tbuckley/cabot-search huggingface dataset:
Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study
Authors: Gretchen L Birbeck, Malcolm E Molyneux, Peter W Kaplan, Karl B Seydel, Yamikani F Chimalizeni, Kondwani Kawaza, Terrie E Taylor
Journal: The Lancet Neurology (2010)

BackgroundCerebral malaria, a disorder characterised by coma, parasitaemia, and no other evident cause of coma, is challenging to diagnose definitively in endemic regions that have high rates of asymptomatic parasitaemia and limited neurodiagnostic facilities. A recently described malaria retinopathy improves diagnostic specificity. We aimed to establish whether retinopathy-positive cerebral malaria is a risk factor for epilepsy or other neurodisabilities.MethodsBetween 2005 and 2007, we did a prospective cohort study of survivors of cerebral malaria with malaria retinopathy in Blantyre, Malawi. Children with cerebral malaria were identified at the time of their index admission and age-matched to concurrently admitted children without coma or nervous system infection. Initially matching of cases to controls was 1:1 but, in 2006, enrolment criteria for cerebral malaria survivors were revised to limit inclusion to children with cerebral malaria and retinopathy on the basis of indirect ophthalmoscopic examination; matching was then changed to 1:2 and the revised inclusion criteria were applied retrospectively for children enrolled previously. Clinical assessments at discharge and standardised nurse-led follow-up every 3 months thereafter were done to identify children with new seizure disorders or other neurodisabilities. A Kaplan-Meier survival analysis was done for incident epilepsy.Findings132 children with retinopathy-positive cerebral malaria and 264 age-matched, non-comatose controls were followed up for a median of 495 days (IQR 195–819). 12 of 132 cerebral malaria survivors developed epilepsy versus none of 264 controls (odds ratio [OR] undefined; p<0·0001). 28 of 121 cerebral malaria survivors developed new neurodisabilities, characterised by gross motor, sensory, or language deficits, compared with two of 253 controls (OR 37·8, 95% CI 8·8–161·8; p<0·0001). The risk factors for epilepsy in children with cerebral malaria were a higher maximum temperature (39·4°C [SD 1·2] vs 38·5°C [1·1]; p=0·01) and acute seizures (11/12 vs 76/120; OR 6·37, 95% CI 1·02–141·2), and male sex was a risk factor for new neurodisabilities (20/28 vs 38/93; OR 3·62, 1·44–9·06).InterpretationAlmost a third of retinopathy-positive cerebral malaria survivors developed epilepsy or other neurobehavioural sequelae. Neuroprotective clinical trials aimed at managing hyperpyrexia and optimising seizure control are warranted.FundingUS National Institutes of Health and Wellcome Trust.
Gall stone recurrence and its prevention: the British/Belgian Gall Stone Study Group's post-dissolution trial.
Authors: K A Hood, D Gleeson, D C Ruppin, R H Dowling
Journal: Gut (1993)

The British/Belgian Gall Stone Study Group (BBGSG) post-dissolution trial was a prospective, multicentre, randomised, double blind trial of: (i) low dose ursodeoxycholic acid, (ii) placebo, and (iii) a high fibre, low refined carbohydrate diet in the prevention of gall stone recurrence in patients with complete gall stone dissolution. Further aims included establishing the timing and frequency of recurrence and its association with biliary symptoms, a comparison of the sensitivity of ultrasonography v oral cholecystectography in detecting recurrent stones, and a search for risk factors predicting recurrence. Ninety three patients entered the study, and 82 were followed up for up to five years (mean (SEM) 28 (1.5) months) with six monthly ultrasonography and yearly oral cholecystectography. There were 21 recurrences (26 by oral cholecystectography or ultrasonography, or both), only two of which were symptomatic, which were detected between 12 and 42 months after trial entry. This corresponded to an actuarial recurrence rate of 33.9 (7.0%) by lifetable analysis at 42 months and subsequently. There were four recurrences in the ursodeoxycholic acid, six in the placebo, and 11 in the diet groups, corresponding to 21.9 (9.9)%, 27.4 (10.1)%, and 45.8 (12.4)% respectively at 42 months by lifetable analysis (NS). Variables including age, obesity, menopausal state, pregnancy, and oestrogen containing drugs were not shown to affect recurrence rate. Men had more frequent recurrence than women (NS). Patients who had had multiple stones experienced more recurrences than did those with single stones (NS). Recurrence did not occur in patients who took non-steroidal anti-inflammatory drugs (NSAIDs) (p &lt; 0.02). The stone free interval between stone dissolution and trial entry proved to be important--those stone free &gt; nine months had a recurrence rate of only 12.7 (6.0)% at 42 months compared with 55.4 (12.5)% in those stone free &lt; nine months (p &lt; 0.01). There was imbalance between the ursodeoxycholic acid and placebo groups for this factor, and after applying a statistical correction, the adjusted recurrence rate in the ursodeoxycholic acid group was 15% compared with 30% in both placebo and diet groups (NS). These data suggest that after medical dissolution, the risk of gall stone recurrence is not reduced by a high fibre, low refined carbohydrate diet: it may be lowered, but not abolished, by low dose ursodeoxycholic acid.
Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma
Authors: Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Masakiyo Sakaguchi, Takuya Fukazawa, Junichi Soh, Hiroaki Asano, Tsuyoshi Ueno, Takayuki Muraoka, Hiromasa Yamamoto, Yasutomo Nasu, Takumi Kishimoto, Harvey I. Pass, Hideki Matsui, Nam-ho Huh, Shinichiro Miyoshi
Journal: Clinical Cancer Research (2011)

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM.
Patient-centred asthma education in the emergency department: the case against
Authors: L. Halimi, P. Chanez
Journal: European Respiratory Journal (2008)

atient education is based on a delicate balance between a suffering individual and a clinician.This professional is supposed to assume a public service duty falling between institutional requirements and the choices of patients.This task is complicated by one indisputable fact: it is impossible to make people do what one wants them to do.In this situation, the ethic considerations may counterbalance the social values.These principles often try to help people against their own will to make them comply better with the established social order.
Improved Outcome in Pediatric Relapsed Acute Myeloid Leukemia: Results of a Randomized Trial on Liposomal Daunorubicin by the International BFM Study Group
Authors: Gertjan J.L. Kaspers, Martin Zimmermann, Dirk Reinhardt, Brenda E.S. Gibson, Rienk Y.J. Tamminga, Olga Aleinikova, Hortensia Armendariz, Michael Dworzak, Shau-Yin Ha, Henrik Hasle, Liisa Hovi, Alexei Maschan, Yves Bertrand, Guy G. Leverger, Bassem I. Razzouk, Carmelo Rizzari, Petr Smisek, Owen Smith, Batia Stark, Ursula Creutzig
Journal: Journal of Clinical Oncology (2013)

In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group.Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years).The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups.DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.
Biochemical changes as a result of prolonged strenuous exercise
Authors: D E R Warburton, R C Welsh, M J Haykowsky, D A Taylor, D P Humen
Journal: British Journal of Sports Medicine (2002)

Objective: To briefly review biochemical changes that may result from prolonged strenuous exercise and to relate these changes to health risk. Methods: Medline and Sports Discus databases were searched for relevant articles. Additional articles were found using cross referencing and the authors' knowledge of the subject area. Results: Prolonged strenuous exercise may result in a series of biochemical changes that are of concern from a health point of view. Generally, these changes are benign, but some, especially hyponatraemia, are potentially life threatening occurrences. Conclusion: Doctors and athletes should be aware of the potentially adverse biochemical changes, especially hyponatraemia, that may result from prolonged strenuous exercise.
Chronicle: a Phase III Trial in Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiation Randomising Postoperative Adjuvant Capecitabine/Oxaliplatin Versus Control
Authors: Rob Glynne-Jones, Nicholas Counsell, Helen Meadows, Jonathan Ledermann, David Sebag-Montefiore
Journal: Annals of Oncology (2013)
Involuntary Treatment of Eating Disorders
Authors: Tureka L. Watson, Wayne A. Bowers, Arnold E. Andersen
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Involuntary treatment of any psychiatric disorder has always been controversial, especially for eating disorders. Patients with an eating disorder of life-threatening severity frequently refuse hospitalization. In this study, the authors compared individual characteristics and treatment outcomes of patients admitted to an inpatient program for voluntary or involuntary treatment of their eating disorder. METHOD: This study examined 397 patients admitted to an inpatient treatment program over 7 years. Demographic measures, length of illness, weight history, and treatment response of patients admitted for voluntary treatment and those legally committed for involuntary treatment were compared. RESULTS: The two groups were similar in age, gender ratio, and marital status, but those legally committed for involuntary treatment had a longer illness duration and significantly more previous hospitalizations. At admission, the patients legally committed for involuntary treatment were lower in weight and required a significantly longer hospitalization to attain a healthy discharge weight. However, there was no statistically significant difference between involuntary and voluntary patients in rate of weight restoration (2.6 versus 2.2 lb/week, respectively). The groups did not differ in history of comorbid substance abuse or clinical depression but did differ significantly on all admission IQ measures. Eating disorder severity, as assessed by the Eating Attitudes Test-26, Eating Disorder Inventory, and MMPI-II, was similar for both patient groups. CONCLUSIONS: This study suggests that a substantial minority of patients with severe eating disorders will not seek treatment unless legally committed to an inpatient program. Despite the involuntary initiation of treatment, the short-term response of the legally committed patients was just as good as the response of the patients admitted for voluntary treatment. Further, the majority of those involuntarily treated later affirmed the necessity of their treatment and showed goodwill toward the treatment process. Only a long-term follow-up study will indicate whether these two populations differ in the enduring nature of their treatment response.
Inhibition of Notch signalling ameliorates experimental inflammatory arthritis
Authors: Jong-Sung Park, Seol-Hee Kim, Kwangmeyung Kim, Cheng-Hao Jin, Ki Young Choi, Jiyeon Jang, Yuri Choi, A-Ryeong Gwon, Sang-Ha Baik, Ui Jeong Yun, Su Young Chae, Seulki Lee, Young Mo Kang, Kang Choon Lee, Thiruma V Arumugam, Mark P Mattson, Jae Hyung Park, Dong-Gyu Jo
Journal: Annals of the Rheumatic Diseases (2013)

To test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.Collagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.The data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.These results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.
Phylogeny of all major groups of cetaceans based on DNA sequences from three mitochondrial genes.
Authors: M C Milinkovitch, A Meyer, J R Powell
Journal: Molecular Biology and Evolution (1994)

Traditionally, living cetaceans (order Cetacea) are classified into two highly distinct suborders: the echolocating toothed whales, Odontoceti, and the filter-feeding baleen whales, Mysticeti. A molecular phylogeny based on 1,352 base pairs of two mitochondrial ribosomal gene segments and the mitochondrial cytochrome b gene for all major groups of cetaceans contradicts this long-accepted taxonomic subdivision. One group of toothed whales, the sperm whales, is more closely related to the morphologically highly divergent baleen whales than to other odontocetes. This finding suggests that the suborder Odontoceti constitutes an unnatural grouping and challenges the conventional scenario of a long, independent evolutionary history of odontocetes and mysticetes. The superfamily Delphinoidea (dolphins, porpoises, and white whales) appears to be monophyletic; the Amazon River dolphin, Inia geoffrensis, is its sister species. This river dolphin is genetically more divergent from the morphologically similar marine dolphins than the sperm whales are from the morphologically dissimilar baleen whales. The phylogenetic relationships among the three families of Delphinoidea remain uncertain, and we suggest that the two cladogenetic events that generated these three clades occurred within a very short period of time. Among the baleen whales, the bowhead is basal, and the gray whale is the sister species to the rorquals (family Balaenopteridae). The phylogenetic position of beaked whales (Ziphioidea) remains weakly supported by molecular data. Based on molecular clock assumptions, the mitochondrial-DNA data suggest a more recent origin of baleen whales (approximately 25 mya) than has been previously assumed (> 40 mya). This revised phylogeny has important implications for the rate and mode of evolution of morphological and physiological innovations in cetaceans.
Conserved Proteins Are Fragile
Authors: Raquel Assis, Alexey S. Kondrashov
Journal: Molecular Biology and Evolution (2013)

Levels of selective constraint vary among proteins. Although strong constraint on a protein is often attributed to its functional importance, evolutionary rate may also be limited if a protein is fragile, such that a large proportion of amino acid replacements reduce its fitness. To determine the relative contributions of essentiality and fragility to selective constraint, we compared relationships of selection against nonsense mutations (snon) and selection against missense mutations (smis) to protein sequence conservation (Ka). As expected, snon is greater than smis; however, the correlation between smis and Ka is nearly three times stronger than the correlation between snon and Ka. Moreover, examination of relationships to gene expression level, tissue specificity, and number of protein-protein interactions shows that smis is more strongly correlated than snon to all three measures of biological function. Thus, our analysis reveals that slowly evolving proteins are under strong selective constraint primarily because they are fragile, and that this association likely exists because allowing a protein to function improperly, rather than removing it from a biological network, can negatively affect the functions of other molecules it interacts with and their downstream products.
Small In-Frame Deletion in the Epidermal Growth Factor Receptor as a Target for ZD6474
Authors: Tokuzo Arao, Hisao Fukumoto, Masayuki Takeda, Tomohide Tamura, Nagahiro Saijo, Kazuto Nishio
Journal: Cancer Research (2004)

Abstract ZD6474 is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 inhibits angiogenesis and growth of a wide range of tumor models in vivo. Gefitinib (“Iressa”) is a selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation. Here, the ability of gefitinib and ZD6474 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro, and a strong correlation was noted between the IC50 values of gefitinib and ZD6474 (r = 0.79). No correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression. The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of an ATP-binding site (exon 19) in the EGFR was detected (delE746-A750–type deletion). To clarify the involvement of the deletional mutation of EGFR in the cellular sensitivity to ZD6474, we examined the effect of this agent on HEK293 stable transfectants expressing deletional EGFR that designed as the same deletion site observed in PC-9 cells (293-pΔ15). These cells exhibited a 60-fold higher sensitivity to ZD6474 compared with transfectants expressing wild-type EGFR. ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold compared with cells with wild-type EGFR. In conclusion, the findings suggested that a small in-frame deletion in the EGFR increased the cellular sensitivity to ZD6474.
THOUGHTS ON THE DIABETIC STATE.*
Authors: ELLEN L. RHODES
Journal: British Journal of Dermatology (1966)

Journal Article THOUGHTS ON THE DIABETIC STATE. Get access ELLEN L. RHODES, M.R.C.P., D.C.H. ELLEN L. RHODES, M.R.C.P., D.C.H. Senior Registrar, Department of Dermatology, King's College Hospital, Denmark Hill, London, S.E. 5 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 78, Issue 11, 1 November 1966, Pages 577–580, https://doi.org/10.1111/j.1365-2133.1966.tb12150.x Published: 01 November 1966
Transcriptional Regulation of the Interleukin-6 Gene in Mesangial Cells
Authors: CHRISTIAN GRASSL, BRUNO LUCKOW, DETLEF SCHLÖNDORFF, ULRICH DENDORFER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Cytokine secretion by mesangial cells (MC) plays a major role in the pathogenesis of glomerulonephritis. To define signaling events that occur during the activation of MC, the cell-specific transcriptional regulation of the interleukin-6 (IL-6) gene was studied. Stimulation with lipopolysaccharide and IL-1β resulted in the full induction of IL-6 expression only if the cells were coincubated with cAMP agonists; this effect was attenuated by protein kinase A inhibitors. In reporter gene experiments, the IL-6 promoter showed a stimulation pattern comparable to that of the endogenous gene. Elimination of individual transcription factor binding sites provided evidence for functional roles for four cis -acting elements, i.e. , activator protein-1, cAMP response element-binding protein (CREB), nuclear factor for IL-6 expression (NF-IL6), and nuclear factor-κB (NF-κB). Electrophoretic mobility shift assays using nuclear extracts from MC revealed that the DNA-binding activities of activator protein-1 and NF-κB were inducible, whereas no change could be observed for CREB and NF-IL6. The presence of several transcription factor proteins, including JunB, JunD, c-Fos, Fra-1, CREB-1, activating transcription factor-2, NF-κB p50, p52, and p65, and CAAT/enhancer-binding protein-δ, was demonstrated by supershift analysis. Of particular interest was the novel finding of the participation of NF-κB p65 in the NF-IL6 complex. In summary, a signal transduction pathway in MC that requires protein kinase A activation in addition to a second signal provided by lipopolysaccharide or IL-1β was identified.