tbuckley/cabot-search huggingface dataset:
Pakistan must reboot its public health programme
Authors: Mahjabeen Khan
Journal: The Lancet Global Health (2013)

1reports that there are four sanctuaries for the polio virus in Pakistan: Karachi, Quetta, and the districts of Qila Abdullah and Pishin. 58 cases were reported from Pakistan in 2012. 2 Polio prevention is not only a national health problem but a social, religious, cultural, security, and political issue in Pakistan. 3 Violence against polio vaccine workers, particularly the killing of female workers in Karachi and Baluchistan, signifi es a need for urgent re programming of Pakistan’s public health approach. The major hurdle facing the polio vaccination programme is the perception by certain groups in the community of the vaccine as a tool with which to sterilise the Muslim population and deter the will of God. In Pakistan, low levels of education and health disparities add to the misconception and mistrust of public health policies. The paternalistic approach of public health managers and policy makers is facing resistance. The introduction of family planning, 4 fl our fortifi cation, and education of girls have been met with similar violence. The polio eradication programme is out of touch with the knowledge, attitude, and practices of the population. It is essential to determine the gaps in such understanding by means of observational and interventional research. There are very few public health graduates, managers, and researchers in the country, and capacity building of health-care providers is urgently needed nationwide. Advocacy for the polio vaccine needs revisiting. 5 Pakistan is a pluralistic society and the customs and languages are diff erent in all the provinces and territories. Health-care providers tend to focus on emergency services in tertiary care and district hospitals, and the public health programme is not the focus of the recently devolved health-care system in Pakistan. There is no health department at the federal level, and in provinces the basic health units are non-functional. The only system working to some extent is the lady health worker system. However, the numbers of lady health workers
Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function
Authors: Angel C. Y. Mak, Clive R. Pullinger, Ling Fung Tang, Jinny S. Wong, Rahul C. Deo, Jean-Marc Schwarz, Alejandro Gugliucci, Irina Movsesyan, Brian Y. Ishida, Catherine Chu, Annie Poon, Phillip Kim, Eveline O. Stock, Ernst J. Schaefer, Bela F. Asztalos, Joseph M. Castellano, Tony Wyss-Coray, Jacque L. Duncan, Bruce L. Miller, John P. Kane, Pui-Yan Kwok, Mary J. Malloy
Journal: JAMA Neurology (2014)

The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.
Assisting Social Security Disability Insurance Beneficiaries With Schizophrenia, Bipolar Disorder, or Major Depression in Returning to Work
Authors: Robert E. Drake, William Frey, Gary R. Bond, Howard H. Goldman, David Salkever, Alexander Miller, Troy A. Moore, Jarnee Riley, Mustafa Karakus, Roline Milfort
Journal: American Journal of Psychiatry (2013)

People with psychiatric impairments (primarily schizophrenia or a mood disorder) are the largest and fastest-growing group of Social Security Disability Insurance (SSDI) beneficiaries. The authors investigated whether evidence-based supported employment and mental health treatments can improve vocational and mental health recovery for this population.Using a randomized controlled trial design, the authors tested a multifaceted intervention: team-based supported employment, systematic medication management, and other behavioral health services, along with elimination of barriers by providing complete health insurance coverage (with no out-of-pocket expenses) and suspending disability reviews. The control group received usual services. Paid employment was the primary outcome measure, and overall mental health and quality of life were secondary outcome measures.Overall, 2,059 SSDI beneficiaries with schizophrenia, bipolar disorder, or depression in 23 cities participated in the 2-year intervention. The teams implemented the intervention package with acceptable fidelity. The intervention group experienced more paid employment (60.3% compared with 40.2%) and reported better mental health and quality of life than the control group.Implementation of the complex intervention in routine mental health treatment settings was feasible, and the intervention was effective in assisting individuals disabled by schizophrenia or depression to return to work and improve their mental health and quality of life.
High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector
Authors: Xiao-Bing Zhang, Brian C. Beard, Grant D. Trobridge, Brent L. Wood, George E. Sale, Reeteka Sud, R. Keith Humphries, Hans-Peter Kiem
Journal: Journal of Clinical Investigation (2008)

Retroviral vector-mediated HSC gene therapy has been used to treat individuals with a number of life-threatening diseases. However, some patients with SCID-X1 developed retroviral vector-mediated leukemia after treatment. The selective growth advantage of gene-modified cells in patients with SCID-X1 suggests that the transgene may have played a role in leukemogenesis. Here we report that 2 of 2 dogs and 1 of 2 macaques developed myeloid leukemia approximately 2 years after being transplanted with cells that overexpressed homeobox B4 (HOXB4) and cells transduced with a control gammaretroviral vector that did not express HOXB4. The leukemic cells had dysregulated expression of oncogenes, a block in myeloid differentiation, and overexpression of HOXB4. HOXB4 knockdown restored differentiation in leukemic cells, suggesting involvement of HOXB4. In contrast, leukemia did not arise from the cells carrying the control gammaretroviral vector. In addition, leukemia did not arise in 5 animals with high-level marking and polyclonal long-term repopulation following transplantation with cells transduced with an identical gammaretrovirus vector backbone expressing methylguanine methyltransferase. These findings, combined with the absence of leukemia in many other large animals transplanted with cells transduced with gammaretroviral vectors expressing genes other than HOXB4, show that HOXB4 overexpression poses a significant risk of leukemogenesis. Our data thus suggest the continued need for caution in genetic manipulation of repopulating cells, particularly when the transgene might impart an intrinsic growth advantage.
Symptom-to-treatment intervals in lung cancer
Authors: Nidhal Belloumi, Nozha Ben Salah, Sonia Toujani, Meriem Mjid, Alaa Akad, Chirine Moussa, Abir Hedhli, Yassine Ouahchi, Bechir Louzir, Jalloul Daghfous, Nadia Mhiri, Jouda Cherif, Majed Beji
Journal: European Respiratory Journal (2014)

Introduction : Lung cancer is a disease with poor outcome, frequently diagnosed in its advanced stages. Reducing the delay of management can be a promoting factor of the prognosis.

Aims and objectives : The aim of the study is to evaluate the length of delays in diagnosis and initiation of treatment among patients with lung cancer.

Methods : A retrospective study was undertaken from the records of all patients with histollogically proven lung cancer, between January 2011, and December 2012. A check list was worked out to facilitate gathering sociodemographic, clinical, paraclinical data.

Results : 99 lung cancer patients were included. The mean age was 61 years. 70 patients had non small cells cancer, 13 patients(18.8%) were stage IIIb and 43(62.3%) were stage IV. 29 patients had small cells cancer and 26 among them(89.6%) were metastatic. Mean delay from symptom to the first consultation is 46 days. The first consultation in a pulmonology department took place after 60 days. Endoscopy was underwent in a delay of 64 days from the first symptom. CT scan was done in a delay of 67 days. Histological confirmation was obtained after 84 days from the first symptom. Treatment onset was 65 days after the first consultation in the department and 125 days after symptoms. Surgery was performed for 2 patients in a delay of 44 days from symptoms. Chemotherapy was performed for 42 patients in a 129 days delay. Radiotherapy was curative for 2 patients and palliative for 6 others, it's done in a delay of 77.8 days from onset of symptoms.

Conclusions : This study shows long delays in the management of lung cancer. Mass sensibilisation, acknowledgment of general practitioners and enhancement of the resources within hospitals will help shortening them.
The Association Between Cardiovascular Autonomic Neuropathy and Mortality in Individuals With Diabetes
Authors: Raelene E. Maser, Braxton D. Mitchell, Aaron I. Vinik, Roy Freeman
Journal: Diabetes Care (2003)

OBJECTIVE—To examine by meta-analysis the relationship between cardiovascular autonomic neuropathy (CAN) and risk of mortality in individuals with diabetes. RESEARCH DESIGN AND METHODS—We searched Medline for English-language articles published from 1966 to 2001. Fifteen studies having a baseline assessment of cardiovascular autonomic function and mortality follow-up were identified. The analyses were stratified according to whether a single abnormality or two or more measures of cardiovascular autonomic function were used to define CAN. A global measure of association (i.e., relative risk) was generated for each group by pooling estimates across the studies using the Mantel-Haenszel procedure. RESULTS—CAN was significantly associated with subsequent mortality in both groups, although the magnitude of the association was stronger for those studies for which two or more measures were used to define CAN. The pooled relative risk for studies that defined CAN with the presence of two or more abnormalities was 3.45 (95% CI 2.66–4.47; P &amp;lt; 0.001) compared with 1.20 (1.02–1.41; P = 0.03) for studies that used one measure. CONCLUSIONS—These results support an association between CAN and increased risk of mortality. The stronger association observed in studies defining CAN by the presence of two or more abnormalities may be due to more severe autonomic dysfunction in these subjects or a higher frequency of other comorbid complications that contributed to their higher mortality risk. Future studies should evaluate whether early identification of subjects with CAN can lead to a reduction in mortality.
Clinical Course of acute‐on‐chronic liver failure syndrome and effects on prognosis
Authors: Thierry Gustot, Javier Fernandez, Elisabet Garcia, Filippo Morando, Paolo Caraceni, Carlo Alessandria, Wim Laleman, Jonel Trebicka, Laure Elkrief, Corinna Hopf, Pablo Solís‐Munoz, Faouzi Saliba, Stefan Zeuzem, Augustin Albillos, Daniel Benten, José Luis Montero‐Alvarez, Maria Teresa Chivas, Mar Concepción, Juan Córdoba, Aiden McCormick, Rudolf Stauber, Wolfgang Vogel, Andrea de Gottardi, Tania M. Welzel, Marco Domenicali, Alessandro Risso, Julia Wendon, Carme Deulofeu, Paolo Angeli, François Durand, Marco Pavesi, Alexander Gerbes, Rajiv Jalan, Richard Moreau, Pere Ginés, Mauro Bernardi, Vicente Arroyo
Journal: Hepatology (2015)

Acute‐on‐chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28‐day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28‐day) follow‐up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28‐day transplant‐free mortality was low‐to‐moderate (6%‐18%) in patients with nonsevere early course (final no ACLF or ACLF‐1) and high‐to‐very high (42%‐92%) in those with severe early course (final ACLF‐2 or ‐3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF‐C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty‐one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short‐ (28‐day) and mid‐term (90‐day) mortality by ACLF grade at 3‐7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF‐C ACLFs &gt;64 at days 3‐7 days, and did not undergo LT, mortality was 100% by 28 days. Conclusions : Assessment of ACLF patients at 3‐7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility. (H epatology 2015;62:243‐252)
Response to Letter Regarding Article, “Initial Results of Posterior Leaflet Extension for Severe Type IIIb Ischemic Mitral Regurgitation”
Authors: Benoit De Varennes, Rakesh Chaturvedi, Surita Sidhu, Annie V. Côté, William Li Pi Shan, Caroline Goyer, Roupen Hatzakorzian, Jean Buithieu, Allan Sniderman
Journal: Circulation (2010)
Learning to Program the Liver
Authors: Curtis D. Klaassen
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Half a century ago, people were learning to program computers. Similarly, we have been trying to learn how to program the liver to protect us from chemicals. We have given various chemicals that activate transcription factors such as the nuclear receptors: These ligand-activated nuclear receptors enter the nucleus of liver cells (hepatocytes) and bind to their specific motifs in DNA to increase the transcription of various genes that protect against chemical-induced injury. Several examples from our laboratory are given to demonstrate this detoxification process: (a) a steroid chemical that increases the expression of a hepatic transporter to enhance the elimination of other chemicals and thus decrease their toxicity, (b) a metal that decreases its own toxicity by increasing the production of a protein to which it binds, and (c) an herbal chemical that activates a transcription factor that serves as a sensor of oxidative stress and electrophiles to protect against cytotoxicity by increasing the expression of numerous antioxidant proteins. In addition, at the present time, we are investigating which bile acids that are synthesized in the liver and altered by bacteria in the intestine may be used to alter the programming of the liver, as well as how the liver reprograms itself after birth in the transition from a hematopoietic organ to one that decreases the toxicity of chemicals.
Biomarkers of early respiratory effects in smoking adolescents
Authors: E. Van Miert, A. Sardella, A. Bernard
Journal: European Respiratory Journal (2011)

Noninvasive biomarkers can be used to evaluate airways damage caused by tobacco smoke, but studies so far have only involved adult smokers. In this study, we evaluated whether such biomarkers can detect early respiratory effects in adolescents passively or actively exposed to tobacco smoke. In a cross-sectional study of 845 adolescents (mean age 16 yrs), we measured exhaled nitric oxide (NO) and various epithelial markers in nasal lavage fluid (NALF) and serum, including Clara cell protein (CC16) and surfactant protein (SP)-D. Information about smoking habits and potential confounders was collected by questionnaire. Four groups of equal size (n=36), of nonsmokers, passive smokers, light smokers (&lt;5 cigarettes·day −1 , median 0.08 pack-yrs) and heavy smokers (≥5 cigarettes·day −1 , median 0.35 pack-yrs), were matched using an automated procedure. The levels of exhaled NO and of CC16 in NALF were significantly decreased in the group of heavy smokers. A trend towards lower levels of CC16 in NALF was observed in passive smokers. There were no significant changes in serum CC16 and SP-D, which suggests that the deep lung epithelium had not yet been affected by smoking. In conclusion, tobacco smoke can cause early changes in the airways of adolescents with a cumulative smoking history of &lt;1 pack-yr.
Phosphorylation of Estrogen Receptor-α at Ser167 Is Indicative of Longer Disease-Free and Overall Survival in Breast Cancer Patients
Authors: Jie Jiang, Naveed Sarwar, David Peston, Elena Kulinskaya, Sami Shousha, R. Charles Coombes, Simak Ali
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Ser167 was first identified as a major phosphorylation site of the estrogen receptor -α (ER) positive in the MCF7 breast cancer cell line. Subsequent studies have shown that Ser167 phosphorylation is important in the regulation of ER activity and have identified p90RSK and AKT as protein kinases that phosphorylate Ser167. The purpose of this study was to determine the importance of Ser167 phosphorylation in breast cancer progression. Experimental Design: Immunohistochemical staining of primary breast cancer biopsies (n = 290) was carried out using antibodies specific for ER phosphorylated at Ser167 and for phosphorylated p44/p42 mitogen-activated protein kinase (MAPK), phosphorylated p90RSK, and phosphorylated AKT. Results: In ER-positive breast cancer patients, Ser167 phosphorylation was associated with low tumor grade (P = 0.011), lymph node negativity (P = 0.034), and relapse-free (P = 0.006) and overall (P = 0.023) survival. Further, Ser167 phosphorylation was strongly associated with phosphorylated p90RSK (P &amp;lt; 0.001), previously shown to phosphorylate Ser167 in vitro, as well as being associated with phosphorylated MAPK (P &amp;lt; 0.0005). The activities of both kinases also seemed to be indicative of better prognosis. There was, however, no association between HER2 positivity and Ser167 phosphorylation nor were the activities of MAPK or p90RSK associated with HER2 status, suggesting that other cell surface receptors may be important in regulating these activities in breast cancer. Conclusions: These findings show that phosphorylation at Ser167 of ER predicts for likelihood of response of ER-positive breast cancer patients to endocrine therapies.
A Role for Mitochondrial Dysfunction in Perpetuating Radiation-Induced Genomic Instability
Authors: Grace J. Kim, Gary M. Fiskum, William F. Morgan
Journal: Cancer Research (2006)

Abstract Radiation-induced genomic instability (RIGI) manifests as a heritable increased rate of genetic alterations in the progeny of irradiated cells generations after the initial insult. The progeny can show an increased frequency of chromosomal translocations, deletions, mutations, micronuclei, and decreased plating efficiency. What perpetuates RIGI is unclear; however, persistently increased levels of reactive oxygen species (ROS) are frequently associated with genomically unstable clones. Furthermore, addition of free radical scavengers (e.g., DMSO, glycerol, and cationic thiol cysteamine) reduces the incidence of instability after irradiation, implicating a ROS-mediated role in RIGI induction. Because mitochondria are a major natural cellular source of ROS, we tested the hypothesis that mitochondrial dysfunction has a role in maintaining the elevated ROS levels in our irradiated, genetically unstable GM10115 Chinese hamster ovary cells. Amplex Red fluorometry measurements indicate that the relative contribution of uncoupler-sensitive mitochondrial hydrogen peroxide production to total cellular hydrogen peroxide generation is greater in unstable cells. Measurements of mitochondrial DNA levels and cell cytometric fluorescent measurements of Mitotracker Green FM indicate that differences in mitochondrial ROS production are not due to varying mitochondrial levels. However, mitochondrial respiration measured in digitonin-permeabilized cells is impaired in unstable clones. In addition, manganese superoxide dismutase, a major mitochondrial antioxidant enzyme, exhibits increased immunoreactivity but decreased enzyme activity in unstable clones, which along with decreased respiration rates may explain the increased levels of cellular ROS. These studies show that mitochondria from unstable cells are abnormal and likely contribute to the persistent oxidative stress in the unstable clones. (Cancer Res 2006; 66(21): 10377-83)