tbuckley/cabot-search huggingface dataset:
Therapeutic Potential of Angiostatin in Diabetic Nephropathy
Authors: Sarah X. Zhang, Joshua J. Wang, Kangmo Lu, Robert Mott, Richard Longeras, Jian-xing Ma
Journal: Journal of the American Society of Nephrology (2006)

Angiostatin is a proteolytic fragment of plasminogen and a potent angiogenic inhibitor. Previous studies have shown that angiostatin inhibits retinal neovascularization and reduces retinal vascular permeability in diabetic retinopathy. Here, it is reported for the first time that angiostatin is also implicated in diabetic nephropathy (DN). Angiostatin levels are dramatically decreased in the kidney of streptozotocin-induced diabetic rats. Consistently, diabetic kidneys also showed decreased expression and proteolytic activities of matrix metalloproteinase-2, an enzyme that releases angiostatin from plasminogen. Adenovirus-mediated delivery of angiostatin significantly alleviated albuminuria and attenuated the glomerular hypertrophy in diabetic rats. Moreover, angiostatin treatment downregulated the expression of vascular endothelial growth factor and TGF-β1, two major pathogenic factors of DN, in diabetic kidneys. In cultured human mesangial cells, angiostatin blocked the overexpression of vascular endothelial growth factor and TGF-β1 that were induced by high glucose while increasing the levels of pigment epithelium–derived factor, an endogenous inhibitor of DN. Moreover, angiostatin effectively inhibited the high-glucose–and TGF-β1–induced overproduction of proinflammatory factors and extracellular matrix proteins <i>via</i> blockade of the Smad signaling pathway. These findings suggest that the decrease of angiostatin levels in diabetic kidney may contribute to the pathologic changes such as inflammation and fibrosis in DN. Therefore, angiostatin has therapeutic potential in DN as a result of its anti-inflammatory and antifibrosis activities.
Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection
Authors: Robert Tamayev, Nsikan Akpan, Ottavio Arancio, Carol M Troy, Luciano D’Adamio
Journal: Molecular Neurodegeneration (2012)

Abstract Background Mutations in either Aβ Precursor protein ( APP ) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1 / PSEN2 , cause familial dementias. Although dementias due to APP / PSEN1 / PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in APP and PSENs promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis. Results Here, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDD KI , which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDD KI mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits. Conclusion These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias.
Augmentation of Intrapericardial Nitric Oxide Level by a Prolonged-Release Nitric Oxide Donor Reduces Luminal Narrowing After Porcine Coronary Angioplasty
Authors: Sang Hong Baek, Joseph A. Hrabie, Larry K. Keefer, Dongming Hou, Naomi Fineberg, Rodney Rhoades, Keith L. March
Journal: Circulation (2002)

Nitric oxide (NO) is a potent vasodilator and antiplatelet agent that suppresses vascular smooth muscle cell proliferation. Hypothesizing that generating NO in the pericardial space would reduce luminal narrowing after coronary angioplasty without affecting systemic hemodynamics, we have determined the effect of a novel NO donor on vascular healing after balloon overstretch. Diazeniumdiolated bovine serum albumin (D-BSA; molecular weight 74 kDa, half-life for NO release 20 days) was radioiodinated and found by intravital gamma-imaging to have a longer residence time in pig pericardium than a low-molecular-weight (0.5 kDa) analogue (22 versus 4.6 hours, respectively). Intrapericardial injection of D-BSA immediately before 30% overstretch of normal left anterior descending and left circumflex coronary arteries dose dependently reduced the intimal/medial area ratio by up to 50% relative to controls treated with underivatized albumin when measured 2 weeks after intervention. Positive remodeling was also noted, which increased luminal area relative to control. Perivascular exposure of coronary arteries to NO via intrapericardial D-BSA administration reduced flow-restricting lesion development after angioplasty in pigs without causing significant systemic effects. The data suggest that intrapericardial delivery of NO donors for which NO release rates and pericardial residence times are matched and optimized might be a beneficial adjunct to coronary angioplasty.
Baseline staging in cutaneous malignant melanoma
Authors: J. Hafner, M.Hess Schmid, W. Kempf, G. Burg, W. Kunzi, C. Meuli-Simmen, P. Neff, V. Meyer, D. Mihic, E. Garzoli, K-P. Jungius, B. Seifert, R. Dummer, H. Steinert
Journal: British Journal of Dermatology (2004)

Baseline staging in patients with primary cutaneous malignant melanoma (MM) is routine, but the diagnostic accuracy and the impact on clinical outcome are still unclear.To evaluate the sensitivity and specificity of baseline staging in the early detection of regional lymph node metastases or distant metastases in patients with MM.One hundred consecutive patients with MM of Breslow's tumour thickness over 1.0 mm were enrolled. All patients had an extensive baseline staging including physical examination, ultrasound (US) of the abdomen and regional lymph nodes, chest X-ray, whole-body positron emission tomography (PET) and sentinel lymph node biopsy. The sensitivity and specificity of detection of macroscopic or microscopic metastases in the regional lymph nodes or at distant sites were calculated for each method.Sentinel lymph node biopsy was positive in 26 patients. US detected two of 26 histologically tumour-positive sentinel nodes (sensitivity 8%, specificity 88%) and PET two of 26 (sensitivity 8%; specificity 100%). There were three lymph node metastases with a diameter > 4 mm. All of them were found suspect at physical examination. Two of them were detectable with US, two with PET, and all were identified with either US or PET. Nine patients had suspect findings at distant sites, which were all false positive on further investigation (specificity of the combined staging procedures 91%). At 18 (6-37) months' follow-up, five of 26 (19%) patients with a positive sentinel node and four of 74 (5%) of patients with a negative sentinel node had recurrent or progressive disease.The combination of physical examination and lymph node US detects the great majority of patients with macroscopic lymph node metastasis (approximately 3% of patients at baseline). Only 10% of patients who have a histologically tumour-positive sentinel node are macroscopically detectable. Altogether, approximately 25% of patients have a positive sentinel node biopsy, among 90% microscopic. The value of whole body staging at baseline remains limited, since distant metastases can hardly ever be detected. The survival benefit of baseline staging and surveillance in patients with cutaneous MM remains to be established by comparative prospective trials.
Report calls for more community based health care in Scotland
Authors: Bryan Christie
Journal: BMJ (2005)

A radical shift away from hospital based care is proposed in a framework document for the future development of the Scottish health service that acknowledges that the status quo cannot be maintained.

It also proposes that Scotland should embrace “preventive, anticipatory care” by targeting packages of support at the most frail and vulnerable people to prevent future ill health and reduce health inequality.

The report has been produced by an advisory group led by David Kerr, professor of cancer therapeutics and clinical pharmacology at Radcliffe Infirmary, Oxford.

It comes after protests across Scotland at the planned closure of …
Clonal stability of blood cell lineages indicated by X-chromosomal transcriptional polymorphism.
Authors: J T Prchal, J F Prchal, M Belickova, S Chen, Y Guan, G L Gartland, M D Cooper
Journal: The Journal of Experimental Medicine (1996)

The idea that stem cells oscillate between a state of activity and dormancy, thereby giving rise to differentiating progeny either randomly or in orderly clonal succession, has important implications for understanding normal hematopoiesis and blood cell dyscrasias. The degree of clonal stability in individuals also has practical implications for the evaluation of clonal lymphomyeloproliferative diseases. To evaluate the clonality pattern of the different types of blood cells as a function of time we have validated the applicability, sensitivity, and reproducibility of a thermostable ligase reaction to detect transcripts of the G6PD allele on the active X-chromosome in normal heterozygous females. While the ratio of the two X-chromosome-derived allelic transcripts varied widely among hemopoietic tissues in a given individual, this allelic ratio was virtually identical in all types of mature myeloid and lymphoid cells. Longitudinal studies indicated constancy of the G6PD allelic ratio in blood cells over a 912-d period of observation in healthy females. The individual variability observed in this allelic ratio suggests that the progeny of a relatively small number of original embryonic hemopoietic stem cells, approximately eight, contribute to the sustained production of all types of blood cells in healthy individuals.
Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis
Authors: Hüseyin Uysal, Robert Bockermann, Kutty S. Nandakumar, Bettina Sehnert, Estelle Bajtner, Åke Engström, Guy Serre, Harald Burkhardt, Marjolein M.G.M. Thunnissen, Rikard Holmdahl
Journal: The Journal of Experimental Medicine (2009)

Antibodies to citrulline-modified proteins have a high diagnostic value in rheumatoid arthritis (RA). However, their biological role in disease development is still unclear. To obtain insight into this question, a panel of mouse monoclonal antibodies was generated against a major triple helical collagen type II (CII) epitope (position 359–369; ARGLTGRPGDA) with or without arginines modified by citrullination. These antibodies bind cartilage and synovial tissue, and mediate arthritis in mice. Detection of citrullinated CII from RA patients' synovial fluid demonstrates that cartilage-derived CII is indeed citrullinated in vivo. The structure determination of a Fab fragment of one of these antibodies in complex with a citrullinated peptide showed a surprising β-turn conformation of the peptide and provided information on citrulline recognition. Based on these findings, we propose that autoimmunity to CII, leading to the production of antibodies specific for both native and citrullinated CII, is an important pathogenic factor in the development of RA.
Anterior mediastinal mass in a young man.
Authors: J M Travaline, G J Criner, P M Ming, F Kueppers
Journal: Thorax (1994)

The case is presented of a patient in whom the diagnosis of Klinefelter9s syndrome was made only after a mediastinal teratoma was discovered. Chest physicians should be aware of this association since they are often the first to evaluate patients with mediastinal masses.
MORTALITY AMONG PATIENTS WITH INVOLUTION MELANCHOLIA
Authors: Benjamin Malzberg
Journal: American Journal of Psychiatry (1937)

Patients with involution melancholia had an average annual crude death rate of 132.4 per 1000 exposures. This is almost twice the rate for patients with manic-depressive psychoses, and four times the rate for patients with dementia præcox. It is the highest rate of any of the functional group of psychoses. On the basis of standardized death rates, patients with involution melancholia had a death rate in excess of that of the general population in the ratio of 6.2 to 1. Among males and females the corresponding ratios were 6.2 to 1 and 6.8 to 1, respectively. Males have higher death rates than females, though the difference is not significant with respect to the probable error. Diseases of the heart constitute the leading cause of death, being responsible for almost 40 per cent of all the deaths. The death rate from these diseases is almost eight times the corresponding rate in the general population, when both are corrected for age. Pneumonia was responsible for only a third as many deaths as diseases of the heart. Tuberculosis ranked third as a cause of death. It is noteworthy, however, that the death rate from tuberculosis exceeded that of patients with dementia præcox.
Characteristic alterations of cutaneous neurogenic factors in photoaged skin
Authors: M. Toyoda, M. Nakamura, K. Nakada, H. Nakagawa, M. Morohashi
Journal: British Journal of Dermatology (2005)

Although it has been recognized that photoageing and chronological ageing differ in various morphological and biological aspects, the characteristic alterations of cutaneous neurogenic factors in photoaged skin are poorly characterized.To characterize cutaneous neurogenic factors, including innervation, neuropeptides, nerve growth factor and interactions of mast cells, in photoaged skin.Paired biopsy specimens were obtained from sun-exposed volar forearm skin and from sun-protected dorsal upper arm skin of 20 elderly subjects. Various cutaneous neurogenic factors, including innervation, neuropeptides, neurokinin receptor, nerve growth factor, neurogenic inflammation and morphology of mast cells, were compared in sun-exposed vs. sun-protected skin quantitatively and qualitatively.Cutaneous neurogenic factors associated with photoageing were characterized by a significant increase in the densities of dermal and intraepidermal nerve fibres, a correlation between epidermal innervation and the severity of photodamage, increases in the number of neuropeptidergic sensory nerve fibres in the dermis and in tissue levels of sensory neuropeptides, increases in the content of nerve growth factor, reduced expression of neurokinin receptor 1 by epidermal keratinocytes and by vascular endothelial cells and a tachykinin-specific reduction of cutaneous neurogenic inflammation. Mast cells in photodamaged skin showed several characteristic morphological features, including various degrees of activation and an intimate association with fibroblasts, which were distinct from those in sun-protected skin. Furthermore, mast cells in photodamaged skin possessed larger amounts of substance P within their granules than did those in sun-protected skin.These findings document for the first time characteristic alterations of cutaneous neurogenic factors in photodamaged skin and suggest that the cutaneous nervous system may be involved in photoageing processes.
Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors
Authors: Mikhail V. Blagosklonny, Shana Trostel, Ganesh Kayastha, Zoya N. Demidenko, Lyubomir T. Vassilev, Larisa Y. Romanova, Susan Bates, Tito Fojo
Journal: Cancer Research (2005)

Abstract Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with histone deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, histone deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53.
Reliability of the qualitative and semiquantitative nailfold videocapillaroscopy assessment in a systemic sclerosis cohort: a two-centre study
Authors: Vanessa Smith, Carmen Pizzorni, Filip De Keyser, Saskia Decuman, Jens T Van Praet, Ellen Deschepper, Alberto Sulli, Maurizio Cutolo
Journal: Annals of the Rheumatic Diseases (2010)

Objective Investigation of the reliability of the qualitative and semiquantitative scoring of nailfold videocapillaroscopy (NVC) assessment between two raters in a systemic sclerosis (SSc) cohort. Methods Two raters from different centres blindly assessed the NVC images of 71 consecutive patients with SSc qualitatively as belonging to the scleroderma spectrum (SDS) category (‘early’, ‘active’, ‘late’ scleroderma pattern or ‘scleroderma-like’ pattern) or to the ‘normal’ category and semiquantitatively by calculating the mean score for capillary loss, giant capillaries, microhaemorrhages and capillary ramifications. Inter-rater/intrarater agreement was assessed by calculation of the proportion of agreement and by κ coefficients. Rater agreement of mean score values of hallmark parameters was assessed by intraclass correlation coefficients. Results The inter-rater/intrarater proportion of agreement to qualitatively assess an image as belonging to the SDS category or not was 90% and 96%, whereas the agreement to distinguish between only ‘early’, ‘active’ and ‘late’ scleroderma NVC patterns was 62% and 81%. The agreement of the semiquantitative scoring, as assessed by intraclass correlation coefficient, was 0.96 and 0.95 for capillary loss, 0.84 and 0.95 for giant capillaries, 0.90 and 0.95 for microhaemorrhages and 0.64 and 0.95 for capillary ramifications. Conclusions This is the first study to demonstrate reliability of the qualitative and semiquantitative NVC assessment in an SSc cohort between raters at different centres. Reliability of NVC assessment is essential for use of this tool in multicentre SSc trials.
Cisplatin and Etoposide in Childhood Germ Cell Tumor: Brazilian Pediatric Oncology Society Protocol GCT-91
Authors: Luiz Fernando Lopes, Carla Renata Pacheco Macedo, Elitânia Marinho Pontes, Simone dos Santos Aguiar, Maria José Mastellaro, Renato Melaragno, Sonia Maria Rossi Vianna, Paula Azevedo Allemand Lopes, Nubia Mendonça, Maria Teresa de Assis Almeida, Viviane Sonaglio, Karina B. Ribeiro, Victor M. Santana, Dominik T. Schneider, Beatriz de Camargo
Journal: Journal of Clinical Oncology (2009)

In 1988, we formed a consortium of Brazilian institutions to develop uniform standards for the diagnostic assessment and multidisciplinary treatment of children and adolescents with germ cell tumors. We also implemented the first childhood Brazilian germ cell tumor protocol, GCT-91, evaluating two-agent chemotherapy with cisplatin and etoposide (PE). We now report on the clinical characteristics and survival of children and adolescents with germ cell tumors treated on this protocol.From May 1991 to April 2000, 115 patients (106 assessable patients) were enrolled onto the Brazilian protocol with a diagnosis of germ cell tumor.Patients were treated with surgery only (n = 35) and chemotherapy (n = 71). Important prognostic factors included stage (P = .025), surgical procedure at diagnosis according to resectability (P < .032), and abnormal lactate dehydrogenase value at diagnosis (P < .001).The improvement in survival by the introduction of a standard protocol is an important achievement. This is of particular importance for smaller institutions with previous limited experience in the treatment of childhood germ cell tumors. In addition, the results of a two-agent regimen with PE were favorable (5-year overall survival rate is 83.3% for patients in the high-risk group [n = 36] who received PE v 58.8% for patients in the high-risk patients group who received PE plus ifosfamide, vinblastine, and bleomycin [n = 17; P = .017]). Thus for selected patients, complex three-agent regimens may not be necessary to achieve long-term survival, even for some patients with advanced disease.
Gefitinib Reverses Chemotherapy Resistance in Gefitinib-Insensitive Multidrug Resistant Cancer Cells Expressing ATP-Binding Cassette Family Protein
Authors: Chih-Hsin Yang, Ching-Ju Huang, Chao-Shun Yang, Yu-Chuan Chu, Ann-Lii Cheng, Jacqueline Whang-Peng, Pan-Chyr Yang
Journal: Cancer Research (2005)

Abstract Gefitinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. It is conceivable that gefitinib may inhibit functions of ATP-binding cassette (ABC) transporters by binding at their ATP-binding sites. The aim of this study is to systematically explore the combined effect of gefitinib and chemotherapeutic agents in gefitinib-insensitive multidrug resistant (MDR) cells that overexpress ABC transporters. MCF7 breast carcinoma cells and CL1 lung adenocarcinoma cells were both insensitive to gefitinib. MDR cancer cells were developed by stepwise escalating concentrations of each chemotherapeutic agent in culture media. Cells that overexpress P-glycoprotein (MCF7/Adr and CL1/Pac), breast cancer–resistant protein (MCF7/TPT and CL1/Tpt), and MDR-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to gefitinib. Gefitinib (0.3-3 μmol/L) added to culture media had no effect on IC50 values of paclitaxel, topotecan, doxorubicin, or etoposide in wild-type MCF7 or CL1 cells. In contrast, these concentrations of gefitinib caused a dose-dependent reversal of resistance to paclitaxel in CL1/Pac cells, to doxorubicin in MCF7/ADR cells, and to topotecan in CL1/Tpt and MCF7/TPT cells. Gefitinib had no influence on sensitivity to etoposide in MDR-associated protein1 overexpressing MCF7/VP cells. Topotecan efflux was inhibited and accumulation was partially restored in CL1/Tpt and MCF7/TPT cells when cells were incubated simultaneously with gefitinib. Our results suggest that the interaction of gefitinib and chemotherapeutic agents does occur in cells expressing one of these two proteins.
Intramural rupture of the oesophagus.
Authors: I. N. Marks, A. D. Keet
Journal: BMJ (1968)

Summary Two cases of intramural rupture of the oesophagus are described. In both cases the diagnosis was made endoscopically and confirmed radiologically. 80th patients were successfully managed conservatively but were later found to have disordered oesophageal motility. The clinical presentation of severe retrosternal chest pain followed by haematemesis and then dysphagia is stressed, and the diagnostic features on barium swallow examination and endoscopy are described. It is suggested that the diagnosis should be made on clinical presentation and barium swallow, and that the possible hazards of endoscopy in the acute stage should be avoided.