tbuckley/cabot-search huggingface dataset:
Pre-implantation genetic testing for hereditary pulmonary arterial hypertension: promise and caution
Authors: Rizwan Hamid, James Loyd
Journal: European Respiratory Journal (2012)

ulmonary arterial hypertension (PAH) is a progressive, fatal disease and most PAH patients have a poor prognosis despite standard-of-care therapies.Heritable PAH (HPAH) is usually (.80%) due to germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene [1][2][3][4].Thus, BMPR2 mutations constitute the largest known risk for developing PAH.One of the most perplexing features of HPAH is its reduced penetrance, which confounds genetic counselling.Nearly 80% of mutation carriers have no clinical symptoms, but they can produce offspring that are affected by HPAH [5].Thus, disease development cannot be predicted in a mutation carrier and this deficiency in our knowledge about disease penetrance results in a significant physical, emotional and economic burden in HPAH families.Because 75% of subjects with HPAH have a New York Heart Association functional class rating of III or IV at the time of diagnosis, they have poor long-term prognosis: average life expectancy is ,3 yrs from the time of diagnosis [6], as the treatment options for PAH, including HPAH, continue to have no impact on the underlying pulmonary vascular disease and limited efficacy.
Blood supply threatened by EU law
Authors: Rory Watson
Journal: BMJ (2001)

Access to life saving blood products from the United States could be at risk from new legislation currently going through the European parliament. The proposed legislation aims to guarantee the highest level of quality and safety throughout the blood transfusion chain in all 15 member states. It sets standards for the collection, testing, processing, storage, and distribution of human blood and blood components, as well as the criteria for training of specialised staff.

The provisions are largely uncontroversial and received the overwhelming support …
Experts Confer on Vasectomy And Prostate Cancer Risk
Authors: J. Bowersox
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Experts Confer on Vasectomy And Prostate Cancer Risk Get access John Bowersox John Bowersox Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 7, 7 April 1993, Pages 527–528, https://doi.org/10.1093/jnci/85.7.527 Published: 07 April 1993
Protective role of intracellular superoxide dismutase against extracellular oxidants in cultured rat gastric cells.
Authors: H Hiraishi, A Terano, T Sugimoto, T Harada, M Razandi, K J Ivey
Journal: Journal of Clinical Investigation (1994)

We examined the role of intracellular superoxide dismutase (SOD) as an antioxidant by studying the effect of diethyldithiocarbamate (DDC) on extracellular H2O2-induced damage in cultured rat gastric mucosal cells. 51Cr-labeled monolayers from rat stomachs were exposed to glucose oxidase-generated H2O2 or reagent H2O2, which both caused a dose-dependent increase in 51Cr release. DDC dose-dependently enhanced 51Cr release by hydrogen peroxide, corresponding with inhibition of endogenous SOD activity. This inhibition was not associated either with modulation of other antioxidant defenses, or with potentiation of injury by nonoxidant toxic agents. Enhanced hydrogen peroxide damage by DDC was significantly prevented by chelating cellular iron with deferoxamine or phenanthroline. Inhibition of cellular xanthine oxidase (possible source of superoxide production) by oxypurinol neither prevented lysis by hydrogen peroxide nor diminished DDC-induced sensitization to H2O2. We conclude that (a) extracellular H2O2 induces dose dependent damage to cultured gastric mucosal cells; (b) intracellular SOD plays an important role in preventing H2O2 damage; (c) generation of superoxide seems to occur intracellularly after exposure to H2O2, but independent of cellular xanthine oxidase; and (d) cellular iron mediates the damage by catalyzing the production of more reactive species from superoxide and H2O2, the process which causes ultimate cell injury.
c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias
Authors: Jiajie Yan, Wei Kong, Qiang Zhang, Eric C. Beyer, Gregory Walcott, Vladimir G. Fast, Xun Ai
Journal: Cardiovascular Research (2012)

c-Jun N-terminal kinase (JNK) activation is implicated in cardiovascular diseases and ageing, which are linked to enhanced propensity to atrial fibrillation (AF). However, the contribution of JNK to AF remains unknown. Thus, we assessed the role of JNK in remodelling of gap junction connexin43 (Cx43) and development of AF. AF induction, optical mapping, and biochemical assays were performed in young and aged New Zealand white rabbit left atria (LA) and cultured HL-1 atrial cells. In aged rabbit LA, pacing-induced atrial arrhythmias were dramatically increased and conduction velocity (CV) was significantly slower compared with young controls. Aged rabbit LA contained 120% more activated JNK and 54% less Cx43 than young LA. Young rabbits treated with JNK activator anisomycin also exhibited increased pacing-induced atrial arrhythmias and reduced Cx43 (by 34%), similar to that found in aged LA. In HL-1 cell cultures, anisomycin treatment for 16 h led to 42% reduction in Cx43, 24% reduction in CV, and an increased incidence of irregular rapid spontaneous activities. These effects were prevented by a specific JNK inhibitor, SP600125. Moreover, a 63% reduction in Cx43 after anisomycin treatment for 24 h led to further slowed CV (by 41%) along with dramatically increased irregular rapid spontaneous activity and highly discontinuous conduction. These JNK-induced functional abnormalities were completely reversed by overexpressed exogenous wild-type Cx43, but not by inactive Cx43. JNK activation contributes to Cx43 reductions that promote development of AF. Modulation of JNK may be a potential novel therapeutic approach to prevent and treat AF.
Diagnosis of Splenic Rupture in Malignant Lymphoma Using Radionuclides
Authors: J C WALLACE
Journal: Clinical Nuclear Medicine (1985)

The case of a 59-year-old woman with malignant lymphoma who was investigated for fever and left upper quadrant abdominal pain is presented. A combined spleen/lung scan showed marked medial displacement of an enlarged spleen and a gallium scan showed increased splenic uptake consistent with Iymphomatous infiltration. The diagnosis of prior splenic rupture with subphrenic hematoma was confirmed at laparotomy.
Dengue Fever in US Military Personnel in Haiti
Authors: Andrew F. Trofa
Journal: JAMA (1997)

To describe clinical manifestations and public health implications of an outbreak of dengue fever (DF) during Operation Uphold Democracy, Haiti, 1994.Consecutive sample.Military combat support hospital, Port-au-Prince, Haiti.A total of 101 US military personnel with acute febrile illnesses.A disease surveillance team collected clinical and epidemiologic data from US military clinics throughout Haiti. Febrile patients admitted to the combat support hospital were evaluated with standardized clinical and laboratory procedures. The surveillance team followed patients daily.Arbovirus isolation and specific antibody determination and symptoms and physical findings.Febrile illnesses accounted for 103 (25%) of the 406 combat support hospital admissions during the first 6 weeks of deployment. All patients with febrile illness recovered. A total of 30 patients had DF; no patient had evidence of infection with malaria. Dengue virus serotypes 1, 2, and 4 were isolated from 22 patients, and 8 patients developed IgM antibody to dengue virus. Patients with DF could not be distinguished from other febrile patients on clinical grounds alone. No arboviruses other than dengue were identified.Active surveillance, with clinical and laboratory evaluation directed by an epidemiologic team, led to the timely recognition of an outbreak of febrile illness among US troops in Haiti. Viral isolation and serological studies were essential in confirming DF. During the surveillance period, DF accounted for at least 30% of the febrile illnesses among hospitalized US troops. Dengue fever is a significant threat to military personnel and civilian travelers in Haiti and has the potential for introduction to and transmission in the United States.
The perils of reconstructive remembering and the value of representative design
Authors: Kim J. Vicente
Journal: Behavioral and Brain Sciences (1996)

Abstract (1) The miscitations of seminal experiments in the base rate literature adds to the existing database of systematic miscitations of wellknown psychological experiments. These miscitations may be caused by a process of reconstructive remembering. (2) Representative design should be the methodological core of Koehler's call for ecologically valid research. This approach can benefit both basic and applied research.
Loss of Polycystin-1 in Human Cyst-Lining Epithelia Leads to Ciliary Dysfunction
Authors: Surya M. Nauli, Sandro Rossetti, Robert J. Kolb, Francis J. Alenghat, Mark B. Consugar, Peter C. Harris, Donald E. Ingber, Mahmoud Loghman-Adham, Jing Zhou
Journal: Journal of the American Society of Nephrology (2006)

A "two-hit" hypothesis predicts a second somatic hit, in addition to the germline mutation, as a prerequisite to cystogenesis and has been proposed to explain the focal nature for renal cyst formation in autosomal dominant polycystic kidney disease (ADPKD). It was reported previously that Pkd1(null/null) mouse kidney epithelial cells are unresponsive to flow stimulation. This report shows that Pkd1(+/null) cells are capable of responding to mechanical flow stimulation by changing their intracellular calcium concentration in a manner similar to that of wild-type cells. This paper reports that human renal epithelia require a higher level of shear stress to evoke a cytosolic calcium increase than do mouse renal epithelia. Both immortalized and primary cultured renal epithelial cells that originate from normal and nondilated ADPKD human kidney tubules display normal ciliary expression of the polycystins and respond to fluid-flow shear stress with the typical change in cytosolic calcium. In contrast, immortalized and primary cultured cyst-lining epithelial cells from ADPKD patients with mutations in PKD1 or with abnormal ciliary expression of polycystin-1 or -2 were not responsive to fluid shear stress. These data support a two-hit hypothesis as a mechanism of cystogenesis. This report proposes that calcium response to fluid-flow shear stress can be used as a readout of polycystin function and that loss of mechanosensation in the renal tubular epithelia is a feature of PKD cysts.
The major allergen of the <i><scp>P</scp>arietaria</i> pollen contains an <scp>LPS</scp>‐binding region with immuno‐modulatory activity
Authors: A. Bonura, S. Corinti, E. Schiavi, D. Giacomazza, F. Gianguzza, G. Di Felice, P. Colombo
Journal: Allergy (2013)

Abstract Background The major allergens in Parietaria pollen, Par j 1 and Par j 2, have been identified as lipid transfer proteins. The family of the Par j 1 allergens is composed of two isoforms, which differ by the presence of a 37 amino acid peptide (Par37) exclusive to the Par j 1.0101 isoform. The goal of this study was to elucidate the biological properties of the Par37 peptide. Methods In silico analysis, spectrofluorimetric experiments and in vitro cell culture assays were used to identify the biological properties of Par37. In addition, a mouse model of sensitization was used to study the influence of Par37 in the murine immune response. Results In silico analysis predicted that Par37 displays characteristics of a host defence peptide. Spectrofluorimetric analysis, real‐time PCR and ELISA assays demonstrated that Par37 possesses an LPS ‐binding activity influencing cell signalling in vitro . In RAW 264.7 cells, LPS ‐induced IL ‐6 and TNF ‐α transcription and translation were inhibited after preincubation with Par37. Consistent with these data, inhibition of IFN ‐γ secretion was observed in murine spleen cells and in human PBMC . Finally, mice immunized with the two Par j 1 isoforms differing in the presence or absence of the Par37 peptide showed different immunological behaviours in vivo . Conclusions This study demonstrates that the Par j 1.0101 allergen displays LPS ‐binding activity due to the presence of a 37 amino acid COOH ‐terminal region and that this region is capable of influencing cytokine and antibody responses in vitro and in vivo .
Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors
Authors: Neeltje Steeghs, Ferry A.L.M. Eskens, Hans Gelderblom, Jaap Verweij, Johan W.R. Nortier, Jan Ouwerkerk, Conny van Noort, Mariangela Mariani, Riccardo Spinelli, Patrizia Carpinelli, Bernard Laffranchi, Maja J.A. de Jonge
Journal: Journal of Clinical Oncology (2009)

Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m(2) in the 6-hour IVS, and from 250 mg/m(2) in the 3-hour IVS, were studied.Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m(2) for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m(2) or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m(2) infused over 6 hours on days 1, 8, and 15 every 28 days.
Oncolytic Virotherapy Trials—Letter
Authors: Akseli Hemminki, Minna Oksanen, Maiju Merisalo-Soikkeli
Journal: Clinical Cancer Research (2013)

We would like to thank Prof. Harrington for his insightful commentary ([1][1]) regarding our article by Kanerva and colleagues ([2][2]). During 2007–2011, the Advanced Therapy Access Program (ATAP) provided a unique opportunity for patients to access a technology they would not otherwise have had
Bisphosphonates for Osteoporosis
Authors: Murray J. Favus
Journal: New England Journal of Medicine (2010)

A 67-year-old woman is referred by her primary care physician for treatment of osteoporosis and progressive bone loss. Oral bisphosphonate therapy is recommended. Bisphosphonates suppress bone resorption by interfering with osteoclast activity. Several of these agents have been shown to prevent fractures and increase bone mineral density in patients with osteoporosis. Long-term bisphosphonate therapy has been associated with osteonecrosis of the jaw and atypical femur fractures.
THE NORMAL SELLA
Authors: C. D. ENFIELD
Journal: JAMA (1922)

Numerous case reports and articles dealing with endocrine disorders have recently mentioned the size and shape of the sella turcica as shown roentgenographically with the inference that conclusions might fairly be drawn as to the function of the pituitary through some departure from the normal in the size or shape of the sella. The type of reference to which I refer is one which deals simply with variations in contour, and does not depend for the diagnosis of a pathologic condition on the presence of erosion, or manifest encroachment of the contents of the sella on adjacent structures. It is doubtless natural that students of endocrinology should incline to enthusiasm with regard to this field of medical research, and should hope to obtain from roentgenography of the sella some information relative to the functional capacity of the pituitary, since the only means of obtaining any information in regard to the
The waning of expression
Authors: S. Spence
Journal: BMJ (1995)

Jackson Pollock and Mark Rothko spared themselves the fate of Willem de Kooning. Pollock crashed his car on a deserted country road; Rothko bled himself to death in front of his last canvas. The New York “school” of abstract expressionism flourished in the middle of this century and was renowned for alcoholism and affective disturbance. De Kooning survived all this; now he apparently has Alzheimer's disease, playing out his last years painting wavy lines on what will become expensive artefacts.

In many ways his predicament is that of the 20th century …
Calcium Supplementation and Prevention of Colorectal Neoplasia: Lessons From Clinical Trials
Authors: María Elena Martínez, Elizabeth T. Jacobs
Journal: JNCI Journal of the National Cancer Institute (2007)

Editorials 99 reporting no relationship [summarized in ( 7 )].However, by contrast to the lack of effect of supplemental calcium in colorectal cancer trials, it has been shown to reduce rates of adenoma recurrence in randomized controlled trials ( 8 , 9 ).It is interesting that higher levels of calcium intake have been associated with reduced risk of adenoma recurrence as compared to levels associated with colorectal cancer .For example, in the Calcium Polyp Prevention Study ( 8 ), 1200 mg of elemental calcium was associated with a modest risk reduction in adenoma recurrence of 15% -19%; baseline mean intake of dietary calcium was approximately 890 mg/day.Even more compelling are the fi ndings in this issue of the Journal ( 10 ) indicating that the protective effect of calcium supplementation for colorectal adenoma recurrence extends as long as 5 years after cessation of supplementation and that this effect is slightly stronger than that observed during the intervention phase .One of the major criticisms of adenoma recurrence trials is that the relatively short (i.e., 3 -5 years) follow-up time is often used as
Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells.
Authors: R C Bargou, F Emmerich, D Krappmann, K Bommert, M Y Mapara, W Arnold, H D Royer, E Grinstein, A Greiner, C Scheidereit, B Dörken
Journal: Journal of Clinical Investigation (1997)

The pathogenesis and etiology of Hodgkin's disease, a common human malignant lymphoma, is still unresolved. As a unique characteristic, we have identified constitutive activation of the transcription factor nuclear factor (NF)-kappaB p50-RelA in Hodgkin/Reed-Sternberg (H/RS) cells, which discriminates these neoplastic cells from most cell types studied to date. In contrast to other lymphoid and nonlymphoid cell lines tested, proliferation of H/RS cells depended on activated NF-kappaB. Furthermore, constitutive NF-kappaB p50-RelA prevented Hodgkin's lymphoma cells from undergoing apoptosis under stress conditions. Consistent with this dual function, Hodgkin's lymphoma cells depleted of constitutive nuclear NF-kappaB revealed strongly impaired tumor growth in severe combined immunodeficient mice. Our findings identify NF-kappaB as an important component for understanding the pathogenesis of Hodgkin's disease and for developing new therapeutic strategies against it.
Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women's Health and Aging Study.
Authors: H E Resnick, A I Vinik, A V Schwartz, S G Leveille, F L Brancati, J Balfour, J M Guralnik
Journal: Diabetes Care (2000)

OBJECTIVE: To determine the role of peripheral nerve dysfunction (PND) in the disablement pathway. RESEARCH DESIGN AND METHODS: Vibration perception threshold (VPT) was measured in 894 women aged &amp;gt; or = 65 years, and those with normal peripheral nerve function and with mild, moderate, and severe PND were identified. Lower-extremity impairments included quadriceps strength (kilograms) and three progressively difficult balance tasks (able/unable). Functional limitations included rising from a chair (able/unable) and usual pace and fast-paced walking speeds (meters/second). Level of PND was related to impairments and functional limitations in linear and logistic regression models that controlled for potentially confounding factors, including reported diabetes. RESULTS: Level of PND was associated with impaired balance (adjusted odds ratios: 2.21, 1.95, and 3.02 for mild, moderate, and severe PND, respectively, relative to normal, P &amp;lt; 0.05). PND was also associated with decrements in both usual and fast-paced walking speeds (-0.08, -0.08, and -0.15 m/s for usual pace and -0.13, -0.12, and -0.24 m/s for fast-paced walking speed for women with mild, moderate, and severe PND, respectively; P &amp;lt; 0.01 for all). Reported diabetes was not associated with these outcomes in the presence of PND. Some, but not all, of the association between PND and functional limitations was explained by the relationship between PND and impairments. CONCLUSIONS: PND is significantly associated with both lower-extremity impairments and functional limitations in older women, and PND appears to have independent effects on functional limitations. The independent effect of diabetes on these outcomes may be limited when PND is considered. Further research is needed to determine if PND is causally related to disability in old age.
Isolation and Characterization of an Abnormal High Density Lipoprotein in Tangier Disease
Authors: Gerd Assmann, Peter N. Herbert, Donald S. Fredrickson, Trudy Forte
Journal: Journal of Clinical Investigation (1977)

The nature of the high density lipoproteins has been investigated in five patients homozygous for Tangier disease (familial high density lipoprotein deficiency). It has been established that Tangier high density lipoproteins, as isolated by ultracentrifugation, are morphologically heterogenous and contain several proteins (Apo B, albumin, and Apo A-II). An abnormal lipoprotein has been isolated from the d = 1.063-1.21 g/ml ultracentrifugal fraction by agarose-column chromatography which contains apoprotein A-II as the sole protein constituent. In negative-stain electron microscopy, these lipoproteins appeared as spherical particles 55-75 A in diameter. By a variety of criteria (immunochemical, polyacrylamide electrophoresis, amino acid composition, and fluorescence measurements), apoprotein A-I the major apoprotein of normal high density lipoproteins and the C apoproteins were absent from this lipoprotein. As demonstrated by (125)I very low density lipoprotein incubation experiments with Tangier plasma, C apoproteins did not associate with lipoproteins of d = 1.063-1.21 g/ml. Tangier apoprotein A-II, isolated to homogeneity by delipidation of the apoprotein A-II-containing lipoprotein or Sephadex G-200 guanidine-HCl chromatography of the d = 1.063-1.21 g/ml fraction, was indistinguishable from control apoprotein A-II with respect to amino acid composition and migration of tryptic peptides in urea-polyacrylamide electrophoresis. The ability of Tangier apoprotein A-II to bind phospholipid was demonstrated by in vitro reconstitution experiments and morphological and chemical analysis of lipid-protein complexes. It is concluded that normal high density lipoproteins, as defined by polypeptide composition and morphological appearance, are absent from Tangier plasma and that as a consequence, the impairment of C apoprotein metabolism contributes to the hypertriglyceridemia and fasting chylomicronemia observed in these patients.