tbuckley/cabot-search huggingface dataset:
Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation
Authors: K. L. Ma, J. Liu, C. X. Wang, J. Ni, Y. Zhang, Y. Wu, L. L. Lv, X. Z. Ruan, B. C. Liu
Journal: Cardiovascular Research (2013)

Our previous studies demonstrated that inflammation contributes to atherosclerosis through disruption of the low density lipoprotein receptor (LDLr) pathway. However, this effect is overridden by rapamycin, which is an inhibitor of mammalian target of rapamycin (mTOR). This study investigated the role of the mTOR pathway in atherosclerosis in vivo and in vitro. To induce inflammation, we used subcutaneous injection of 10% casein in apolipoprotein E knockout (ApoE KO) mice and lipopolysaccharide stimulation in rat vascular smooth muscle cells (VSMCs). Results showed that inflammation increased lipid accumulation in aortas of ApoE KO mice and in VSMCs, which were correlated with increased expressions of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 as well as with enhanced translocation of SCAP/SREBP-2 complex from the endoplasmic reticulum (ER) to the Golgi. Furthermore, inflammation increased both the percentage of cells in the S phase of cell cycle and protein expressions of the phosphorylated forms of retinoblastoma tumour suppressor protein (Rb), mTOR, eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and P70 S6 kinase. After treatment with rapamycin or mTOR siRNA, the activity of the mTOR pathway was blocked. Interestingly, the expression levels of LDLr, SCAP, and SREBP-2 and the translocation of SCAP/SREBP-2 complex from the ER to the Golgi in treated VSMCs were decreased even in the presence of inflammatory stress. Our findings demonstrate for the first time that inflammation disrupts LDLr feedback regulation through the activation of the mTOR pathway. Increased mTORC1 activity was found to up-regulate SREBP-2-mediated cholesterol uptake through Rb phosphorylation.
Children and the Quality of Ambulatory Care
Authors: Sharon B. Meropol
Journal: New England Journal of Medicine (2008)

Acute hepatitis A virus infection: a review of prognostic factors from 25 years experience in a tertiary referral center.Hepatogastroenterology 2002;49:524-8. The author replies:In response to Betz: although the relative risk indicated an approximately 30% higher risk among recipients of vaccine than among recipients of immune globulin, absolute risks were low, and absolute risk differences were never greater than 1.5%.Still, in our report, my colleagues and I draw attention to the potential relevance of these differences for persons who are likely to have severe illness if infected with the hepatitis A virus.Indeed, the Advisory Committee on Immunization Practices considered these small differences when updating recommendations for postexposure prophylaxis. 1Several of Betz's characterizations of our findings merit clarification.It is arguable whether the proportions of vaccine recipients and immuneglobulin recipients with detectable hepatitis A virus RNA (62% and 56%, respectively; P = 0.761) are different; they might equally well be considered equivalent.As we noted, the study was not designed to measure disease severity.Furthermore, alanine aminotransferase levels should be interpreted with caution, since measurements were performed once at nonstandardized time points during the course of the illness; in addition, differences were limited to levels among children.Finally, although in the modified intention-to-treat population, the relative risk with vaccine as compared with immune globulin was lower in the first week after exposure than in the second week, in the per-protocol population, it was higher in the first week after exposure than in the second week (1.73 vs. 1.30).
Cardiovascular risk factors in British children from towns with widely differing adult cardiovascular mortality
Authors: P. H Whincup, D. G Cook, F. Adshead, S. Taylor, O. Papacosta, M. Walker, V. Wilson
Journal: BMJ (1996)

<h3>Abstract</h3> Objective: To examine whether cardiovascular risk factors differ in children from towns in England and Wales with widely differing adult cardiovascular death rates. Design: School based survey conducted during 1994 in 10 towns, five with exceptionally high adult cardiovascular mortality (standardised mortality ratio 131-143) and five with exceptionally low adult cardiovascular mortality (64-75). Towns were surveyed in high-low pairs. Subjects: 3415 white children aged 8-11 years with physical measurements (response rate 75%), including 1287 with blood samples (response rate 64%), of whom 515 had blood samples taken 30 minutes after a glucose load. Results: Children in towns with high cardiovascular mortality were on average shorter than those in towns with low mortality (mean difference 1.2 cm; 95% confidence interval 0.3 to 2.1 cm; P = 0.02) and had a higher ponderal index (0.34 kg/m3; 0.16 to 0.52 kg/m3; P = 0.006). Mean systolic pressure was higher in high mortality towns, particularly after adjustment for height (2.0 mm Hg; 0.8 to 3.2 mm Hg; P = 0.009). Mean waist:hip ratio, total cholesterol concentration, and 30 minute post-load glucose measurements were similar in high and low mortality towns. The differences in height and blood pressure between high and low mortality towns were unaffected by standardisation for birth weight. Conclusions: The differences in height, ponderal index, and blood pressure between towns with high and low cardiovascular mortality, if persistent, may have important future public health implications. Their independence of birth weight suggests that the childhood environment rather than the intrauterine environment is involved in their development. <h3>Key messages</h3> Development of cardiovascular risk factors in British children living in areas with widely different adult cardiovascular mortality has been little stud- ied Children in areas of high mortality are on average shorter and have higher ponderal indices and higher blood pressures (particularly when height differences are taken into account) than those in areas of low mortality Total cholesterol concentration, waist:hip ratio, and post-load glucose/glucose tolerance are very similar in high and low mortality areas The differences in height, ponderal index, and blood pressure are independent of birth weight, suggesting that childhood rather than intrauterine factors may be important in their development
1088. Stem Cell Gene Therapy with No Pre-Conditioning for the ADA-Deficiency Patients Leads to Generalized Detoxification and Delayed, but Steady Hematological Reconstitution
Authors: Makoto Otsu, Satoru Nakajima, Miyuki Kida, Yoshihiro Maeyama, Nariaki Toita, Norikazu Hatano, Nobuaki Kawamura, Ryouji Kobayashi, Osamu Tatsuzawa, Masafumi Onodera, Fabio Candotti, Pawan Bali, Michael S. Hershfield, Yukio Sakiyama, Tadashi Ariga
Journal: Molecular Therapy (2006)

In the previous meeting, we reported the initial follow-up of the two patients with adenosine deaminase (ADA)-deficiency whom we had treated in a clinical trial of retroviral-mediated stem cell gene therapy (SCGT). Our protocol is unique in that patients do not receive any kinds of marrow-preparative conditioning prior to infusion of gene-corrected autologous bone marrow (BM) cells. Since the successful cases of ADA gene therapy reported from Italy used low-dose busulfan to enhance the engraftment of gene-transduced BM cells, it is intriguing to see how the lack of conditioning affects the hematological and immunological reconstitution in our patients. Two patients (pt 1, a 4 year-old girl; pt 2, a 13 year-old boy) were given i.v. BM CD34+ cells transduced with the retroviral vector GCsapM-ADA following the cessation of ADA-enzyme (PEG- ADA) replacement. The first evidence of clinical benefits emerged in a form of systemic detoxification as we previously reported. Steady decrease of toxic metabolites, once accumulated shortly after PEG-ADA discontinuation, is still ongoing at present, 2 years after SCGT. Slow, but gradual increase of lymphocyte counts has followed as the second, reaching the recent values that rather surpass the pre- GT levels. T cells have been the most abundant population among the emerging lymphocytes in both patients, exhibiting relatively rapid development. Most striking is the appearance of peripheral B cells in pt 1 after long latency; B cells had never appeared during the first year, but then emerged and has shown a steady increase thereafter. NK cells showed similar reconstitution kinetics, with the evidence of 100% positive for the presence of ADA-transgene. Consistent with these observations, the proviral copy numbers in peripheral blood lymphocytes (PBL) of pt 1 have now reached 0.7 copies/cell and the latest value of ADA enzyme activity in PBL was shown to be near normal. Although pt 2 has shown much slower kinetics of lymphocyte development, he maintains healthy status with the recent evidence of improvement in T cell function. No serious adverse events, including clonal expansion of certain cell types, have been observed. Although some prophylactic measures are still necessary, both patients have been completely off PEG-ADA for longer than 2 years and now are ready for their new lives; pt 1 entering an elementary school and pt 2 proceeding to a high school. These results suggest that SCGT for ADA-deficiency without pre-conditioning can lead to meaningful hematological reconstitution and be a safe and effective treatment option for the patient who needs SCGT, especially when the conditioning may not be tolerated.
Food policies for healthy populations and healthy economies
Authors: C. Hawkes
Journal: BMJ (2012)

We calculated new birthweight and head circumference centiles for boys and girls between 24 and 42 weeks9 gestation from 20,713 singleton live births at our hospital between 1978 and 1984. Among the 803 babies born at or before 34 weeks9 gestation, 28% were delivered electively for fetal problems; they were considerably lighter than babies born after spontaneous preterm labour. In contrast, they showed only a small deficit in head circumference, possibly due to a brain sparing effect in growth retarded infants. Electively delivered preterm infants cause a bias in birthweight and head circumference centiles and we recommend that these babies should be excluded when these centiles are calculated.
Abstract 4555: Design and discovery of novel small molecule redox modulators as therapies for pancreatic cancer.
Authors: Divya Pathania, Mario Sechi, Michele Palomba, Vanna Sanna, Francesco Berrettini, Angela Sias, Laleh Taheri, Nouri Neamati
Journal: Cancer Research (2013)

Abstract Pancreatic cancer is a complex disease. Late stage detection, poor prognosis, and resistance to available chemotherapeutics highlight the need to discover new and potent anticancer agents for its effective treatment. Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most forms of cancer including pancreatic cancer. Cancer cells are more prone to reactive oxygen species (ROS)-mediated cell death due to their inherent elevated basal oxidative stress as compared to normal cells. Increased basal ROS levels could represent the Achilles’ heel of cancer cells. Even though cancer cells have adapted to survive in an oxidative stress environment, exogenous oxidative insults can overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death We have identified a novel class of compounds that act as redox modulators and specifically induce cell death in cancer cells. Compound 3a was identified through a medium throughput screen of ∼1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics using XF 24 extracellular flux analyzer (Seahorse Bioscience, Billerica, MA). Further structural optimizations led to the discovery of a more potent analog, 3b that displayed anti-proliferative activities at low micromolar levels in both drug-sensitive and drug-resistant cancer cell lines. Treatment with compound 3b causes Akt activation resulting in increased cellular oxygen consumption, oxidative stress and depletion of cellular antioxidant pool in pancreatic cancer cells. Akt is a pro-survival kinase that is upregulated in several forms of human cancers. Hyperactive Akt inhibits apoptosis induced by numerous stimuli. However, Akt is unable to inhibit ROS-mediated cell death, and in fact, Akt aids in ROS-directed cell death by inducing cellular oxygen consumption, promoting ROS generation, and impairing ROS degeneration. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) and resulted in cancer cell apoptosis. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity. In conclusion, our novel class of compounds are promising leads that by exacerbating oxygen consumption, ROS production, and reducing the antioxidant capacity of cancer cells tip the balance towards activation of stress kinases that ultimately leads to cell death. Citation Format: Divya Pathania, Mario Sechi, Michele Palomba, Vanna Sanna, Francesco Berrettini, Angela Sias, Laleh Taheri, Nouri Neamati. Design and discovery of novel small molecule redox modulators as therapies for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4555. doi:10.1158/1538-7445.AM2013-4555
Increased Incidence of Carpal Tunnel Syndrome up to 10 Years Before Diagnosis of Diabetes
Authors: Martin C. Gulliford, Radoslav Latinovic, Judith Charlton, Richard A.C. Hughes
Journal: Diabetes Care (2006)

The frequency of carpal tunnel syndrome (CTS) is increased in patients with peripheral neuropathy from a variety of causes (1). Abnormal glucose metabolism may be implicated in the etiology of “idiopathic” polyneuropathy in subjects who do not have diabetes (2). We investigated whether the incidence of CTS, Bell’s palsy, and other peripheral nerve disorders is increased before the diagnosis of diabetes.

A cohort study was implemented (3) using THIN, a database containing medical records from family practices in England and Wales (4). The study was approved by the South East Research Ethics Committee. Data were analyzed for 114 family practices with 644,495 registered patients aged ≤100 years. Diabetes cases were selected if their diagnosis date was between 1 November 2003 and 31 October 2004 and if they were aged between 30 and 89 years at diagnosis and had never been prescribed insulin or diagnosed with type 1 diabetes. These criteria produced 2,655 cases. Two control groups were randomly selected, matching for age, sex, and practice, from subjects who were never diagnosed with diabetes or prescribed oral hypoglycemic drugs or insulin. Eight cases, for whom two respective control subjects could not be identified, were omitted.

Each patient’s medical record was searched for first occurrences of CTS, including carpal tunnel release and carpal tunnel injection (5). We also identified new occurrences of Bell’s facial palsy. …
Phase III Randomized Trial of Conventional-Dose Chemotherapy With or Without High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Rescue As First-Line Treatment for Patients With Poor-Prognosis Metastatic Germ Cell Tumors
Authors: Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl
Journal: Journal of Clinical Oncology (2007)

Purpose To investigate the role of high-dose chemotherapy (HDCT) as first-line treatment in patients with metastatic germ cell tumor (GCT) and poor-prognostic clinical features. Serum tumor marker decline during chemotherapy was assessed prospectively as a predictor of treatment outcome. Patients and Methods In this randomized phase III trial, previously untreated patients with intermediate- or poor-risk GCT received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP alone), or two cycles of BEP followed by two cycles of HDCT containing carboplatin and then by hematopoietic stem-cell rescue (BEP + HDCT). Serum tumor markers alpha-fetoprotein and human chorionic gonadotrophin were correlated with treatment outcome as a secondary end point. Results Two hundred nineteen patients were randomly assigned: 108 to BEP + HDCT and 111 to BEP alone. The 1-year durable complete response rate was 52% after BEP + HDCT and 48% after BEP alone (P = .53). Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P = .02 and P = .03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P = .03). Conclusion The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of outcome.
A CASE OF DIPHTHEEIA AT SEVENTY-SIX YEAES OF AGE.
Authors: A. BELCHAM KEYES
Journal: JAMA (1904)

<h3>History.</h3> —Some time ago I was called to see P. D., aged 76, who complained of a slight indisposition and of having had on the previous day a slight stiffness of the neck, from which he had recovered before my visit. <h3>Examination.</h3> —The pulse was 82 and temperature 99 F., condition of vascular system somewhat arteriosclerotic, heart, lungs and urine negative. On the right leg was a varicose ulcer about the size of a silver dollar. I examined the throat in a routine way, and found on the left anterior pillar a small, oval-shaped, whitish-gray patch about half the diameter of a dime, and laughingly remarked that the patient was getting the children's diseases over again, and promised to return later and make a culture before prescribing any antiseptic gargle or spray so as not to interfere with the growth on the culture media.
Evaluation and Management of Menstrual Dysfunction in Athletes
Authors: Mona Shangold
Journal: JAMA (1990)

The prevalence of menstrual dysfunction is greater among athletes than in the general population. Many factors undergo change during the course of an athletic training program and any or all of these may contribute to disturbances in menstrual cyclicity. All athletes with oligomenorrhea, amenorrhea, or menarcheal delay require thorough evaluation to rule out serious pathological conditions, since the diagnosis of exercise-associated menstrual dysfunction can be made only by excluding other etiologic factors. Most athletes who have these problems should be treated to prevent undesirable sequelae.
P159 HOT HMV UK: sleep disruption following initiation of domiciliary NIV in hypercapnic COPD
Authors: P. Murphy, M. I. Polkey, N. Hart
Journal: Thorax (2010)

<h3>Introduction</h3> The use of domiciliary NIV for the treatment of chronic hypercapnic respiratory failure (CHRF) in COPD remains controversial. Previous data from randomised controlled trials do not show a sustained clinical benefit, but to date there has been no RCT that has titrated NIV to nocturnal oximetry and capnometry. Although one randomised cross-over trial has shown that high intensity NIV produced greater improvements in health-related quality of life (HRQL) compared to low intensity set up (Dreher et al <i>Thorax</i> 2010) concern remains that this strategy may cause significant sleep disruption that would be expected to adversely effect the clinical benefits. <h3>Method</h3> Patient who remained persistently hypercapnic (PaCO<sub>2</sub> &gt;7 kPa) following acute exacerbations of COPD requiring NIV were offered participation in the home oxygen therapy versus home mechanical ventilation in COPD trial (HOT-HMV Trial). Baseline arterial blood gas analysis, HRQL and lung function parameters were performed prior to randomisation. Patients had nasal oxygen therapy or NIV established over a 3 day in-patient hospital stay. Sleep disruption and daytime activity was monitored for 7 days following HMV or HOT set up using a sleep diary and actigraphy (Actiwatch spectrum, Phillips-Respironics, Murrysville, PA, USA). <h3>Results</h3> 7 patients were enrolled (4 HMV, 3 HOT). Mean ± SD age of 65 ± 11 years, BMI 25.5 ± 6.4 kg/m<sup>2</sup>, FEV<sub>1</sub> 30 ± 12%, FVC 58 ± 14%, FEV<sub>1</sub>/FVC 39 ± 12%, PaCO<sub>2</sub> 8.22 ± 0.72 kPa, PaO<sub>2</sub> 6.65 ± 0.58 kPa and MRC dyspnoea score of 4 ± 1. Actigraphy analysis showed HMV patients total sleep time (TST) was 241 ± 29 min with wake after sleep onset (WASO) time of 111 ± 41 min and a mobile time of 709 ± 119 min. Patients in the HOT arm had a TST of 373 ± 143 min with a WASO 116 ± 87 min and a mobile time 674 ± 132 min. No significant between group differences could be demonstrated in the sleep or activity variables. HMV settings Ipap 26 ± 3 cm H<sub>2</sub>O, Epap 5 ± 1 cm H<sub>2</sub>O, back up rate 15 ± 1 bpm. <h3>Conclusion</h3> Although these data must be interpreted with caution, as the number of patients currently enrolled in this trial is small, there was no difference between the HOT and HMV groups. These data support the view that high pressure HMV does not cause significant sleep disruption when compared with HOT.
The protein tyrosine kinase p56lck regulates cell adhesion mediated by CD4 and major histocompatibility complex class II proteins.
Authors: M S Kinch, A Sanfridson, C Doyle
Journal: The Journal of Experimental Medicine (1994)

The CD4 protein is expressed on a subset of human T lymphocytes that recognize antigen in the context of major histocompatibility complex (MHC) class II molecules. Using Chinese hamster ovary (CHO) cells expressing human CD4, we have previously demonstrated that the CD4 protein can mediate cell adhesion by direct interaction with MHC class II molecules. In T lymphocytes, CD4 can also function as a signaling molecule, presumably through its intracellular association with p56lck, a member of the src family of protein tyrosine kinases. In the present report, we show that p56lck can affect cell adhesion mediated by CD4 and MHC class II molecules. The expression of wild-type p56lck in CHO-CD4 cells augments the binding of MHC class II+ B cells, whereas the expression of a mutant p56lck protein with elevated tyrosine kinase activity results in decreased binding of MHC class II+ B cells. Using site-specific mutants of p56lck, we demonstrate that the both the enzymatic activity of p56lck and its association with CD4 are required for this effect on CD4/MHC class II adhesion. Further, the binding of MHC class II+ B cells induces CD4 at the cell surface to become organized into structures resembling adhesions-type junctions. Both wild-type and mutant forms of p56lck influence CD4-mediated adhesion by regulating the formation of these structures. The wild-type lck protein enhances CD4/MHC class II adhesion by augmenting the formation of CD4-associated adherens junctions whereas the elevated tyrosine kinase activity of the mutant p56lck decreases CD4-mediated cell adhesion by preventing the formation of these structures.