tbuckley/cabot-search huggingface dataset:
The clinic embraces all aspects of SEM from 'exercise on prescription' and 'functional rehabilitation programmes' to specialist image guided spinal injections
Authors: Simon Petrides
Journal: British Journal of Sports Medicine (2011)

Simon is a Musculoskeletal and Sports physician and Director of the Blackberry Clinic in Milton Keynes. Simon has a special interest in prolotherapy injections as an adjunct to intense rehabilitation programmes for unremitting low back pain (LBP). This has culminated in successful treatment of many elite athletes and footballers. Most clinical trials on the treatment have shown significant benefits but no prominent trials have used patients with specific back pain diagnoses using selective block injections to determine which patients are most likely to benefit. Rowing has a LBP incidence of 100% and over 20 GB rowers have been successfully treated using this technique. The lecture will summarise his experience in the use of prolotherapy in these athlete.
Parathyroidectomy in Patients on Renal Replacement Therapy
Authors: FABIO MALBERTI, DANIELE MARCELLI, FERRUCCIO CONTE, AURELIO LIMIDO, DONATELLA SPOTTI, FRANCESCO LOCATELLI
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Secondary hyperparathyroidism is a frequent complication of long-term dialysis treatment, and despite recent advances in medical therapy, surgical parathyroidectomy (PTx) is necessary in a considerable number of uremic patients. A prevalence of PTx of 22% was reported in Europe in 1988 in patients on dialysis from 10 to 15 yr, but no large-scale epidemiologic study has been published since then. The aim of the study was to evaluate the prevalence, incidence, and risk factors for PTx in patients on renal replacement therapy (RRT) in Lombardy and to determine whether the incidence has changed over time. The study involved 14,180 patients included in the Lombardy Registry of Dialysis and Transplantation who received RRT for end-stage renal disease (ESRD) between 1983 and 1996. Cox-proportional hazards regression models were used to evaluate the risk factors of PTx, the explanatory covariates being age on admission to RRT, gender, underlying renal disease (nondiabetic or diabetic nephropathy), and dialysis modality (peritoneal dialysis or hemodialysis). The prevalence of PTx in the 7371 ERSD patients who were alive on December 31, 1996, was 5.5% and increased with the duration of RRT (9.2% after 10 to 15 yr, 20.8% after 16 to 20 yr). Similarly, the incidence of PTx increased from 3.3 per 1000 patient-years in patients who had been on RRT for <5 yr to 30 per 1000 patient-years in those receiving RRT for >10 yr. The Cox regression models showed that the relative risk for PTx was significantly higher in women and lower in elderly and diabetic patients. The relative risk for PTx (adjusted for gender, age, and nephropathy) was higher in the patients on peritoneal dialysis than in those on hemodialysis and decreased after transplantation. During the course of a follow-up of 7 yr, the incidence of PTx in patients who started RRT between 1990 and 1992 was no different from that observed in patients who started RRT between 1983 and 1985. In conclusion, the prevalence and incidence of PTx in patients receiving RRT in Lombardy is lower than that in Europe and Italy as a whole, as reported by the 1988 European Dialysis and Transplantation Association Registry; its frequency has not changed significantly during the past few years. The need for PTx decreases markedly after successful transplantation. The epidemiologic finding that the rate of PTx is greater in women, young patients, and individuals who do not have diabetes suggests the need for a more aggressive medical treatment of secondary hyperparathyroidism particularly in such patients.
Hepatocellular adenoma as a risk factor for hepatocellular carcinoma in a non-cirrhotic liver: a plea against
Authors: Caroline D M Witjes, Fiebo J W ten Kate, Susanna M van Aalten, Roy S Dwarkasing, François E J A Willemssen, Cornelis Verhoef, Robert A de Man, Jan N M IJzermans
Journal: Gut (2012)

In their paper published in Gut , Farges et al report that in 23 out of 218 patients, areas of hepatocellular carcinoma (HCC) within hepatocellular adenoma (HCA) were observed, and the risk of malignant transformation was 4% in women and 47% in men.1 Hypothesising that HCC may arise from HCA is based on the assumption that at a certain point in time residual HCA or a transition zone with dysplastic changes (as found in colorectal cancers) is present within the malignant liver lesion.2

The postulated theory presented by Farges et al may have great implications for the management of HCA. HCA, a rare benign liver tumour mostly occurring in young women, carries a small risk of malignant transformation …
Laminar Flow Activates Peroxisome Proliferator-Activated Receptor-γ in Vascular Endothelial Cells
Authors: Yi Liu, Yi Zhu, Francois Rannou, Tzong-Shyuan Lee, Kitty Formentin, Lingfang Zeng, Xiaohui Yuan, Nanping Wang, Shu Chien, Barry M. Forman, John Y.-J. Shyy
Journal: Circulation (2004)

Steady laminar flow is atheroprotective, in part because of its antiinflammatory effects on vascular endothelial cells (ECs). We studied the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in ECs in response to laminar flow and the associated antiinflammatory effect.Using flow channel with cultured ECs, we found that laminar flow activated the PPARgamma-mediated PPAR-responsive element (PPRE) activity and increased the mRNA encoding CD36, a PPARgamma-targeted gene. Analysis of the CD36 promoter revealed that PPRE was required for flow activation. Laminar flow induced the GAL-PPARgamma-LBD fusion protein, which suggests that flow activation of PPARgamma was ligand dependent. The pharmaceutical inhibitors of phospholipase A2 (PLA2) and cytochrome P450 epoxygenases (CYP450s) were able to block the laminar flow-activated PPARgamma. We also showed that lipid extracts from flow media contained ligands for the activation of PPARgamma in other cell types. This paracrine activation exerted antiinflammatory effects in ECs and THP-1 cells, including the suppression of cytokine-induced nuclear factor-kappaB activation and expression of intercellular adhesion molecule-1.Laminar flow activates endogenous PPARgamma in ECs, which is ligand dependent. The flow production of PPARgamma ligands is through the PLA2-CYP450 pathway, and the induced PPARgamma ligands exert antiinflammatory effects in several types of cells.
Treatment of SARS with human interferons
Authors: J Cinatl, B Morgenstern, G Bauer, P Chandra, H Rabenau, HW Doerr
Journal: The Lancet (2003)

Effective antiviral agents are needed to treat severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection. We assessed the antiviral potential of recombinant interferons against two clinical isolates of SARS-CoV—FFM-1, from Frankfurt patients, and Hong Kong—replicated in Vero and Caco2 cells. Interferon β was five to ten times more effective in Caco2 cells. Interferon α effectively inhibited SARS-CoV replication, but with a selectivity index 50–90 times lower than that for interferon β. Interferon γ was slightly better than interferon α in Vero cell cultures, but was completely ineffective in Caco2 cell cultures. Interferon β could be useful alone or in combination with other antiviral drugs for the treatment of SARS.
Breast Cancer: Factors Associated With Stage at Diagnosis in Black and White Women
Authors: C. P. Hunter, C. K. Redmond, V. W. Chen, D. F. Austin, R. S. Greenberg, P. Correa, H. B. Muss, M. R. Forman, M. N. Wesley, R. S. Blacklow, R. J. Kurman, J. J. Dignam, B. K. Edwards, S. Shapiro
Journal: JNCI Journal of the National Cancer Institute (1993)

Numerous studies have reported differences in cancer staging at diagnosis and in survival between Black and White patients with breast cancer. Utilizing data obtained from the National Cancer Institute's (NCI's) Black/White Cancer Survival Study for the period 1985-1986, a new study is presented here that systematically examines multiple explanatory factors (e.g., lack of mammograms) associated with these cancer-staging differences.We evaluated within a single study the relationship of selected demographic, lifestyle, antecedent medical experiences, and health care access factors to cancer staging at diagnosis in Black and White breast cancer patients.Data utilized in this population-based cohort study of 1222 eligible women (649 Black and 573 White) newly diagnosed for the period 1985-1986 with histologically confirmed primary breast cancer were obtained from the NCI's Black/White Cancer Survival Study. Sources of data included abstracts of hospital medical records, central review of histology slides by a study consultant pathologist, and patient interviews obtained from three metropolitan areas: Atlanta, New Orleans, and San Francisco-Oakland. Within each area, 70% of all Black incident cases were randomly selected, and a sample of White cases, frequency matched by age groups (20-49 years, 50-64 years, and 65-79 years), was selected for comparison. Stage of breast cancer at diagnosis was classified according to the international tumor-lymph node-metastases (TNM) system. Statistical models utilized in this study included the log-linear and polychotomous logistic regression with multiple predictor variables.Factors associated with cancer staging were differentially expressed in Blacks and Whites. Indicators of access to health care, a lack of mammograms, and an increased body mass index significantly (P < .02) contributed to stage differences in Blacks, whereas income was marginally associated (P = .06) with stage for Whites only. Nuclear grade, having a breast examination by a physician, and a history of patient delay explained approximately 50% of the excess risk for stage III-IV cancer versus stage I-IIN0 cancer among Blacks compared with Whites (odds ratio reduction from 2.19 to 1.68).These findings suggest that no single factor or group of factors can explain more than half of the race-stage differences noted in this study with respect to Black and White breast cancer patients.
Toll-Like Receptor 4 Ligation on Intrinsic Renal Cells Contributes to the Induction of Antibody-Mediated Glomerulonephritis via CXCL1 and CXCL2
Authors: Heather J. Brown, Helen R. Lock, Tim G.A.M. Wolfs, Wim A. Buurman, Steven H. Sacks, Michael G. Robson
Journal: Journal of the American Society of Nephrology (2007)

Autoimmune diseases such as glomerulonephritis are exacerbated by infection. This study examined the effect of the Toll-like receptor 4 (TLR4) ligand lipid A on the development of heterologous nephrotoxic nephritis. Administration of nephrotoxic antibody resulted in significant glomerular neutrophil infiltration and albuminuria only when a TLR4 ligand was administered simultaneously. The contribution of TLR4 on renal cells and circulating leukocytes was assessed. Bone marrow chimeras were constructed with TLR4 only on renal cells or bone marrow-derived cells. The administration of nephrotoxic serum and lipid A caused a neutrophil influx in both chimeric groups greater than in sham chimeras that were totally TLR4 deficient but significantly less than in sham chimeras that were totally TLR4 sufficient. Both chimeric groups had greater albuminuria than totally TLR4-deficient sham chimeras; however, the chimeras with TLR4 only on intrinsic renal cells had significantly less than the sham positive group. In situ hybridization showed expression of TLR4 mRNA in mesangial cells and glomerular epithelial cells. For investigation of the potential mechanism by which renal cells could contribute to disease exacerbation, mesangial cells were cultured and found to express mRNA for TLR4, and stimulation of wild-type and TLR4-deficient mesangial cells with LPS caused production of CXC chemokines by wild-type cells only. Treatment of chimeras with TLR4 present only on intrinsic renal cells with anti-CXCL1 and anti-CXCL2 antibody before disease induction significantly reduced renal neutrophil infiltration. These results show that TLR4 on both circulating leukocytes and intrinsic renal cells contributes to the inflammatory effects of antibody deposition within the glomerulus, which depends at least in part on the production of CXC chemokines by intrinsic renal cells.
Combined <i>In vivo</i> Effect of A12, a Type 1 Insulin-Like Growth Factor Receptor Antibody, and Docetaxel against Prostate Cancer Tumors
Authors: Jennifer D. Wu, Kathy Haugk, Ilsa Coleman, Lillie Woodke, Robert Vessella, Peter Nelson, R. Bruce Montgomery, Dale L. Ludwig, Stephen R. Plymate
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A human type 1 insulin-like growth factor receptor antibody (A12) has been shown to effectively inhibit human xenograft tumor growth, including androgen-dependent and androgen-independent prostate tumors. Docetaxel, either as a single agent or combined with others, has shown a survival benefit in prostate cancer patients. Based on these data, we investigated the combined in vivo effect of A12 and docetaxel on human androgen-independent and osseous prostate tumor growth. Experimental Design: To study human androgen-independent prostate cancer model, LuCaP35V tumors were implanted s.c. into castrated severe combined immunodeficient mice. When tumors reached about 100 mm3, animals were treated with vehicle control docetaxel (10 or 20 mg/kg) and docetaxel in combination with A12 (40 μg/kg) for 4 weeks. To study human osseous prostate cancer model, LuCaP 23.1 tumors were implanted intratibiae. When serum prostate-specific antigen reached 5 to 10 ng/mL, treatments were initiated. Results: A12 markedly augmented the inhibition of docetaxel on tumor growth. When docetaxel is combined with A12, the inhibition of tumor growth continued after treatment cessation, which was associated with continued apoptosis and decreased proliferation of tumor cells. Gene expression profiles indicated that the posttreatment suppression of tumor growth may be due to enhanced negative regulation of cell cycle progression– and/or cell survival–associated genes, some of which have been shown to induce resistance to docetaxel. Conclusions: Our findings suggest that targeting type 1 insulin-like growth factor receptor can enhance the therapeutic effect of docetaxel on advanced prostate cancer. Our findings also suggest a potential mechanism to improve the treatment efficacy of docetaxel in prostate cancer.
Family size, childhood infections and atopic diseases. The Aberdeen WHEASE Group
Authors: C. Bodner, D. Godden, A. Seaton
Journal: Thorax (1998)

This study addresses the causes of the increases in childhood asthma and allergic disease. On the basis of an observed inverse relationship between family size and allergic disease or atopy, it has been proposed that a fall in common childhood infections may have been responsible for the rise in asthma. This study was undertaken to investigate the relationships between family size and reported allergic disease and to test the hypothesis that an inverse relationship between the two is a consequence of childhood infections.Data had been obtained in a 1964 cross sectional survey of a random sample of Aberdeen schoolchildren aged between 10 and 14 in that year. Records of the presence or absence of asthma, eczema, or hay fever at the time of the survey and a history of measles, pertussis, varicella, rubella, and mumps before and after the age of three years were available for 2111 subjects.The risks of hay fever (odds ratio 0.2, 95% CI 0.1 to 0.8) and eczema (OR 0.3, CI 0.1 to 0.7) were inversely related to having had three or more older siblings, whilst the risk of asthma (OR 0.4, CI 0.1 to 0.9) was inversely related to having had three or more younger siblings. Increasing total numbers of siblings showed a significant trend in protection against both eczema and hay fever. A weak protective effect against asthma was found for measles after the age of three (OR 0.5, CI 0.3 to 0.9) and slight increases in the risk of eczema were associated with having had rubella or pertussis and of asthma with having had varicella. The number of infections before the age of three was associated with a significant trend in the odds ratios towards increased risk of asthma (p = 0.025). There were significant trends in the odds ratios towards greater risk of eczema and hay fever with increasing exposure to rubella, mumps, and varicella. These relations between infection and atopic diseases were independent of the potential confounding factors age, sex, father's social class, and total number of siblings.These data add to the accumulating evidence that membership of a large sibship confers some protection against atopic disease. This does not appear to be explained by the common childhood infections which show conflicting relationships with atopic disease, in that measles may have some protective effect against asthma but the more infections a child has had, the more likely he or she is to have atopic disease. The explanation of the sibship effect is likely to lie elsewhere and the fall in common childhood infections is unlikely to explain the rise in atopic disease.
Rapidly Evolving Mitochondrial Genome and Directional Selection in Mitochondrial Genes in the Parasitic Wasp Nasonia (Hymenoptera: Pteromalidae)
Authors: D. C. S. G. Oliveira, R. Raychoudhury, D. V. Lavrov, J. H. Werren
Journal: Molecular Biology and Evolution (2008)

We sequenced the nearly complete mtDNA of 3 species of parasitic wasps, Nasonia vitripennis (2 strains), Nasonia giraulti, and Nasonia longicornis, including all 13 protein-coding genes and the 2 rRNAs, and found unusual patterns of mitochondrial evolution. The Nasonia mtDNA has a unique gene order compared with other insect mtDNAs due to multiple rearrangements. The mtDNAs of these wasps also show nucleotide substitution rates over 30 times faster than nuclear protein-coding genes, indicating among the highest substitution rates found in animal mitochondria (normally <10 times faster). A McDonald and Kreitman test shows that the between-species frequency of fixed replacement sites relative to silent sites is significantly higher compared with within-species polymorphisms in 2 mitochondrial genes of Nasonia, atp6 and atp8, indicating directional selection. Consistent with this interpretation, the Ka/Ks (nonsynonymous/synonymous substitution rates) ratios are higher between species than within species. In contrast, cox1 shows a signature of purifying selection for amino acid sequence conservation, although rates of amino acid substitutions are still higher than for comparable insects. The mitochondrial-encoded polypeptides atp6 and atp8 both occur in F0F1ATP synthase of the electron transport chain. Because malfunction in this fundamental protein severely affects fitness, we suggest that the accelerated accumulation of replacements is due to beneficial mutations necessary to compensate mild-deleterious mutations fixed by random genetic drift or Wolbachia sweeps in the fast evolving mitochondria of Nasonia. We further propose that relatively high rates of amino acid substitution in some mitochondrial genes can be driven by a "Compensation-Draft Feedback"; increased fixation of mildly deleterious mutations results in selection for compensatory mutations, which lead to fixation of additional deleterious mutations in nonrecombining mitochondrial genomes, thus accelerating the process of amino acid substitutions.
Tbx3 Is Required for Outflow Tract Development
Authors: Karim Mesbah, Zachary Harrelson, Magali Théveniau-Ruissy, Virginia E. Papaioannou, Robert G. Kelly
Journal: Circulation Research (2008)

Conotruncal and ventricular septal congenital heart anomalies result from defects in formation and division of the embryonic outflow tract. Cardiac remodeling during outflow tract and ventricular septation converts the tubular embryonic heart into a parallel circulatory system with an independent left ventricular outlet and right ventricular inlet. Tbx3 encodes a T-box-containing transcription factor expressed in the developing conduction system of the heart. Mutations in TBX3 cause ulnar-mammary syndrome. Here we show that mice lacking Tbx3 develop severe outflow tract defects, including connection of both the aorta and pulmonary trunk with the right ventricle, in addition to aortic arch artery anomalies and abnormal communication between the right atrium and left ventricle. Alignment defects are preceded by a delay in caudal displacement of the arterial pole of the heart during aortic arch artery formation. Embryonic anterior-posterior patterning and cardiac chamber development are unaffected in Tbx3 mutant embryos. However, the contribution of second heart field derived progenitor cells to the arterial pole of the heart is impaired. Tbx3 is expressed in pharyngeal epithelia and neural crest cells in the pharyngeal region, suggesting an indirect role in second heart field deployment. Loss of Tbx3 affects multiple signaling pathways regulating second heart field proliferation and outflow tract morphogenesis, including fibroblast growth factor signaling, leading to a failure of normal heart tube extension and consequent atrioventricular and ventriculoarterial alignment defects.
Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer
Authors: M. Crul, G. J. de Klerk, M. Swart, L. J. van’t Veer, D. de Jong, L. Boerrigter, P. A. Palmer, C. J. Bol, H. Tan, G. C. de Gast, J. H. Beijnen, J. H.M. Schellens
Journal: Journal of Clinical Oncology (2002)

To determine the maximum-tolerated dose, toxicities, and pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered continuously via the oral route.Patients with advanced solid malignancies were treated with R115777 using an interpatient dose escalation scheme starting at 50 mg bid. Pharmacokinetics were assessed on days 1, 28, and 56.Twenty-eight patients were entered onto the study and the median duration of treatment was 55 days. The dose-limiting toxicities were myelosuppression and neurotoxicity. At a dose of 400 mg bid, grade 4 leukocytopenia and neutropenia were seen in two of four patients. Neurotoxicity grade 3 developed in one of five patients at 500 mg bid and in one of 13 at 300 mg bid after 8 weeks of treatment. Common nonhematologic toxicities were nausea, vomiting, and fatigue. The recommended dose for phase II/III testing in this scheme is 300 mg bid. The pharmacokinetic studies indicated dose proportionality. Little accumulation occurred and steady-state levels were reached within 2 to 3 days. Analyses of historic tumor material showed that five of 15 of patients had a K-ras mutation in codon 12. Three patients with pancreatic, colon, and cervix carcinomas had stable disease and one patient with a colon carcinoma had a minor response accompanied by a more than 50% decrease in carcinoembryonic antigen tumor marker. A fifth patient, with platinum-refractory non-small-cell lung cancer, showed a partial response that lasted for 5 months.Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.
The Role of Hemochromatosis C282Y and H63D Gene Mutations in Type 2 Diabetes
Authors: Omer T. Njajou, Behrooz Z. Alizadeh, Norbert Vaessen, Jeannete Vergeer, Jeannine Houwing-Duistermaat, Albert Hofman, Huibert A.P. Pols, Cornelia M. van Duijn
Journal: Diabetes Care (2002)

Diabetes is a disease commonly found in patients with hemochromatosis (1). The hemochromatosis C282Y and H63D mutations in the HFE gene are associated with increased iron stores (2), which in turn are associated with glucose intolerance and insulin resistance (3). Whether these HFE mutations play an important role in the pathogenesis of type 2 diabetes is still a matter of controversy.

We have studied the frequencies of the C282Y and H63D mutations in 254 subjects with glucose intolerance, 220 patients with type 2 diabetes, and 595 normoglycemic individuals (control subjects), all derived from a population-based cohort study (Rotterdam Study) …