tbuckley/cabot-search huggingface dataset:
Generation and Characterization of a genetic zebrafish model of SMA carrying the human SMN2gene
Authors: Le T Hao, Arthur HM Burghes, Christine E Beattie
Journal: Molecular Neurodegeneration (2011)

Animal models of human diseases are essential as they allow analysis of the disease process at the cellular level and can advance therapeutics by serving as a tool for drug screening and target validation. Here we report the development of a complete genetic model of spinal muscular atrophy (SMA) in the vertebrate zebrafish to complement existing zebrafish, mouse, and invertebrate models and show its utility for testing compounds that alter SMN2 splicing.The human motoneuron disease SMA is caused by low levels, as opposed to a complete absence, of the survival motor neuron protein (SMN). To generate a true model of SMA in zebrafish, we have generated a transgenic zebrafish expressing the human SMN2 gene (hSMN2), which produces only a low amount of full-length SMN, and crossed this onto the smn-/- background. We show that human SMN2 is spliced in zebrafish as it is in humans and makes low levels of SMN protein. Moreover, we show that an antisense oligonucleotide that enhances correct hSMN2 splicing increases full-length hSMN RNA in this model. When we placed this transgene on the smn mutant background it rescued the neuromuscular presynaptic SV2 defect that occurs in smn mutants and increased their survival.We have generated a transgenic fish carrying the human hSMN2 gene. This gene is spliced in fish as it is in humans and mice suggesting a conserved splicing mechanism in these vertebrates. Moreover, antisense targeting of an intronic splicing silencer site increased the amount of full length SMN generated from this transgene. Having this transgene on the smn mutant fish rescued the presynaptic defect and increased survival. This model of zebrafish SMA has all of the components of human SMA and can thus be used to understand motoneuron dysfunction in SMA, can be used as an vivo test for drugs or antisense approaches that increase full-length SMN, and can be developed for drug screening.
A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Authors: David H. Miller, Omar A. Khan, William A. Sheremata, Lance D. Blumhardt, George P.A. Rice, Michele A. Libonati, Allison J. Willmer-Hulme, Catherine M. Dalton, Katherine A. Miszkiel, Paul W. O'Connor
Journal: New England Journal of Medicine (2003)

In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
Hemodynamic Data and Survival in Children With Pulmonary Hypertension
Authors: Martha L Clabby, Charles E Canter, James H Moller, Nancy D Bridges
Journal: Journal of the American College of Cardiology (1997)

Objectives. Using data from a multi-institutional data base, we sought to determine whether hemodynamic data predict duration of survival in children with primary or secondary pulmonary hypertension. Background. Lung transplantation is a therapeutic option for children with pulmonary hypertension. Appropriate timing of lung transplantation requires reliable methods of predicting duration of survival in potential candidates. Methods. A regional data base was used to obtain cardiac catheterization data on 50 children with mean pulmonary artery pressure (mPAP) >25 mm Hg and indexed pulmonary resistance (Rp) >4.5 Wood units. Data on survival were obtained from the participating centers. Results. There were 15 patients without congenital heart disease (group 1) and 35 patients with congenital heart disease (group 2) for analysis. Actuarial survival at 1, 2 and 5 years was 86%, 69% and 69% in group 1 and 88%, 88% and 77% in group 2, respectively (p = NS). Hemodynamic variables that predicted survival on univariate analysis were mean right atrial pressure (mRAP) (p < 0.0001), mPAP (p = 0.034), Rp (p < 0.0001) and pulmonary flow (p = 0.003), as well as a variable that we generated—mRAP × Rp (p < 0.0001). On multivariate stepwise logistic regression analysis, mRAP × Rp was independently related to survival. A model using mRAP × Rp allows for the estimation of probability of death at 1 and 2 years after catheterization. Conclusions. Hemodynamic variables can predict survival in children with pulmonary hypertension in the presence or absence of congenital heart defects. This information can be used to determine the optimal timing of listing for lung transplantation.
Changes in Coronary Venous Inosine Concentration and Myocardial Wall Thickening during Regional Ischemia in the Pig
Authors: JAN WILLEM DE JONG, SIDNEY GOLDSTEIN
Journal: Circulation Research (1974)

Correlations between local mechanical and metabolic events were studied during a partial decrease in flow in the left anterior descending coronary artery in 14 open-chest pigs. A decrease in flow to 28% (19-39%) of the control value was achieved with an adjustable screw clamp. A flow probe was placed around the artery. Blood samples were taken from the regional anterior coronary vein and the femoral artery. Myocardial wall thickening was measured with a harpoon type of mercury strain gauge. During ischemia, systolic myocardial wall thickening decreased to 44.5 ± 5.1% ( SE ) of its control value ( P &lt; 0.001). The mean concentrations of plasma potassium and whole blood inosine, hypoxanthine, and lactate in three serial 2-minute samples obtained during a 6-minute control period were compared with those obtained during a 6-minute period of partial occlusion. During ischemia, venous inosine concentration increased from 10.9 ± 0.7 µ M to 18.5 ± 1.8 µM ( P &lt; 0.005), venous hypoxanthine concentration increased from 28.5 ± 1.4 µ M to 33.0 ± 1.5 µ M ( P &lt; 0.005), venous potassium concentration increased from 3.77 ± 0.10 m M to 4.08 ± 0.13 m M ( P &lt; 0.001), and venous lactate concentration increased from 1.04 ± 0.19 m M to 1.52 ± 0.17 m M ( P &lt; 0.001). The arterial level of potassium increased very little. The arterial concentration of the other compounds did not change significantly during the 6-minute period of ischemia. Myocardial lactate extraction changed from a control value of 42.6 ± 6.7% to -4.6 = 12.5% ( P &lt; 0.05). A negative correlation ( r s = -0.79, P &lt; 0.01) was observed between venous inosine concentration and myocardial wall thickening (percent of control) during ischemia. This study indicates that the local venous inosine concentration is a sensitive indicator of regional myocardial ischemia in the pig.
Cytokeratin expression in steatocystoma multiplex
Authors: I. Kurokawa, S. Nishijima, K. Kusumoto, H. Senzaki, N. Shikata, A. Tsubura
Journal: British Journal of Dermatology (2002)

Sir, The origin of steatocystoma multiplex (SCM) is uncertain. The aim of our study was to investigate cytokeratin (CK) expression in SCM and to evaluate the origin of these tumours. The immunohistochemical localization of CK in SCM was studied using six antikeratin antibodies. The CK expression in SCM was comparable to that in sebaceous ductal cells, and SCM may be derived from sebaceous ducts. SCM occurs in adolescence and develops under the influence of androgens.1 Electronmicroscopically, the cyst wall seems related to the sebaceous duct.1, 2 CK is a useful marker to evaluate the origin of epithelial tumours.3 Cysts were surgically excised from 15 patients (five male and 10 female, age range 21–77 years, mean 35·3) with SCM. Six specimens were obtained from the forearm, three from the axillae, and one each from eyelid, chest, abdomen, back, thigh, and leg. The specimens were fixed with formalin, embedded with paraffin and cut into 4‐µm‐thick sections. The specimens were incubated with six different antikeratin antibodies: 34βB4 (CK1),4 LHP1 (CK10),5 LL001 (CK14),6 LL025 (CK16),7 E3 (CK17),8 b170 (CK19).9 The immunohistochemical method was performed in accordance with our previous report.10
Cardiac Autonomic Control in Obstructive Sleep Apnea
Authors: MICHAEL C. K. KHOO, VASILY BELOZEROFF, RICHARD B. BERRY, CATHERINE S. H. SASSOON
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

To determine how long-term treatment with continuous positive airway pressure (CPAP) affects cardiac autonomic function, we measured R-R interval (RRI), respiration, and blood pressure in 13 awake patients with moderate-to-severe obstructive sleep apnea (OSA) in both supine and standing postures, before and after 3 to 9 mo of home therapy. Using visual feedback, the subjects controlled their respiration to track a randomized breathing pattern. From the RRI spectrum, we computed high-frequency power and the ratio of low-frequency to high-frequency power (LHR). To correct for differences in breathing, the average transfer gain relating respiration to RRI changes (G(RSA)) and the modified low-frequency to high-frequency ratio (MLHR) were also derived. CPAP therapy did not change the conventional spectral indices of heart rate variability (HRV). However, G(RSA) increased with average nightly CPAP use in supine (p < 0.01) and standing (p < 0.03) postures, whereas MLHR decreased with CPAP compliance during standing (p < 0.03). Supine mean heart rate decreased with compliance (p < 0.03). None of the estimated parameters was correlated with duration of therapy when actual CPAP use was not taken into account. These results suggest that CPAP treatment improves vagal heart rate control in patients with OSA and that the degree of improvement varies directly with compliance level.
Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis
Authors: S M van der Kooij, S le Cessie, Y P M Goekoop-Ruiterman, J K de Vries-Bouwstra, D van Zeben, P J S M Kerstens, J M W Hazes, D van Schaardenburg, F C Breedveld, B A C Dijkmans, C F Allaart
Journal: Annals of the Rheumatic Diseases (2008)

To compare the clinical and radiological efficacy of initial vs delayed treatment with methotrexate (MTX) and infliximab (IFX) in patients with recent onset rheumatoid arthritis (RA).In a post hoc analysis of the BeSt study (for Behandel Stratagieen, Dutch for treatment strategies), 117 patients who started initial MTX+IFX were compared with 67 patients who started MTX+IFX treatment after failing (disease activity score (DAS)>2.4; median delay to IFX: 13 months) on > or =3 traditional DMARDs. If the DAS remained >2.4, the protocol dictated IFX dose increases to 6, 7.5 and 10 mg/kg. In case of a DAS < or =2.4 for > or =6 months, IFX was tapered and finally stopped. We aimed to correct for allocation bias using propensity scores. Functional ability was measured by the Health Assessment Questionnaire (HAQ), radiological progression by Sharp/van der Heijde scoring (SHS).Baseline differences between the initial and delayed groups were no longer significant after propensity score adjustment. At 3 years after baseline, patients treated with initial MTX+IFX experienced more improvement in HAQ over time and were less likely to have SHS progression than patients treated with delayed MTX+IFX (p = 0.034). At 2 years after IFX initiation, more patients in the initial group compared with the delayed group could discontinue IFX after a good response (56% vs 29%, p = 0.008).The results of this post hoc analysis suggest that using MTX+IFX as initial treatment for patients with recent onset RA is more effective than reserving MTX+IFX for patients who failed on traditional DMARDs, with more HAQ improvement over time, more IFX discontinuation and less progression of joint damage.
INTRAPERITONEAL LYSIS OF TUBERCLE BACILLI
Authors: Wilfred H. Manwaring, J. Bronfenbrenner
Journal: The Journal of Experimental Medicine (1913)

1. Tubercle bacilli injected into the peritoneal cavities of tuberculous guinea pigs, rats, rabbits, dogs, and monkeys, rapidly disappear from the peritoneal fluids, while persisting in the peritoneal fluids of normal control animals. 2. This disappearance is in part due to an adhesion of the injected bacilli to the peritoneal leucocytes and a fixation of the leucocytes on the omentum. 3. The injected tubercle bacilli can be recovered quantitatively from the peritoneal cavities of normal guinea pigs from one and one half to two hours after the injection, while from tuberculous guinea pigs only 65 per cent. of the bacilli can be recovered at this time. 4. Isolated peritoneal tissues from tuberculous guinea pigs have the power of destroying tubercle bacilli in vitro. 5. A second factor reducing the number of tubercle bacilli free in the peritoneal fluid is therefore an actual lysis of the bacilli. 6. The intraperitoneal lysis is not due solely to substances present in the circulating fluids, since the phenomenon cannot be produced by these fluids in vitro, and since a lytic power cannot be passively conferred even by a direct transfusion of blood from tuberculous to normal animals. 7. The intraperitoneal lysis is apparently due to specific changes in the fixed peritoneal cells of the tuberculous animals.
Mobilization of Dendritic Cell Precursors Into the Circulation by Administration of MIP-1 in Mice
Authors: Y. Zhang, H. Yoneyama, Y. Wang, S. Ishikawa, S.-i. Hashimoto, J.-L. Gao, P. Murphy, K. Matsushima
Journal: JNCI Journal of the National Cancer Institute (2004)

Dendritic cells (DCs) play a central role in immune responses and may be useful adjuvants for tumor vaccine therapy. We previously reported that F4/80(-)B220(-)CD11c(+) DC precursors expressing the CC chemokine receptors CCR1 and CCR5 are mobilized rapidly into the circulation in mice injected with Propionibacterium acnes and are recruited into inflammatory tissue by macrophage inflammatory protein 1alpha (MIP-1alpha), which binds to CCR1 and CCR5. Here we investigate the mechanisms of DC precursor mobilization and the antitumor effect of these cells in mice.Numbers of DC precursors in peripheral blood were determined in P. acnes-treated mice (groups of 10 C57BL/B6 [B6] wild-type mice, CCR1(-/-) mice, CCR5(-/-) mice, and B6 mice treated with antibody to MIP-1alpha or control antibody) and in B6 mice injected with recombinant MIP-1alpha. MIP-1alpha-mobilized DC precursors matured by treatment with granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor-alpha and pulsed with B16 melanoma lysates were assayed for their ability to confer protective immunity against tumor challenge in vivo and to induce cytotoxic T lymphocytes against B16 tumor cells in vitro.The recruitment of DC precursors into the circulation by P. acnes administration was higher in B6 mice (12.6%, 95% confidence interval [CI] = 9.1% to 16.1%) than in CCR1(-/-) (9.0%, 95% CI = 7.5% to 10.5%), CCR5(-/-) (6.3%, 95% CI = 5.2% to 7.3%), or anti-MIP-1alpha antibody-treated (6.6%, 95% CI = 5.7% to 7.5%) mice. Injection of MIP-1alpha also mobilized DC precursors into the circulation (13.1%, 95% CI = 10.8% to 15.6%). Matured MIP-1alpha-mobilized-DC precursors pulsed with B16 tumor lysates elicited B16-specific antitumor immunity in vitro and in vivo.MIP-1alpha and its receptors are important in recruiting DC precursors into the circulation. DC precursors mobilized rapidly by MIP-1alpha may provide sufficient useful DC precursors for DC-based vaccination in cancer treatment.
Comparison of intermittent versus continuous methotrexate plus 6-mp in maintenance regimen for standard risk acute lymphoblastic leukemia in children (GBTLI ALL-99)
Authors: S. R. Brandalise
Journal: Journal of Clinical Oncology (2007)

9512 Objectives: To compare by randomization the conventional use of 6-MP (50 mg/m 2 daily) / MTX (25 mg/m 2 /wk) regimen with the intermittent use of MTX (200 mg/m 2 /IV 6 h infusion each 21 days)/ 6-MP (100 mg/m 2 /day × 10) in maintenance therapy. Methods: Newly diagnosed ALL children up to 18 yrs of age registered in the GBTLI ALL-99 Protocol. The eligibility criteria for standard-risk group were age &gt;1 &lt;9 years and WBC count at diagnosis &lt;50,000/mm 3 and good responders at D7/D14. Randomization was made after the late consolidation phase (week 42) prior to the maintenance treatment. Treatment Schedule: Induction: [DX(Pred), DNM, VCR, L-ASP, CICLO, Ara-C, 6-MP], Intensification: (MTX 2 g/m 2 6 h inf. × 4, 6-MP) Late Consolidation: (DX, VCR, DOXO, L-ASP, CICLO, ARA-C, 6-TG) plus prolonged triple intratecal therapy, were done previously to maintenance therapy. Total treatment duration was two years. No CNS radiation was done. Toxicities were defined according to NCI-version 2001 criteria. Results: 560 pts were enrolled in the study. 22 slow responders pts (4.1%) moved to high risk group. The total number of analyzed pts was 512. Two hundred and thirty pts entered group 1 [continuous (conventional) 6MP-MTX] and 230 pts entered group 2 (Intermittent MTX/6-MP). Remission rate was 95.3%. 439 pts (87.9%) are in CCR. The mean follow up period is 2.2 years. The estimated 5 years OS rate for both groups is 88.1% ± 2.1%. The estimated 5 years EFS for both groups is 80% ± 2.9%. According to maintenance regimen, the 5 years EFS rate is 80.2% ± 4.5% and 88.3% ± 3.7% for group 1 and group 2, respectively (p=0.048). Grade 3 and 4 hepatic toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.019). Grade 3 CNS toxicities were 13 episodes (group 1) and 5 in group 2. Grade 4 hematological toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.003). Conclusions: Despite the short mean time follow-up (2.2 years) the patients with the intermittent regimen (Group 2) had better EFS rate (p = 0.048) and less hematological, CNS and hepatic toxicities, comparing with patients that received conventional maintenance treatment (group 1). No significant financial relationships to disclose.
326 PRO-205 OF LARGE HEPATITIS DELTA ANTIGEN AND PRO-62 OF MAJOR HEPATITIS B SURFACE ANTIGEN INFLUENCE THE ASSEMBLY OF HEPATITIS D VIRUS OF DIFFERENT GENOTYPES
Authors: H.H. Shih, C. Shih, H.-W. Wang, I.-J. Sheen, C.-W. Su, J.-C. Wu
Journal: Journal of Hepatology (2010)
Effect of static stretching of quadriceps and hamstring muscles on knee joint position sense
Authors: R Larsen, H Lund, R Christensen, H Røgind, B Danneskiold-Samsøe, H Bliddal
Journal: British Journal of Sports Medicine (2004)

To evaluate if a stretch regimen consisting of three 30 second stretches would alter joint position sense (JPS).A blinded, randomised, cross over design with a washout time of 24 hours was used with 20 healthy volunteers. JPS was estimated from the ability to reproduce the same position in one knee (target versus estimated angle) expressed as the difference between target and estimated angle (constant error, CE). Measurements were repeated three times in a sitting and a prone position on the dominant leg measured before and immediately after the static stretch. The static stretch consisted of a 30 second stretch followed by a 30 second pause, repeated three times.At baseline, the mean (SD) CE was -2.71 (3.57) degrees in the sitting position. No difference (p = 0.99) in CE between stretching and control was observed (0.00; 95% confidence interval -0.98 to 0.99). At baseline, the CE was -3.28 (4.81) degrees in the prone position. No difference (p = 0.89) in CE between stretching and control was observed (0.12; 95% confidence interval -1.52 to 1.76).A static stretch regimen had no effect on JPS in healthy volunteers.
Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.
Authors: D M Hurley, D Accili, C A Stratakis, M Karl, N Vamvakopoulos, E Rorer, K Constantine, S I Taylor, G P Chrousos
Journal: Journal of Clinical Investigation (1991)

Familial glucocorticoid resistance is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations in the absence of stigmata of Cushing's syndrome. Our previous studies of the first reported kindred showed a two- to threefold reduction in glucocorticoid receptor-ligand binding affinity in the propositus, and a lesser reduction in affinity in his mildly affected son and nephew. Glucocorticoid receptor cDNA from these three patients was amplified by polymerase chain reaction and sequenced. The cDNA nucleotide sequence was normal, except for nucleotide 2054, which substituted valine for aspartic acid at amino acid residue 641. The propositus was homozygous while the other relatives were heterozygous for the mutation. COS-7 monkey kidney cells were cotransfected with expression vectors for either wild type or Val 641-mutant receptors, together with the reporter plasmid pMMTV-CAT. Dexamethasone increased chloramphenicol acetyltransferase activity in cells expressing wild type receptor, but had no effect in cells expressing Val 641-mutant receptors, despite similar receptor concentrations, as indicated by Western blotting. The binding affinity for dexamethasone of the Val 641-mutant receptor was threefold lower than that of the wild type receptor. These results suggest that glucocorticoid resistance in this family is due to a point mutation in the steroid-binding domain of the glucocorticoid receptor.