tbuckley/cabot-search huggingface dataset:
Antidepressant-Induced Liver Injury: A Review for Clinicians
Authors: Cosmin Sebastian Voican, Emmanuelle Corruble, Sylvie Naveau, Gabriel Perlemuter
Journal: American Journal of Psychiatry (2013)

Antidepressant drugs can cause drug-induced liver injury (DILI). The authors review clinical data relevant to antidepressant-induced liver injury and provide recommendations for clinical practice. A PubMed search was conducted for publications from 1965 onward related to antidepressant-induced liver injury. The search terms were "liver injury," "liver failure," "DILI," "hepatitis," "hepatotoxicity," "cholestasis," and "aminotransferase," cross-referenced with "antidepressant." Although data on antidepressant-induced liver injury are scarce, 0.5%-3% of patients treated with antidepressants may develop asymptomatic mild elevation of serum aminotransferase levels. All antidepressants can induce hepatotoxicity, especially in elderly patients and those with polypharmacy. Liver damage is in most cases idiosyncratic and unpredictable, and it is generally unrelated to drug dosage. The interval between treatment initiation and onset of liver injury is generally between several days and 6 months. Life-threatening antidepressant-induced liver injury has been described involving fulminant liver failure or death. The underlying lesions are often of the hepatocellular type and less frequently of the cholestatic and mixed types. The antidepressants associated with greater risks of hepatotoxicity are iproniazid, nefazodone, phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine. The antidepressants that seem to have the least potential for hepatotoxicity are citalopram, escitalopram, paroxetine, and fluvoxamine. Cross-toxicity has been described, mainly for tricyclic and tetracyclic antidepressants. Although an infrequent event, DILI from antidepressant drugs may be irreversible, and clinicians should be aware of it. Aminotransferase surveillance is the most useful tool for detecting DILI, and prompt discontinuation of the drug responsible is essential. The results of antidepressant liver toxicity in all phases of clinical trials should be available and published. Further research is needed before any new and rigorously founded recommendations can be made.
Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease
Authors: Andrew W. Roberts, John F. Seymour, Jennifer R. Brown, William G. Wierda, Thomas J. Kipps, Seong Lin Khaw, Dennis A. Carney, Simon Z. He, David C.S. Huang, Hao Xiong, Yue Cui, Todd A. Busman, Evelyn M. McKeegan, Andrew P. Krivoshik, Sari H. Enschede, Rod Humerickhouse
Journal: Journal of Clinical Oncology (2011)

BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(l) and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax.Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology.Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(l) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies.BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.
Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover
Authors: Roger H. Unger, Alan D. Cherrington
Journal: Journal of Clinical Investigation (2012)

The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor–null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.
Effect of a High-Fiber Diet Compared With a Moderate-Fiber Diet on Calcium and Other Mineral Balances in Subjects With Type 2 Diabetes
Authors: Meena Shah, Manisha Chandalia, Beverley Adams-Huet, Linda J. Brinkley, Khashayar Sakhaee, Scott M. Grundy, Abhimanyu Garg
Journal: Diabetes Care (2009)

OBJECTIVE High levels of dietary fiber, especially soluble fiber, are recommended to lower serum cholesterol levels and improve glycemic control in patients with type 2 diabetes. It is not clear, however, how high levels of fiber affect mineral balance. RESEARCH DESIGN AND METHODS In a randomized crossover study, 13 patients with type 2 diabetes were fed a high-fiber (50 g total and 25 g soluble fiber) and a moderate-fiber (24 g total and 8 g soluble fiber) diet of the same energy, macronutrient, calcium, magnesium, and phosphorus content for 6 weeks each. Intestinal calcium absorption was determined by fecal recovery of 47Ca. Stool weight and mineral content were assessed during 3 days, and 24-h urinary mineral content and serum chemistry were assessed over 5 days at the end of each phase. The results were compared by repeated-measures ANOVA. RESULTS Compared with the moderate-fiber diet, the high-fiber diet increased stool weight (165 ± 53 vs. 216 ± 63 g/day, P = 0.02) and reduced 24-h urinary calcium (3.3 ± 1.7 vs. 2.4 ± 1.2 mmol/day, P = 0.003) and phosphorus (29.2 ± 5.5 vs. 26.0 ± 3.2 mmol/day, P = 0.003) excretion and serum calcium concentration (2.33 ± 0.06 vs. 2.29 ± 0.07 mmol/l, P = 0.04). Calcium absorption, stool calcium, magnesium, and phosphorus content and serum phosphorus concentration were not significantly different with the two diets. CONCLUSIONS A high-fiber diet rich in soluble fiber has a small impact on calcium and phosphorus balance in subjects with type 2 diabetes. It may be prudent to ensure adequate intake of calcium and other minerals in individuals consuming a high-fiber diet.
HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility
Authors: P Donaldson
Journal: Gut (2001)

Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided.We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease.There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease.These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.
A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea
Authors: J. C. M. Lam, B. Lam, T. J. Yao, A. Y. K. Lai, C. G. Ooi, S. Tam, K. S. L. Lam, M. S. M. Ip
Journal: European Respiratory Journal (2009)

The effects of treatment of obstructive sleep apnoea (OSA) on glucose metabolism have been investigated previously with conflicting results. This study evaluated the impact of nasal continuous positive airway pressure (nCPAP) treatment of OSA on insulin sensitivity. Males with moderate/severe OSA and no significant comorbidity were randomised to a therapeutic or sham nCPAP treatment group for 1 week and then reassessed. Those who received therapeutic nCPAP were further evaluated at 12 weeks. Insulin sensitivity (K itt ) was estimated by the short insulin tolerance test. Other evaluations included blood pressure, metabolic profile, urinary catecholamines and intra-abdominal fat. In total, 61 Chinese subjects were randomised. 31 subjects receiving therapeutic nCPAP showed an increase in K itt (6.6±2.9 to 7.6±3.2 %·min −1 ; p = 0.017), while the 30 patients on sham CPAP had no significant change, and the changes in K itt were different between the two groups (p = 0.022). At 12 weeks, improvement in K itt was seen in 20 subjects with BMI ≥25 kg·m −2 (median (interquartile range) 28.3 (26.6–31.5); p = 0.044), but not in the nine subjects with BMI&lt;25 kg·m −2 , or the entire group. The findings indicate that therapeutic nCPAP treatment of OSA for 1 week improved insulin sensitivity in nondiabetic males, and the improvement appeared to be maintained after 12 weeks of treatment in those with moderate obesity.
Hepatitis C virus (HCV) genotypes and the influence of HCV subtype 1b on the progression of chronic hepatitis C in Korea: a single center experience
Authors: Eun Ju Cho, Su Hyeon Jeong, Byung Hoon Han, Sang Uk Lee, Byung Chul Yun, Eun Taek Park
Journal: Clinical and Molecular Hepatology (2012)

Background/Aims There is some controversy regarding whether or not hepatitis C virus (HCV) subtype 1b is more influential than non-1b subtypes on the progression of chronic hepatitis (CH) C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Methods We retrospectively analyzed 823 patients with chronic HCV infection, including 443 CH patients, 264 LC patients, and 116 HCC patients, who were HCV RNA positive and HBsAg negative. These patients had not received any prior treatment with either interferon alone or a combination of interferon and ribavirin. Results HCV subtypes 1b (51.6%) and 2a/2c (39.5%) were the two most common genotypes. The proportions of genotypes 2 (2a/2c, 2b, and 2) and 3 were 45.8% and 1.1%, respectively. One case of genotype 4 was found. HCV subtype 1b (47.3%) was less common than the non-1b subtypes (52.7%) in non-LC patients, but its proportion (56.9%) was higher than that of non-1b subtypes (43.1%) in LC patients (P=0.006). The proportions of patients with HCV subtype 1b did not differ significantly between the LC (55.3%) and HCC (60.3%) groups. Older age, male gender, and the relative progression of liver damage (non-LC vs. compensated LC vs. decompensated LC) were significant risk factors for HCC, with odds ratios of 1.081 (95% confidence interval [CI], 1.056-1.106), 5.749 (95% CI, 3.329-9.930), and 2.895 (95% CI, 2.183-3.840), respectively. HCV subtype 1b was not a significant risk factor for HCC (odds ratio, 1.423; 95% CI, 0.895-2.262). Conclusions HCV subtypes 1b and 2a/2c were the two most common HCV genotypes. HCV subtype 1b seemed to be more influential than non-1b subtypes on the progression of CH to LC, but not on the development of HCC from LC. Keywords: Genotype; Hepatitis C; Hepatocellular carcinoma; Liver cirrhosis
Thrombin receptor 14-amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P-selectin-dependent mechanism.
Authors: Y Sugama, A B Malik
Journal: Circulation Research (1992)

Thrombin cleaves its receptor at arginine-41, resulting in the generation of a new receptor NH2-terminus with the sequence SFLLRNPNDKYEPF. This peptide (TRP-14) may signal a variety of thrombin's responses. We examined the effects of TRP-14 in inducing endothelial cell hyperadhesivity and neutrophil (PMN) adhesion to endothelial cell monolayers. Human umbilical vein endothelial cells (HUVECs) challenged with TRP-14 (10(-4) to 10(-5) M) produced concentration-dependent increases in endothelial adhesivity to PMN. In contrast, position 1 to 2 inverted peptide (FSLLRNPNDKYEPF) did not induce the response. The adhesion response was transient; that is, PMN adhesion increased within 15 minutes and decreased by 75 minutes after TRP-14 challenge of HUVECs. The transient endothelial adhesiveness paralleled the time course of P-selectin expression. TRP-14-induced release of P-selectin from intracellular stores may be a critical determinant of the response since treatment of endothelial cells with anti-P-selectin monoclonal antibody (mAb) G1 prevented the increase in PMN adhesion. Control nonneutralizing anti-P-selectin mAb S12 and mAb RR1/1 directed against intercellular adhesion molecule-1 (ICAM-1) on HUVECs were ineffective. The results indicate that the "tethered ligand" of the thrombin receptor created by the proteolytic action of thrombin on its receptor (i.e., TRP-14) signals increased endothelial adhesiveness by a P-selectin-dependent mechanism. Thrombin-induced PMN adhesion may involve formation of a new NH2-terminus of the endothelial thrombin receptor with the sequence SFLLRNPNDKYEPF followed by activation of endothelial second messenger pathways and the transient expression of P-selectin.
Palliative intubation for malignant strictures of the oesophagus
Authors: J. N. Leverment, D. M. Milne
Journal: Thorax (1974)

<b>Leverment, J. N. and Mearns Milne, D. (1974).</b><i>Thorax</i>, <b>29</b>, 228-231. <b>Palliative intubation for malignant strictures of the oesophagus.</b> Over a 16-year period the Mousseau-Barbin tube was used for palliation in 50 patients suffering from malignant stricture of the oesophagus. In only two cases was the Souttar tube used. Thirty-seven cases were intubated as a primary method of treatment—21 cases without preliminary exploration, 13 cases following exploration, and three cases as a `delayed9 procedure. Twelve cases were secondarily intubated as a result of recurrence of malignancy following an earlier oesophagogastrectomy. In three cases perforation of the oesophagus was recognized at the time of intubation, following which palliative oesophagogastrectomies were attempted. Intubation remains one method of relieving the patient9s most distressing symptom, but in the majority of cases prolongation of life was seldom for more than three months. The hazards of this form of treatment are discussed.
Prion-like spread of protein aggregates in neurodegeneration
Authors: Magdalini Polymenidou, Don W. Cleveland
Journal: The Journal of Experimental Medicine (2012)

Protein misfolding is common to most neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Recent work using animal models with intracellular α-synuclein and tau inclusions adds decisively to a growing body of evidence that misfolded protein aggregates can induce a self-perpetuating process that leads to amplification and spreading of pathological protein assemblies. When coupled with the progressive nature of neurodegeneration, recognition of such cell-to-cell aggregate spread suggests a unifying mechanism underlying the pathogenesis of these disorders.
Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression
Authors: David Brent, Graham Emslie, Greg Clarke, Karen Dineen Wagner, Joan Rosenbaum Asarnow, Marty Keller, Benedetto Vitiello, Louise Ritz, Satish Iyengar, Kaleab Abebe, Boris Birmaher, Neal Ryan, Betsy Kennard, Carroll Hughes, Lynn DeBar, James McCracken, Michael Strober, Robert Suddath, Anthony Spirito, Henrietta Leonard, Nadine Melhem, Giovanna Porta, Matthew Onorato, Jamie Zelazny
Journal: JAMA (2008)

<h3>Context</h3> Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy. <h3>Objective</h3> To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. <h3>Design, Setting, and Participants</h3> Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006. <h3>Interventions</h3> Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy. <h3>Main Outcome Measures</h3> Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children's Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. <h3>Results</h3> Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%;<i>P</i> = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%;<i>P</i> = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. <h3>Conclusions</h3> For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00018902
Astrocyte Elevated Gene-1 is a Novel Prognostic Marker for Breast Cancer Progression and Overall Patient Survival
Authors: Jun Li, Nu Zhang, Li-Bing Song, Wen-Ting Liao, Li-Li Jiang, Li-Yun Gong, Jueheng Wu, Jie Yuan, Hui-Zhong Zhang, Mu-Sheng Zeng, Mengfeng Li
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The present study was aimed at clarifying the expression of astrocyte elevated gene-1 (AEG-1), one of the target genes of oncogenic Ha-ras, in breast cancer and its correlation with clinicopathologic features, including the survival of patients with breast cancer. Experimental Design: The expression of AEG-1 in normal breast epithelial cells, breast cancer cell lines, and in four cases of paired primary breast tumor and normal breast tissue was examined using reverse transcription-PCR and Western blot. Real-time reverse transcription-PCR was applied to determine the mRNA level of AEG-1 in the four paired tissues, each from the same subject. Furthermore, AEG-1 protein expression was analyzed in 225 clinicopathologically characterized breast cancer cases using immunohistochemistry. Statistical analyses were applied to test for the prognostic and diagnostic associations. Results: Western blot and reverse transcription-PCR showed that the expression level of AEG-1 was markedly higher in breast cancer cell lines than that in the normal breast epithelial cells at both mRNA and protein levels. AEG-1 expression levels were significantly up-regulated by up to 35-fold in primary breast tumors in comparison to the paired normal breast tissue from the same patient. Immunohistochemical analysis revealed high expression of AEG-1 in 100 of 225 (44.4%) paraffin-embedded archival breast cancer biopsies. Statistical analysis showed a significant correlation of AEG-1 expression with the clinical staging of the patients with breast cancer (P = 0.001), as well as with the tumor classification (P = 0.004), node classification (P = 0.026), and metastasis classification (P = 0.001). Patients with higher AEG-1 expression had shorter overall survival time, whereas patients with lower AEG-1 expression had better survival. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of patients with breast cancer. Conclusions: Our results suggest that AEG-1 protein is a valuable marker of breast cancer progression. High AEG-1 expression is associated with poor overall survival in patients with breast cancer.