tbuckley/cabot-search huggingface dataset:
Long-term Amelioration of Feline Mucopolysaccharidosis VI After AAV-mediated Liver Gene Transfer
Authors: Gabriella Cotugno, Patrizia Annunziata, Alessandra Tessitore, Thomas O'Malley, Anita Capalbo, Armida Faella, Rosa Bartolomeo, Patricia O'Donnell, Ping Wang, Fabio Russo, Meg M Sleeper, Van W Knox, Steven Fernandez, Leah Levanduski, John Hopwood, Elvira De Leonibus, Mark Haskins, Alberto Auricchio
Journal: Molecular Therapy (2010)

Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 1013 genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 1012 gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients. Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 1013 genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 1012 gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.
Plastic Surgery: Homotransplantation, Congenital Anomalies, Wound Healing, and Skin Storage
Authors: B Cannon
Journal: Annual Review of Medicine (1958)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Mechanoelectric feedback in the atrium of the isolated guinea-pig heart
Authors: S. A. Nazir, M. J. Lab
Journal: Cardiovascular Research (1996)

Atrial arrhythmias are prevalent during clinically abnormal myocardial loading, e.g. when the atrium is dilated or stretched. The initiating cause of the first premature beat that leads to this arrhythmia is unclear, as are the reasons for sustaining it. One possibility is that abnormal mechanical factors induce electrophysiological changes conductive to arrhythmia via 'mechanoelectric feedback'. The aim of this study is to investigate the concept that atrial stretch modulates the electrophysiological properties of the atrium via mechanoelectric feedback, and that mechanoelectric feedback can produce atrial arrhythmias.Guinea-pigs were humanely killed by cervical dislocation and the hearts removed and perfused with oxygenated Krebs-Henseleit solution by the Langendorff method. The heart was paced at an atrial site near the sinus node. Monophasic action potentials and electrocardiograms were recorded form the left atrium and left ventricle with suction electrodes. Transient stretch was induced by inflating a fluid-filled intra-atrial latex balloon catheter.Increase in atrial volume produced several significant changes in the epicardial monophasic action potentials. It produced (i) decreases in the amplitude; (ii) a decrease in duration from 62.55 to 51.95 ms measured at 50% repolarisation (10.6 +/- 3.6 ms, P < 0.05, n = 6); (iii) an increase in duration from 122.45 to 140 ms measured at 90% repolarisation (17.55 +/- 4.5 ms, P < 0.05, n = 6) --due to the presence of early afterdepolarisations. (iv) These load-induced electrophysiological changes coincided with the occurrence of arrhythmia or premature atrial beats.Load changes in the atrium can produce electrophysiological changes of a kind that may be relevant to clinical atrial arrhythmia.
Early vitronectin receptor downregulation in a melanoma cell line during all-trans retinoic acid-induced apoptosis
Authors: A. Baroni, I. Paoletti, I. Silvestri, E. Buommino, M.V. Carriero
Journal: British Journal of Dermatology (2003)

Summary Background Recent evidence assigns the vitronectin receptors (VnRs) an important role in regulating tumour cell invasion and dissemination. In vivo and in vitro studies document that all trans-retinoid acids (ATRAs) inhibit growth-inducing apoptosis in melanomas. Objectives We have analysed the effects of ATRA treatment on melanoma cell adhesion and motility. Methods Human M14 melanoma cells were treated with 10 µmol L−1 ATRA for different times and stained with rhodamine–phalloidin to analyse the effect of treatment on cytoskeleton organization. Cell adhesion and cell migration assays were performed to analyse the role of VnRs in the ATRA-induced early stages of apoptosis. VnR expression was evaluated by Western blot, immunoprecipitation and immunocytochemistry assays. Results First, using an annexin V assay, we found that apoptosis was triggered by 48 h with 10 µmol L−1 ATRA exposure. At this time point, decrease in the F-actin polymerization as well as inhibition of cell adhesive ability to vitronectin (Vn) was exerted by ATRA treatment. In the presence of serum, exposure to 10 µmol L−1 ATRA for 48 h produced a dramatic inhibition of the cell adhesion ability that was comparable with that exerted by untreated cells preincubated with anti-αvβ3 or anti-αvβ5 VnR monoclonal antibodies. Functionally, the treatment of melanoma cells with 10 µmol L−1 ATRA for 48 h causes an inhibition of directional cell migration towards Vn-coated filters. Therefore, we analysed the effect of ATRA on the VnR expression. Both αvβ3 and αvβ5 VnR levels were reduced upon exposure to 10 µmol L−1 ATRA for 48 h as shown by Western blot, immunoprecipitation and immunocytochemistry assays. Conclusions Altogether, our data indicate that treatment of M14 melanoma cells with ATRA downregulates VnR expression and that this reduction is closely correlated with the ATRA-dependent inhibition of actin-fibre organization, cell adhesion and migration. Although the mechanism by which ATRA regulates the expression of VnR in M14 melanoma cells needs further elucidation, this system may represent a model for understanding the molecular basis of ATRA therapy in melanoma.
Effect of Artemether-Lumefantrine Policy and Improved Vector Control on Malaria Burden in KwaZulu–Natal, South Africa
Authors: Karen I Barnes, David N Durrheim, Francesca Little, Amanda Jackson, Ushma Mehta, Elizabeth Allen, Sicelo S Dlamini, Joyce Tsoka, Barry Bredenkamp, D. Jotham Mthembu, Nicholas J White, Brian L Sharp
Journal: PLoS Medicine (2005)

Background Between 1995 and 2000, KwaZulu–Natal province, South Africa, experienced a marked increase in Plasmodium falciparum malaria, fuelled by pyrethroid and sulfadoxine-pyrimethamine resistance. In response, vector control was strengthened and artemether-lumefantrine (AL) was deployed in the first Ministry of Health artemisinin-based combination treatment policy in Africa. In South Africa, effective vector and parasite control had historically ensured low-intensity malaria transmission. Malaria is diagnosed definitively and treatment is provided free of charge in reasonably accessible public-sector health-care facilities. Methods and Findings We reviewed four years of malaria morbidity and mortality data at four sentinel health-care facilities within KwaZulu–Natal's malaria-endemic area. In the year following improved vector control and implementation of AL treatment, malaria-related admissions and deaths both declined by 89%, and outpatient visits decreased by 85% at the sentinel facilities. By 2003, malaria-related outpatient cases and admissions had fallen by 99%, and malaria-related deaths had decreased by 97%. There was a concomitant marked and sustained decline in notified malaria throughout the province. No serious adverse events were associated causally with AL treatment in an active sentinel pharmacovigilance survey. In a prospective study with 42 d follow up, AL cured 97/98 (99%) and prevented gametocyte developing in all patients. Consistent with the findings of focus group discussions, a household survey found self-reported adherence to the six-dose AL regimen was 96%. Conclusion Together with concurrent strengthening of vector control measures, the antimalarial treatment policy change to AL in KwaZulu–Natal contributed to a marked and sustained decrease in malaria cases, admissions, and deaths, by greatly improving clinical and parasitological cure rates and reducing gametocyte carriage.
A Legionella-like Bacterium Related to WIGA in a Fatal Case of Pneumonia
Authors: BERENICE M. THOMASON
Journal: Annals of Internal Medicine (1979)

An unusual bacterium serologically related to a "rickettsia-like agent," designated previously as WIGA, was seen in lung tissue from a patient who died of pneumonia of unknown cause. A fluorescent antibody conjugate prepared with the WIGA organism, isolated in 1959, was used to stain the lung tissue. Enormous numbers of fluorescent bacteria in the lungs of this patient confirm the pathogenicity of this unusual bacterium.
Effect of verapamil and sodium cromoglycate on leukotriene D4 induced bronchoconstriction in patients with asthma.
Authors: J A Roberts, I W Rodger, N C Thomson
Journal: Thorax (1986)

Leukotriene D4 (LTD4) may be an important mediator in asthma. The effect of verapamil and sodium cromoglycate on LTD4 induced bronchoconstriction has been examined in seven patients with asthma. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.0032-50 micrograms/ml) was assessed by measuring changes in FEV1, specific airways conductance, and flow rate at 30% of vital capacity (V30(p)). Results were expressed as the provocation concentration (PC) producing a 10% fall in FEV1 (PC10FEV1), a 35% fall in specific airways conductance (PC35SGaw), and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Neither verapamil nor cromoglycate inhibited LTD4 induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatic patients LTD4 induced bronchoconstriction is not mediated via verapamil or cromoglycate sensitive mechanisms.
Genome-wide association study identifies susceptibility loci for IgA nephropathy
Authors: Ali G Gharavi, Krzysztof Kiryluk, Murim Choi, Yifu Li, Ping Hou, Jingyuan Xie, Simone Sanna-Cherchi, Clara J Men, Bruce A Julian, Robert J Wyatt, Jan Novak, John C He, Haiyan Wang, Jicheng Lv, Li Zhu, Weiming Wang, Zhaohui Wang, Kasuhito Yasuno, Murat Gunel, Shrikant Mane, Sheila Umlauf, Irina Tikhonova, Isabel Beerman, Silvana Savoldi, Riccardo Magistroni, Gian Marco Ghiggeri, Monica Bodria, Francesca Lugani, Pietro Ravani, Claudio Ponticelli, Landino Allegri, Giuliano Boscutti, Giovanni Frasca, Alessandro Amore, Licia Peruzzi, Rosanna Coppo, Claudia Izzi, Battista Fabio Viola, Elisabetta Prati, Maurizio Salvadori, Renzo Mignani, Loreto Gesualdo, Francesca Bertinetto, Paola Mesiano, Antonio Amoroso, Francesco Scolari, Nan Chen, Hong Zhang, Richard P Lifton
Journal: Nature Genetics (2011)
Molecular genetics of steroid 5 alpha-reductase 2 deficiency.
Authors: A E Thigpen, D L Davis, A Milatovich, B B Mendonca, J Imperato-McGinley, J E Griffin, U Francke, J D Wilson, D W Russell
Journal: Journal of Clinical Investigation (1992)

Two isozymes of steroid 5 alpha-reductase encoded by separate loci catalyze the conversion of testosterone to dihydrotestosterone. Inherited defects in the type 2 isozyme lead to male pseudohermaphroditism in which affected males have a normal internal urogenital tract but external genitalia resembling those of a female. The 5 alpha-reductase type 2 gene (gene symbol SRD5A2) was cloned and shown to contain five exons and four introns. The gene was localized to chromosome 2 band p23 by somatic cell hybrid mapping and chromosomal in situ hybridization. Molecular analysis of the SRD5A2 gene resulted in the identification of 18 mutations in 11 homozygotes, 6 compound heterozygotes, and 4 inferred compound heterozygotes from 23 families with 5 alpha-reductase deficiency. 6 apparent recurrent mutations were detected in 19 different ethnic backgrounds. In two patients, the catalytic efficiency of the mutant enzymes correlated with the severity of the disease. The high proportion of compound heterozygotes suggests that the carrier frequency of mutations in the 5 alpha-reductase type 2 gene may be higher than previously thought.
Inhibition of human macrophage colony formation by interleukin 4.
Authors: J H Jansen, G J Wientjens, W E Fibbe, R Willemze, H C Kluin-Nelemans
Journal: The Journal of Experimental Medicine (1989)

We investigated the effects of human rIL-4 on in vitro hematopoiesis. A profound inhibition of macrophage colony formation by IL-4 was observed, whereas colony growth of other lineages was not affected. Inhibition of macrophage colony growth was not restricted to GM-CSF-induced colony growth but was also present in cultures stimulated with M-CSF. This inhibition was not only observed in cultures of light density bone marrow cells, but also in cultures of monocyte- and T lymphocyte-depleted bone marrow cells. Since a similar inhibition was observed in cultures of CD34+HLA-DR+-enriched bone marrow cells, a direct action of IL-4 on monocyte-committed progenitor cells is suggested.
Status Asthmaticus
Authors: Charles H. Scoggin
Journal: JAMA (1977)

A retrospective analysis of 811 patients admitted to the hospital for status asthmaticus over a nine-year period was performed. Eight patients died, and 19 required mechanical ventilation. All persons who died of status asthmaticus were in the group that required mechanical ventilation. In 12 of the patients who received ventilation, no definite cause for the acute exacerbation could be identified, although initial arterial blood gas analyses showed profound hypoxemia, hypercapnia, and acute respiratory acidosis. Seventy-eight major complications occurred during mechanical ventilation. Pneumothorax, endotracheal tube malfunction, alveolar hypoventilation on the ventilator, and pneumonia were associated with decreased survival. Mucous plugging of the airways was found in all autopsied patients. Mechanical ventilation in status asthmaticus is a life-support system associated with substantial morbidity and should be instituted only when it becomes evident that maximal medical therapy will not be efficacious.
AT-101 (-/- Gossypol) in Combination with Trastuzumab Triggers Apoptosis Through Inhibiting BCL-2, BCL-XL AND MCL-1 Protein Levels in Human HER2-Positive Breast Cancer Cells
Authors: B. Cakar, G. Bulut, A. Kisim, E. Bozkurt, H. Atmaca, S. Uzunoglu, R. Uslu, B. Karaca
Journal: Annals of Oncology (2013)
Capillary basement membrane structure: a comparative study of diabetics and sexual ateliotic dwarfs
Authors: Thomas J. Merimee, Marvin D. Siperstein, Judith D. Hall, S. Edwin Fineberg
Journal: Journal of Clinical Investigation (1970)

A group of 32 sexual ateliotic dwarfs with an isolated deficiency of human growth hormone (HGH) were shown previously to resemble subjects with genetic diabetes mellitus in terms of hyperlipemia, carbohydrate intolerance, and patterns of insulin secretion. 11 of these dwarfs had needle biopsies of the quadriceps femoris carried out and tissue fixed for electron microscopy. Capillary basement membrane thickness was measured and compared with measurements previously obtained in diabetics and normal controls. Measurements were similar in controls and dwarfs (1080 +/-27 A and 1086 +/-90 A, respectively) and significantly less than in diabetics (2403 +/-119 A). Placed in juxtaposition with the absence of retinopathy in dwarfs and the high incidence in the diabetic group (41%), the data support the thesis that these anatomical abnormalities are largely independent of serum lipid and carbohydrate abnormalities. The data are consistent with a supportive, if not causative role of growth hormone in the pathogenesis of these lesions.
First drug is approved under scheme that gives patients access to unlicensed medicines
Authors: N. Hawkes
Journal: BMJ (2015)

The first drug to be made available to patients in the United Kingdom before it is formally licensed will be pembrolizumab, a treatment for advanced melanoma.

Its use is made possible by the Early Access to Medicines Scheme (EAMS), in which medicines that have yet to complete their trials and gain a licence can be provided so long as they show a good balance of risk and benefit and where there is a clear unmet need. The scheme was developed with government support by the Medicines and Healthcare Products Regulatory Agency in response to criticism that patients in the UK often have to wait too long for new treatments to be made available.

Pembrolizumab, a monoclonal antibody, will be made available free of charge under the scheme by its manufacturer, MSD. The designation of the drug under EAMS lasts for a year but can …
The Role of Family Planning in the Primary Prevention of Mental Illness
Authors: RICHARD A. SCHWARTZ
Journal: American Journal of Psychiatry (1969)

After reviewing the mental health implications of unregulated fertility in the areas of illegitimacy, premarital pregnancy, poverty, postpartum psychosis, and overpopulation, the author concludes that family planning services can be an important addition to preventive psychiatry techniques. Psychiatric centers might feasibly offer case-finding, education, and referral services and, in some instances, direct contraceptive advice to their clients. At the level of community action, psychiatrists can also help to educate community leaders and the public about the need for expanded family planning services.
Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies
Authors: L. Lansbury, F. Bath-Hextall, W. Perkins, W. Stanton, J. Leonardi-Bee
Journal: BMJ (2013)

<b>Objectives</b> To assess the effects of treatments for non-metastatic invasive squamous cell carcinoma (SCC) of the skin using evidence from observational studies, given the paucity of evidence from randomised controlled trials. <b>Design</b> Systematic review of observational studies. <b>Data sources</b> Medline, Embase, to December 2012. <b>Review methods</b> Observational studies of interventions for primary, non-metastatic, invasive, SCC of the skin that reported recurrence during follow-up, quality of life, initial response to treatment, adverse events, cosmetic appearance, or death from disease. Studies were excluded if data for primary cutaneous SCC was not separable from other data. Data were extracted independently by two reviewers. Meta-analysis was performed where appropriate using a random effects model to estimate the pooled proportion of an event with 95% confidence intervals. <b>Results</b> 118 publications were included, covering seven treatment modalities. Pooled estimates of recurrence of SCCs were lowest after cryotherapy (0.8% (95% confidence interval 0.1% to 2%)) and curettage and electrodesiccation (1.7% (0.5% to 3.4%)), but most treated SCCs were small, low risk lesions. After Mohs micrographic surgery, the pooled estimate of local recurrence during variable follow-up periods from 10 studies was 3.0% (2.2% to 3.9%), which was non-significantly lower than the pooled average local recurrence of 5.4% (2.5% to 9.1%) after standard surgical excision (12 studies), and 6.4% (3.0% to 11.0%) after external radiotherapy (7 studies). After an apparently successful initial response of SCCs to photodynamic therapy, pooled average recurrence of 26.4% (12.3% to 43.7%; 8 studies) was significantly higher than other treatments. Evidence was limited for laser treatment (1 study) and for topical and systemic treatments (mostly single case reports or small non-comparative series with limited follow-up). <b>Conclusions</b> Many observational studies have looked at different treatment modalities for SCC, but the evidence base for the effectiveness of these interventions is poor. Comparison of outcomes after different treatments should be interpreted cautiously owing to biases inherent in the types of study included, and lack of direct comparisons to enable the estimation of relative treatment effect. Further evidence is needed to develop a prognostic model and stratify individuals at high risk of developing SCC, to improve the evidence base for this common cancer and to optimise clinical management. <b>Protocol registration</b> International Prospective Register of Systematic Reviews (PROSPERO) registration number CRD42011001450.
On the Reanalysis of the GISSI-Prevenzione
Authors: Alexander Leaf
Journal: Circulation (2002)

he reanalysis 1 of the results of the GISSI-Prevenzione secondary prevention trial appearing in this issue of Circulation greatly increases the importance of this large, well-conducted clinical trial.The original publication of the GISSI-Prevenzione 2 reported that when 11 323 patients surviving a very recent myocardial infarction (MI) were randomized to 1.0 g daily of a concentrate of fish oil n-3 polyunsaturated fatty acids (PUFAs, nϭ2835), vitamin E (300 mg daily, nϭ2830), both (nϭ2830), or no treatment (nϭ2828) on top of usual pharmacological treatment and lifestyle, significant reductions in mortality were observed over the 42 months of follow-up.However, probably two or three features of the outcome drew the attention of the investigators.These were (1) the very early separation of the mortality curves (or probability of mortality) between the subjects receiving the n-3 supplement versus the control groups, (2) the absence of any reduction in plasma cholesterol levels, and (3) the finding that the major factor in the mortality reduction by n-3 PUFAs resulted from a striking 45% reduction in sudden cardiac deaths, which had not been a stated primary end point for the GISSI-Prevenzione trial.Indeed, an early reduction in mortality has become a hallmark of the beneficial effects of n-3 PUFAs on coronary heart disease.This relationship is further strengthened when the benefit occurs in the absence of a reduction in cholesterol levels.Both were noted by Burr and associates in their 1989 publication of the Death and Reinfarction Trial 3 and in the Lyon Heart Study by DeLorgeril et al 4 in 1994.So the GISSI Investigators wisely decided that a careful time-course analysis of the results of GISSI-Prevenzione was warranted, and their resulting present publication adds greatly to the importance of their investigations.