tbuckley/cabot-search huggingface dataset:
Psychotic (delusional) major depression: should it be included as a distinct syndrome in DSM-IV?
Authors: A F Schatzberg, A J Rothschild
Journal: American Journal of Psychiatry (1992)

To review data supporting or not supporting the designation of unipolar psychotic major depression as a distinct syndrome in DSM-IV, the authors used computerized literature searches to identify reports of studies that have directly compared the characteristics, biology, familial transmission, course/outcome, and response to treatment of psychotic and nonpsychotic major depression. The review showed that statistically significant differences between the two types of depression have been found on each of these dimensions. There are greater guilt feelings and psychomotor disturbance, among other features, in psychotic depression. Studies have found significant differences between patients with psychotic and nonpsychotic depression in glucocorticoid activity, dopamine beta-hydroxylase activity, levels of dopamine and serotonin metabolites, sleep measures, and ventricle-to-brain ratios. Family studies show higher rates of bipolar disorder in first-degree relatives of probands with psychotic major depression than of probands with nonpsychotic major depression. Greater morbidity and residual impairment have also been reported in patients with psychotic major depression, and they respond more poorly to placebo and to tricyclic antidepressants. Differences between patients with psychotic and nonpsychotic major depression on many of these measures were not due to differences in severity or endogenicity. Since the data indicate that psychotic and nonpsychotic major depression can be separated, the frequency with which the diagnosis of psychotic major depression is missed and its unique course and response to treatment point to the practical importance of a separate diagnosis for this disorder. However, further studies are needed to resolve important methodological issues and to develop an optimal set of operational criteria.
Anti-tumor effects of combination therapy with anti-EGFR and anti-Src therapy in colorectal cancer
Authors: Scott Kopetz, Ji Wu, Faye Johnson, Nicholas Donato
Journal: Clinical Cancer Research (2006)

B51   Background: Cetuximab is a monoclonal antibody to the ligand-binding domain of the EGFR used in treatment of metastatic colorectal cancer. Despite this apparently clear mechanism of action, neither levels of EGFR in tumors nor EGFR mutations predict clinical efficacy of cetuximab, suggesting that other factors may determine sensitivity to this agent. One potential mediator of colon cancer chemoresistance is activation of Src, a non-receptor protein tyrosine kinase. Increased Src activity in colorectal cancer has been shown to correlate with poor prognosis. Combined inhibition of Src and EGFR may provide clinical benefit in metastatic colorectal cancer.Methods: In this report, we investigated the effects of cetuximab, a monoclonal antibody to EGFR, in combination with dasatinib, a tyrosine kinase inhibitor with activity against Src, in human HT29 and LS174T metastatic colorectal cell lines. EGFR is not mutated in these cell lines, which have moderate (LS174T) and low (HT29) levels of EGFR protein expression. MTT assays were performed after 48 h of drug exposure. Clonogenic assays were analyzed after 14 days of continuous drug treatment.Results: In the MTT assay, HT29 cells are not responsive to cetuximab alone at clinically relevant doses, while LS174T cells show minimal inhibitory effects without reaching an IC50. Likewise, both LS174T and HT29 cells are minimally sensitive to dasatinib, with an IC50 outside a clinically relevant range. The combination of cetuximab and dasatinib resulted in supra-additive growth inhibition for both cell lines. This effect was confirmed with clonogenic assays that demonstrated significant augmentation in the inhibition of clone formation with the combination. Initial results suggest that combination treatment is associated with an increase in apoptosis. Molecular studies to elucidate the mechanism of the interaction of EGFR and Src inhibition are currently in progress and will be presented.Conclusions: Cetuximab and dasatinib have at least supra-additive effects  in vitro . Based on these findings, the ability of combination therapy with cetuximab and dasatinib in colorectal cancer xenografts is planned. These results suggest that combined inhibition with cetuximab and dasatinib is a promising strategy in the treatment of metastatic colorectal cancer.
206. Adenovirus-Mediated GTP Cyclohydrolase I Gene Delivery Augments Tetrahydrobiopterin and Restores Nitric Oxide Synthase Function in Hyperglycaemic Human Aortic Endothelial Cells
Authors: Shijie Cai, Keith M. Channon
Journal: Molecular Therapy (2004)

Top of pageAbstract
Introduction: Endothelial dysfunction is a marker of diabetic vascular disease, characterised by decreased nitric oxide (NO) bioactivity and increased superoxide (SO) production in endothelium. Reduced levels of tetrahydrobiopterin (BH4), an essential cofactor of endothelial NO synthase (eNOS), leads to enzymatic uncoupling of eNOS and instability of eNOS homodimers. We set out to augment BH4 levels in hyperglycaemic human aortic endothelial cells (HAEC) by gene transfer of GTP cyclohydrolase I (GTPCH, the rate-limiting enzyme for the de novo BH4 synthesis), in order to determine whether genetic modulation of BH4 biosynthesis could rescue eNOS activity and dimerisation.

Methods: HAEC were cultured in media with low glucose (5.5 mM) or high glucose (30 mM). After 5 days, the cells with/without GTPCH gene transfer (cells alone and AdeGFP as controls) were prepared for assays of (1) NO with EPR; (2) SO with cytochrome C reduction and DHE; (3) BH4 with HPLC; (4) eNOS expression and dimerisation with immunoblotting (densitometric quantification of blots). All experiments were repeated twice (n = 6), and p value < 0.05 is considered to be significant.

Results: HAEC in high glucose cultures compared with the low glucose had 30% decrease in NO and two-fold increase in SO, with reduced levels of total biopterin (7.2 vs. 10.8) and BH4 (1.0 vs. 2.9). eNOS expression in the high glucose was increased 1.5-fold, but mainly existed in the monomeric form (dimer:monomer ratio 0.3 vs 0.5). GTPCH gene transfer increased biopterins 30-40 fold as compared with controls. GTPCH gene transfer also increased NO production 1.6-fold, led to 30% SO reduction. Furthermore, augmented BH4 promoted eNOS dimerisation. The dimer:monomer ratio in GTPCH was 2.6-fold higher than in the controls.

Conclusion: This study demonstrates a critical role for BH4 in regulating eNOS function in hyperglycaemic human endothelial cells. GTPCH gene transfer is a powerful approach to investigate eNOS regulation and potential therapeutic significance in diabetes.
361. Reduction of Polyethylenimine Buffering Capacity Enhances In-Vitro Gene Delivery Activity
Authors: M. Laird Forrest, Nathan Gabrielson, Daniel W. Pack
Journal: Molecular Therapy (2004)

Because of their potential safety and relatively facile manufacture, synthetic gene delivery vectors, especially polyplexes, may ultimately replace viral vectors for many human gene therapies. However, none of the currently available polymers is satisfactory. All lack sufficient safety or efficiency for clinical applications. Successful development of polyplex gene delivery hinges upon discovery of new materials.
820. Cost-Effective, Pharmaceutical-Grade Plasmid Production Method for Commercial Use
Authors: Henry Hebel, Sriram Ramakrishnan, Hugo Gonzalez, Heather Attra
Journal: Molecular Therapy (2004)

Cost-effective production of commercial-scale batches of pharmaceutical-grade plasmid DNA remains a challenge for the maturing industry of plasmid-based biologics. A process is required that meets the quality standards for human pharmaceutical products and yet is economically suitable for use in veterinary medicine or as an in-process product for viral therapeutic production. Previously described scaleable cell lysis requires a substantial capital investment. Also, these techniques contaminate the process stream with unnecessary impurity levels. A simple, effective purification strategy requires elimination of all animal-derived enzymes, without adding costly column-based chromatography steps. The method described herein has produced multi-gram batches of pharmaceutical-grade plasmid at a fraction of the cost of previously described methods.
Impotence more common after prostatectomy than previously thought
Authors: Scott Gottlieb
Journal: BMJ (2000)

Impotence occurs far more frequently after radical prostatectomy than previous studies have shown, according to the first nationally representative study to evaluate long term outcomes after prostate surgery.

The new, broad based population study found far more patients admitting that they had problems after the operation than earlier estimates, which have been as low as 20%.

In the current study, researchers followed 1291 men aged 39–79 who were randomly sampled from six National Cancer Institute cancer registries across the United States. They found that 60% were impotent 18 months after the surgery, 8% experienced total urinary incontinence, and 40% had occasional genitourinary problems ( JAMA 2000;283:354-60).

Men surveyed in the study had all undergone …
Meta-Analysis: Cysticidal Drugs for Neurocysticercosis: Albendazole and Praziquantel
Authors: Oscar H. Del Brutto, Karen L. Roos, Christopher S. Coffey, Héctor H. García
Journal: Annals of Internal Medicine (2006)

Background: Conflicting reports have caused controversy on whether cysticidal drugs modify the natural course of neurocysticercosis. Purpose: To perform a meta-analysis of randomized trials assessing the effect of cysticidal drugs on neuroimaging and clinical outcomes of patients with neurocysticercosis. Data Sources: Search of MEDLINE, Cochrane Database of Systematic Reviews, and Literatura Latino-Americana y del Caribe en Ciencias de la Salud (LILACS) between 1979 and 2005. There were no language restrictions. Study Selection: Randomized trials of cysticidal drug therapy for neurocysticercosis that met predefined criteria designed to allow characterization of the disease and objective evaluation of therapy. Data Abstraction: The authors independently reviewed articles. Abstracted data included study design, number of randomly assigned patients and withdrawals, intervention, adverse events, timing of neuroimaging studies, and outcomes. Data Synthesis: Eleven studies met the inclusion criteria. Six trials randomly assigned 464 patients with cystic lesions (vesicular cysticerci), and 5 trials randomly assigned 478 patients with enhancing lesions (colloidal cysticerci). Parasites were located in the brain parenchyma or subarachnoid space at the convexity of the cerebral hemispheres. Cysticidal drug therapy was associated with complete resolution of cystic lesions (44% vs. 19%; P = 0.025). Trials on enhancing lesions showed a trend toward lesion resolution favoring the use of cysticidal drugs (72% vs. 63%; P = 0.38) that became statistically significant when an outlier trial was excluded from the analysis (69% vs. 55%; P = 0.006). Risk for seizure recurrence was lower after cysticidal treatment in patients with enhancing lesions (14% vs. 37%; P < 0.001). The single trial evaluating the frequency of seizures in patients with cystic lesions showed a 67% reduction in the rate of generalized seizures with treatment (P = 0.006). Limitations: Not all studies focused on the control of seizures as an outcome. Conclusions: Cysticidal drug therapy results in better resolution of colloidal and vesicular cysticerci, lower risk for recurrence of seizures in patients with colloidal cysticerci, and a reduction in the rate of generalized seizures in patients with vesicular cysticerci.
Growth Hormone for “Antiaging”
Authors: Thierry Hertoghe, Suzie Schuder
Journal: JAMA (2006)

To the Editor: The Commentary by Dr Perls and colleagues1 discusses provision or distribution of human growth hormone (HGH or GH) for the purpose of antiaging. Contrary to the authors' belief, antiaging medical doctors do not prescribe uncontrolled and inactive Internet GH products.
Regressing Merkel cell carcinoma—a case showing replacement of tumour cells by foamy cells
Authors: K. Maruo, K-I. Kayashima, T. Ono
Journal: British Journal of Dermatology (2000)

Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumour with a high rate of recurrence and metastasis. However, some cases of spontaneous regression have recently been reported. We describe the clinical course of an 80-year-old Japanese woman with regressing MCC. We also report histological findings of the regressing tumour for the first time. After the patient's first visit to our hospital, the lesion was a rapidly progressive tumour, but suddenly began decreasing in size, and rapidly regressed. The surface of the tumour flattened, the colour changed from red to dark red, and finally the lesion appeared as a small yellowish plaque. Histopathological analysis of the completely regressed tumour revealed that the tumour cells were completely replaced by numerous foamy cells. This is the first report demonstrating the histopathological features of regressing MCC.
Abstract 3110: Adherence to Beta-blockers and ACE Inhibitors/Angiotensin Receptor Blockers in the First Year after Diagnosis of Heart Failure: 10 Year Observational Trends
Authors: Darcy A Lamb, Dean T Eurich, Finlay A McAlister, Ross Tsuyuki, William M Semchuk, Thomas W Wilson, David F Blackburn
Journal: Circulation (2008)

Introduction: As prescriptions for evidence based medications in patients with heart failure (HF) have increased over the past 10 years, we aimed to determine if adherence to HF medications has also increased over this time. Methods: A retrospective cohort was created using administrative databases from the province of Saskatchewan, Canada. Subjects discharged alive from their first hospitalization for HF between 1994 and 2003 were eligible for study. Those filling a prescription for a beta blocker (BB), ACE inhibitor (ACEI), or angiotensin receptor blocker (ARB) within six months after discharge were selected. The proportion of subjects with optimal 1-year adherence (≥ 80%) was determined and divided according to the year of entry into the study. Results: Of 8,805 eligible patients, 67% of BB users (941/1414) and 74% of ACEI/ARB users (4441/5991) exhibited 1-year adherence ≥ 80%. When grouped by year of initial HF hospitalization, the proportion of patients with optimal 1-year adherence improved from 54% to 75% with BB and from 67% to 80% with ACEI/ARBs between 1994/95 and 2002/03 [Figure ]. Mean 1-year adherence improved from 71% to 83% and 80% to 88% for BB and ACEI/ARBs, respectively. After covariate adjustment using multivariate logistic regression, year of initial HF hospitalization remained independently associated with optimal 1-year adherence. Subjects discharged in 2003 were significantly more likely to exhibit optimal adherence to a BB (OR 2.04; 95% CI 1.21–3.44) or an ACEI/ARB (OR 1.65; 95% CI 1.30–2.08) than those prescribed therapy in 1994/95. Conclusion: One year adherence to BB and ACEI/ARB is improving over time in patients newly diagnosed with HF.
Safety and Tolerability of the Treatment of Youth-Onset Type 2 Diabetes
Authors: Neil H. White, Laura Pyle, Steven M. Willi, Trang Pham, Steven D. Chernausek, Robin Goland, Daniel E. Hale, Morey W. Haymond, Kristen J. Nadeau, Sumana Narasimhan
Journal: Diabetes Care (2013)

Data related to the safety and tolerability of treatments for pediatric type 2 diabetes are limited. The TODAY clinical trial assessed severe adverse events (SAEs) and targeted nonsevere adverse events (AEs) before and after treatment failure, which was the primary outcome (PO).Obese 10- to 17-year-olds (N = 699) with type 2 diabetes for <2 years and hemoglobin A1c (A1C) ≤ 8% on metformin monotherapy were randomized to one of three treatments: metformin, metformin plus rosiglitazone (M + R), or metformin plus lifestyle program (M + L). Participants were followed for 2-6.5 years.Gastrointestinal (GI) disturbance was the most common AE (41%) and was lower in the M + R group (P = 0.018). Other common AEs included anemia (20% before PO, 14% after PO), abnormal liver transaminases (16, 15%), excessive weight gain (7, 9%), and psychological events (10, 18%); the AEs were similar across treatments. Permanent medication reductions/discontinuations occurred most often because of abnormal liver transaminases and were lowest in the M + R group (P = 0.005). Treatment-emergent SAEs were uncommon and similar across treatments. Most (98%) were unrelated or unlikely related to the study intervention. There were no deaths and only 18 targeted SAEs (diabetic ketoacidosis, n = 12; severe hypoglycemia, n = 5; lactic acidosis, n = 1). There were 62 pregnancies occurring in 45 participants, and 6 infants had congenital anomalies.The TODAY study represents extensive experience managing type 2 diabetes in youth and found that the three treatment approaches were generally safe and well tolerated. Adding rosiglitazone to metformin may reduce GI side effects and hepatotoxicity.
Experts Ponder Pediatric Research Ethics
Authors: Tracy Hampton
Journal: JAMA (2005)

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The role of hematopoietic stem cell transplantation for relapsed and refractory <scp>H</scp>odgkin lymphoma
Authors: Shinichi Kako, Koji Izutsu, Koji Kato, Sung‐Won Kim, Takehiko Mori, Takahiro Fukuda, Naoki Kobayashi, Hirofumi Taji, Hisako Hashimoto, Tadakazu Kondo, Hisashi Sakamaki, Yasuo Morishima, Koji Kato, Ritsuro Suzuki, Junji Suzumiya
Journal: American Journal of Hematology (2014)

The optimal treatment strategy with the use of hematopoietic stem cell transplantation (HSCT) for relapsed and refractory Hodgkin lymphoma (HL) remains unclear. We performed a retrospective analysis using registry data from the Japanese Society for Hematopoietic Cell Transplantation. Adult patients with HL who underwent a first autologous or a first allogeneic HSCT between 2002 and 2009 were included. Patients who underwent HSCT in first complete remission (CR) were excluded. Autologous and allogeneic HSCT were performed in 298 and 122 patients, respectively. For autologous HSCT, overall survival at 3 years (3yOS) was 70%, and sex, age, disease status, and performance status (PS) at HSCT were prognostic factors. OS was favorable even in patients who underwent autologous HSCT in disease status other than CR. For allogeneic HSCT, 3yOS was 43%, and sex and PS at HSCT were prognostic factors. Disease status at HSCT, previous autologous HSCT, and conditioning intensity did not affect OS. Moreover, graft-versus-host disease did not affect progression-free survival or relapse/progression rate. A first allogeneic HSCT without a previous autologous HSCT was performed in 40 patients. 3yOS was 45%, and was significantly inferior to that in patients who underwent their first autologous HSCT. This result was retained after the correction by the different patient characteristics according to the type of HSCT. In conclusion, autologous HSCT is effective in prolonging survival in patients with relapsed and refractory HL. Allogeneic HSCT might be beneficial even to relapsed HL after autologous HSCT, although establishing the role of allogeneic HSCT remains a challenge.
Abstract 11162: Multi-Vessel Percutaneous Coronary Stenting versus Multi-Vessel Coronary Bypass Grafting in the Emergent Setting: 11-Year Nationwide Propensity Score Matched Study
Authors: Rafael Marroquin, Nadish Garg, Arun Kumar, Kevin C Dellsperger, Raja R Gopaldas
Journal: Circulation (2011)

Background: Recently, using multivessel percutaneous coronary intervention with stenting (mPCI) has increased. While clinical trials evaluated the role of elective mPCI against multivessel Coronary...
Mapping of a novel locus for an autosomal recessive form of palmoplantar keratoderma on chromosome 3q27.2-q29
Authors: S. Khan, S. Muzaffar, M. Tariq, A. Khan, S. Basit, W. Ahmad
Journal: British Journal of Dermatology (2010)

Background Palmoplantar keratodermas (PPKs) are a group of highly heterogeneous diseases causing hyperkeratosis of the palms and soles. They can be inherited in an autosomal recessive, dominant, mitochondrial or possibly X‐linked recessive fashion. The present study describes clinical and molecular genetic analysis of a consanguineous Pakistani family showing a severe form of PPK inherited in an autosomal recessive manner. Objectives To map the gene responsible for an autosomal recessive form of PPK. Methods Human genome scan using polymorphic microsatellite markers was performed to localize the disease gene. Eleven candidate genes, located in the linkage interval, were screened to identify the potential sequence variants. Results All five affected members of the family showed severe bilateral involvement of palms and soles with minor nail involvement, severe fissuring with bleeding, painful walking, and problems in grasping. Linkage analysis in the family mapped a novel locus for the disease on chromosome 3q27.2‐q29. The candidate region flanked by markers D3S1530 and D3S1272 spans 28·22 cM, which corresponds to a physical distance of 11·63 Mb. The maximum two‐point LOD score of 3·13 at θ = 0·00 was obtained with marker D3S2748 along the disease locus. DNA sequence analysis of 11 candidate genes, located in the linkage interval, failed to detect functional sequence variants. Conclusions A novel locus for an autosomal recessive form of PPK was mapped on chromosome 3q27.2‐q29 in a consanguineous Pakistani family. Failure to detect pathogenic sequence variants in the 11 candidate genes suggests either that the variants are located in the regulatory regions of the genes or that another unknown gene, responsible for the disease, is present in the region.