improved lung function in patients with pulmonary tuberculosis, a large proportion of patients has residual impairment. The most significant factor influencing post-treatment lung function status, as measured by forced expiratory volume in one second (% predicted), is the pretreatment and post-treatment radiographic score, which acts as a marker of the extent of pulmonary parenchymal involvement in tuberculosis.