tbuckley/cabot-search huggingface dataset:
Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial
Authors: M. M Rahman, S. H Vermund, M. A Wahed, G. J Fuchs, A. H Baqui, J. O Alvarez
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To evaluate the effect of simultaneous zinc and vitamin A supplementation on diarrhoea and acute lower respiratory infections in children. <b>Study design:</b> Randomised double blind placebo controlled trial. <b>Setting:</b> Urban slums of Dhaka, Bangladesh. <b>Participants and methods:</b> 800 children aged 12-35 months were randomly assigned to one of four intervention groups: 20 mg zinc once daily for 14 days; 200 000 IU vitamin A, single dose on day 14; both zinc and vitamin A; placebo. The children were followed up once a week for six months, and morbidity information was collected. <b>Results:</b> The incidence and prevalence of diarrhoea were lower in the zinc and vitamin A groups than in the placebo group. Zinc and vitamin A interaction had a rate ratio (95% confidence interval) of 0.79 (0.66 to 0.94) for the prevalence of persistent diarrhoea and 0.80 (0.67 to 0.95) for dysentery. Incidence (1.62; 1.16 to 2.25) and prevalence (2.07; 1.76 to 2.44) of acute lower respiratory infection were significantly higher in the zinc group than in the placebo group. The interaction term had rate ratios of 0.75 (0.46 to 1.20) for incidence and 0.58 (0.46 to 0.73) for prevalence of acute lower respiratory infection. <b>Conclusions:</b> Combined zinc and vitamin A synergistically reduced the prevalence of persistent diarrhoea and dysentery. Zinc was associated with a significant increase in acute lower respiratory infection, but this adverse effect was reduced by the interaction between zinc and vitamin A. <h3>What is already known on this topic</h3> Trials of vitamin A supplementation have failed to show a beneficial effect on morbidity in children Experimental studies have shown that, in the presence of zinc deficiency, vitamin A supplementation fails to reverse vitamin A deficiency Coexistence of deficiencies of zinc and vitamin A could be a reason for the failure of vitamin A supplementation, but data in humans are limited <h3>What this paper adds</h3> Combined zinc and vitamin A supplementation is more effective in reducing persistent diarrhoea and dysentery than either vitamin A or zinc alone Zinc alone increased respiratory illnesses, but interaction between zinc and vitamin A reduced this adverse effect
Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage.
Authors: C Baylis, B Mitruka, A Deng
Journal: Journal of Clinical Investigation (1992)

Tonic basal release of nitric oxide (NO) by vascular endothelial cells controls blood pressure (BP) in the basal state. In these studies we investigated the effects of chronic inhibition of basal NO synthesis in the rat for a 2-mo period. Significant systemic hypertension developed in chronically NO-blocked rats compared to controls. Marked renal vasoconstriction was also observed with elevations in glomerular blood pressure (PGC) and reductions in the glomerular capillary ultrafiltration coefficient (Kf). Chronically NO-blocked rats also develop proteinuria and glomerular sclerotic injury compared to controls. These studies therefore describe a new model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous NO synthesis. These observations highlight the importance of the endogenous NO system in control of normal vascular tone and suggest that hypertensive states may result from relative NO deficiency.
Interferons, <i>Mx</i> Genes, and Resistance to Influenza Virus
Authors: Michel A. Horisberger
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Human influenza is primarily an infection of the upper respiratory tract and central airways. The interferon (IFN) system appears to have a role in limiting viral spread and initiating recovery before the development of T-cell and B-cell responses in primary infection. All cellular responses to IFNs result from interaction with cell surface receptors that trigger the expression of a number of cellular genes. Among the IFN-inducible gene products, the Mx proteins have attracted much attention because they have potential activity against influenza virus and possibly against other viruses. Mx proteins are guanosine triphosphate (CTP)-binding proteins with intrinsic GTPase activity. They seem to act indirectly against viruses by modifying cellular functions needed along the viral replication pathway. In mice the Mx1 protein has been shown to be necessary and sufficient to protect against influenza virus infection because the resistance does not require a functioning immune system. In humans the MxA protein has antiviral activities against influenza viruses. The MxA protein is encoded on the distal part of the long arm of chromosome 21 together with several other proteins implicated in the IFN system. Patients with Down's syndrome (trisomy 21) have an increased expression of MxA protein, and their cells display an increased sensitivity to IFNs in vitro because of gene dosage effects. These patients, however, are more susceptible to upper respiratory infection than normal individuals. This susceptibility has been related to deficiencies in the immune system. Therefore, induction of MxA in man does not seem sufficient to prevent influenza spreading, and, in contrast to the murine Mx system, a functioning immune system is necessary for protection. Horisberger MA. Interferons, Mx genes, and resistance to influenza virus.
Mortality in Mental Disorders and Global Disease Burden Implications
Authors: Elizabeth Reisinger Walker, Robin E. McGee, Benjamin G. Druss
Journal: JAMA Psychiatry (2015)

<h3>Importance</h3> Despite the potential importance of understanding excess mortality among people with mental disorders, no comprehensive meta-analyses have been conducted quantifying mortality across mental disorders. <h3>Objective</h3> To conduct a systematic review and meta-analysis of mortality among people with mental disorders and examine differences in mortality risks by type of death, diagnosis, and study characteristics. <h3>Data Sources</h3> We searched EMBASE, MEDLINE, PsychINFO, and Web of Science from inception through May 7, 2014, including references of eligible articles. Our search strategy included terms for mental disorders (eg,<i>mental disorders</i>,<i>serious mental illness</i>, and<i>severe mental illness</i>), specific diagnoses (eg,<i>schizophrenia</i>,<i>depression</i>,<i>anxiety</i>, and<i>bipolar disorder</i>), and mortality. We also used Google Scholar to identify articles that cited eligible articles. <h3>Study Selection</h3> English-language cohort studies that reported a mortality estimate of mental disorders compared with a general population or controls from the same study setting without mental illness were included. Two reviewers independently reviewed the titles, abstracts, and articles. Of 2481 studies identified, 203 articles met the eligibility criteria and represented 29 countries in 6 continents. <h3>Data Extraction and Synthesis</h3> One reviewer conducted a full abstraction of all data, and 2 reviewers verified accuracy. <h3>Main Outcomes and Measures</h3> Mortality estimates (eg, standardized mortality ratios, relative risks, hazard ratios, odds ratios, and years of potential life lost) comparing people with mental disorders and the general population or people without mental disorders. We used random-effects meta-analysis models to pool mortality ratios for all, natural, and unnatural causes of death. We also examined years of potential life lost and estimated the population attributable risk of mortality due to mental disorders. <h3>Results</h3> For all-cause mortality, the pooled relative risk of mortality among those with mental disorders (from 148 studies) was 2.22 (95% CI, 2.12-2.33). Of these, 135 studies revealed that mortality was significantly higher among people with mental disorders than among the comparison population. A total of 67.3% of deaths among people with mental disorders were due to natural causes, 17.5% to unnatural causes, and the remainder to other or unknown causes. The median years of potential life lost was 10 years (n = 24 studies). We estimate that 14.3% of deaths worldwide, or approximately 8 million deaths each year, are attributable to mental disorders. <h3>Conclusions and Relevance</h3> These estimates suggest that mental disorders rank among the most substantial causes of death worldwide. Efforts to quantify and address the global burden of illness need to better consider the role of mental disorders in preventable mortality.
Endogenous adenosine is an autacoid feedback inhibitor of chloride transport in the shark rectal gland.
Authors: G G Kelley, O S Aassar, J N Forrest
Journal: Journal of Clinical Investigation (1991)

The present studies define the physiologic role of endogenous adenosine in the perfused shark rectal gland, a model epithelia for hormone-stimulated chloride transport. Chloride ion secretion, and venous adenosine and inosine concentrations increased in parallel in response to hormone stimulation. From a basal rate of 157 +/- 26 mu eq/h per g, chloride secretion increased to 836 +/- 96 and 2170 +/- 358 with 1 and 10 microM forskolin, venous adenosine increased from 5.0 +/- 1 to 126 +/- 29 and 896 +/- 181 nM, and inosine increased from 30 +/- 9 to 349 +/- 77 and 1719 +/- 454 nM (all P less than 0.01). Nitrobenzylthioinosine (NBTI), a nucleoside transport inhibitor, completely blocked the release of adenosine and inosine. Inhibition of chloride transport with bumetanide, an inhibitor of the Na+/K+/2Cl- cotransporter, or ouabain, an inhibitor of Na+/K+ ATPase activity, reduced venous adenosine and inosine to basal values. When the interaction of endogenous adenosine with extracellular receptors was prevented by adenosine deaminase, NBTI, or 8-phenyltheophylline, the chloride transport response to secretagogues increased by 1.7-2.3-fold. These studies demonstrate that endogenous adenosine is released in response to hormone-stimulated cellular work and acts at A1 adenosine receptors as a feedback inhibitor of chloride transport.
Objectively measured sleep characteristics and prevalence of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis Sleep study
Authors: Pamela L Lutsey, Robyn L McClelland, Daniel Duprez, Steven Shea, Eyal Shahar, Mako Nagayoshi, Matthew Budoff, Joel D Kaufman, Susan Redline
Journal: Thorax (2015)

<h3>Background</h3> We tested whether objectively measured indices of obstructive sleep apnoea (OSA) and sleep quality are associated with coronary artery calcification (CAC) prevalence independent of obesity, a classic confounder. <h3>Methods</h3> 1465 Multi-Ethnic Study of Atherosclerosis participants (mean age 68 years), who were free of clinical cardiovascular disease, had both coronary CT and in-home polysomnography and actigraphy performed. OSA categories were defined by the Apnea-Hypopnea Index (AHI). Prevalence ratios (PRs) for CAC &gt;0 and &gt;400 (high burden) were calculated. <h3>Results</h3> Participants with severe OSA (AHI ≥30; 14.6%) were more likely to have prevalent CAC, relative to those with no evidence of OSA, after adjustment for demographics and smoking status (PR 1.16; 95% CI 1.06 to 1.26), body mass index (1.11; 1.02 to 1.21) and traditional cardiovascular risk factors (1.10; 1.01 to 1.19). Other markers of hypoxaemia tended to be associated with a higher prevalence of CAC &gt;0. For CAC &gt;400, a higher prevalence was observed with both a higher arousal index and less slow-wave sleep. Overall, associations were somewhat stronger among younger participants, but did not vary by sex or race/ethnicity. <h3>Conclusions</h3> In this population-based multi-ethnic sample, severe OSA was associated with subclinical coronary artery disease (CAC &gt;0), independent of obesity and traditional cardiovascular risk factors. Furthermore, the associations of the arousal index and slow-wave sleep with high CAC burden suggest that higher nightly sympathetic nervous system activation is also a risk factor. These findings highlight the potential importance of measuring disturbances in OSA as well as sleep fragmentation as possible risk factors for coronary artery disease.
Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells
Authors: Qi-En Wang, Keisha Milum, Chunhua Han, Yi-Wen Huang, Gulzar Wani, Jürgen Thomale, Altaf A Wani
Journal: Molecular Cancer (2011)

While platinum-based chemotherapeutic agents are widely used to treat various solid tumors, the acquired platinum resistance is a major impediment in their successful treatment. Since enhanced DNA repair capacity is a major factor in conferring cisplatin resistance, targeting of DNA repair pathways is an effective stratagem for overcoming cisplatin resistance. This study was designed to delineate the role of nucleotide excision repair (NER), the principal mechanism for the removal of cisplatin-induced DNA intrastrand crosslinks, in cisplatin resistance and reveal the impact of DNA repair interference on cisplatin sensitivity in human ovarian cancer cells. We assessed the inherent NER efficiency of multiple matched pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines and their expression of NER-related factors at mRNA and protein levels. Our results showed that only the cisplatin-resistant ovarian cancer cell line PEO4 possessed an increased NER capacity compared to its inherently NER-inefficient parental line PEO1. Several other cisplatin-resistant cell lines, including CP70, CDDP and 2008C13, exhibited a normal and parental cell-comparable NER capacity for removing cisplatin-induced DNA intrastrand cross-links (Pt-GG). Concomitant gene expression analysis revealed discordance in mRNA and protein levels of NER factors in various ovarian cancer cell lines and NER proteins level were unrelated to the cisplatin sensitivity of these cell lines. Although knockdown of NER factors was able to compromise the NER efficiency, it only caused a minimal effect on cisplatin sensitivity. On the contrary, downregulation of BRCA2, a critical protein for homologous recombination repair (HRR), significantly enhanced the efficacy of cisplatin in killing ovarian cancer cell line PEO4. Our studies indicate that the level of NER factors in ovarian cancer cell lines is neither a determinant of their NER capacity nor of the sensitivity to cisplatin, and suggest that manipulation of the HRR but not the NER factor expression provides an effective strategy for sensitizing cisplatin-resistant tumors to platinating agents.
Recovery from diabetes in mice by β cell regeneration
Authors: Tomer Nir, Douglas A. Melton, Yuval Dor
Journal: Journal of Clinical Investigation (2007)

The mechanisms that regulate pancreatic β cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing β cells is often irreversible, adult β cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the β cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of β cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in β cells, resulting in apoptosis of 70%–80% of β cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of β cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving β cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited β cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.
Low-Dose Isotretinoin Versus -Carotene to Prevent Oral Carcinogenesis: Long-term Follow-up
Authors: V. A. Papadimitrakopoulou, W. K. Hong, J. S. Lee, S. M. Lippman, J. W. Martin, J. J. Lee, J. G. Batsakis
Journal: JNCI Journal of the National Cancer Institute (1997)

26) of the patients are alive in the b-carotene and isotretinoin maintenance groups, respectively. Both patients who developed carcinoma during maintenance therapy were receiving b-carotene. The similar longer-term rates of cancer development in the two groups indicate that the retinoid becomes less effective over time after treatment. Multiple primary squamous cell carcinomas developed in four patients treated with b-carotene and in one patient treated with low-dose isotretinoin (Table 1). In all, there were 20 invasive squamous cell carcinomas, mostly stage I and II: six cancers developed in four isotretinoin-treated patients and 14 cancers in seven b-carotene-treated patients. In situ carcinoma developed in two patients in each arm. The difference in oral premalignant lesion progression rates (during maintenance) for patients who developed cancer and for those who did not was statistically significant: oral premalignant lesion progression in 10 (67%) of 15 patients who developed cancer versus eight (18%) of 44 patients who did not (P<.001). Malignant transformation of the original oral premalignancy site occurred in 21 cases, and that of a different head and neck site was observed in three.
A Phase I Dose-Escalation Study of Tivantinib (ARQ 197) in Adult Patients with Metastatic Solid Tumors
Authors: Lee S. Rosen, Neil Senzer, Tarek Mekhail, Ram Ganapathi, Feng Chai, Ronald E. Savage, Carol Waghorne, Giovanni Abbadessa, Brian Schwartz, Robert Dreicer
Journal: Clinical Cancer Research (2011)

Tivantinib, an oral, non-ATP competitive, selective c-MET inhibitor, exhibited antitumor activity in preclinical models. This open-label, phase I, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of tivantinib in patients with advanced or metastatic solid tumors refractory to standard therapy.Thirteen dose levels of tivantinib ranging from 10 to 360 mg twice a day were administered to patient cohorts in 21-day cycles (14 days on/7 days off); three active pharmaceutical ingredient forms of tivantinib (amorphous, crystalline A, and crystalline B) were also investigated. Treatment was continued until the occurrence of unacceptable toxicity, tumor progression, patient withdrawal, or death.A total of 79 patients with advanced solid tumors were enrolled. A maximum tolerated dose was not determined. Tivantinib was well tolerated, with mild to moderate toxicities. Two patients discontinued the study drug due to treatment-emergent adverse events. Dose-limiting grade of 3 or more toxicities including leukopenia, neutropenia, thrombocytopenia, vomiting, and dehydration, were observed in 2 patients treated with tivantinib 360 mg twice a day. The rate of absorption of tivantinib peaked approximately 2 to 4 hours after initial dosing, followed by a linear decrease in plasma concentrations. Increases in tivantinib exposure were not dose proportional. There was significant interpatient pharmacokinetic variability; however the clinical safety of tivantinib seemed unaffected. Three patients (3.8%) achieved a partial response and 40 patients (50.6%) maintained stable disease for a median of 19.9 weeks.Tivantinib 360 mg twice a day was well tolerated in patients with refractory advanced solid tumors. The results of this trial warrant further clinical investigation. Clin Cancer Res; 17(24); 7754-64. ©2011 AACR.
Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates
Authors: Ulrike Wille-Reece, Barbara J. Flynn, Karin Loré, Richard A. Koup, Aaron P. Miles, Allan Saul, Ross M. Kedl, Joseph J. Mattapallil, Walter R. Weiss, Mario Roederer, Robert A. Seder
Journal: The Journal of Experimental Medicine (2006)

There is a remarkable heterogeneity in the functional profile (quality) of T cell responses. Importantly, the magnitude and/or quality of a response required for protection may be different depending on the infection. Here, we assessed the capacity of different Toll like receptor (TLR)-binding compounds to influence T helper cell (Th)1 and CD8+ T cell responses when used as adjuvants in nonhuman primates (NHP) with HIV Gag as a model antigen. NHP were immunized with HIV Gag protein emulsified in Montanide ISA 51, an oil-based adjuvant, with or without a TLR7/8 agonist, a TLR8 agonist, or the TLR9 ligand cytosine phosphate guanosine oligodeoxynucleotides (CpG ODN), and boosted 12 wk later with a replication-defective adenovirus-expressing HIV-Gag (rAD-Gag). Animals vaccinated with HIV Gag protein/Montanide and CpG ODN or the TLR7/8 agonist had higher frequencies of Th1 responses after primary immunization compared to all other vaccine groups. Although the rAD-Gag boost did not elevate the frequency of Th1 memory cytokine responses, there was a striking increase in HIV Gag-specific CD8+ T cell responses after the boost in all animals that had received a primary immunization with any of the TLR adjuvants. Importantly, the presence and type of TLR adjuvant used during primary immunization conferred stability and dramatically influenced the magnitude and quality of the Th1 and CD8+ T cell responses after the rAD-Gag boost. These data provide insights for designing prime-boost immunization regimens to optimize Th1 and CD8+ T cell responses.
Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG
Authors: A. Olivieri, G. Santini, C. Patti, T. Chisesi, C. De Souza, A. Rubagotti, S. Aversa, A. Billio, A. Porcellini, M. Candela, R. Centurioni, A.M. Congiu, M. Brunori, S. Nati, M. Spriano, R. Vimercati, G. Marino, A. Contu, L. Tedeschi, I. Majolino, M. Crugnola, M.R. Sertoli
Journal: Annals of Oncology (2005)