tbuckley/cabot-search huggingface dataset:
Specificity of cytotoxic effector cells directed against trinitrobenzene sulfonate-modified syngeneic cells. Failure to recognize cell surface- bound trinitrophenyl dextran
Authors: PA Henkart, A Schmitt-Verhulst, GM Shearer
Journal: The Journal of Experimental Medicine (1977)

Mouse splenic lymphocytes and lymphoid tumor cells were modified with the trinitrophenyl (TNP) group either by treatment with trinitrobenzene sulfonate (TNBS) (which covalently modifies cell surface proteins) or with TNP stearoyl dextran (TSD) (which binds to the cell by noncovalent forces). These cell preparations were compared for their ability to: (a) sensitive syngeneic splenic lymphocytes leading to the generation of cytotoxic effector cells; (b) serve as lysable targets in a 4-h(51)Cr- release assay for effector cells generated in (a); and (c) act as blocking cells in the lysis of TNBS-medified targets lysed by TNP self effector cells generated in (a). In none of these three experimental systems did TSD-medified syngeneic spleen or H-2-matched tumor cells act either as a sensitizing immunogen or as a target antigen, despite the demonstration that quantitatively equivalent mounts of TNP were exposed on the cell surface in the TNBS- and TSD-modified cells. In contrast, TNBS-modified spleen cells sensitized syngeneic lymphocytes to generate effectors against TNBS-modified syageneic targets. Furthermore, TNBS- modified, H-2-matched cells served as specific lysable targets and as inhibiting cells for such effectors. These results indicate that the manner in which TNP is associated with the cell surface is important in the immunogenicity and antigenicity of hapten-modified syngeneic stimulating cells in generating H-2-associated cell-mediated lympholysis (CML) reactions. These findings raise the possibility that a covalent or at least a stable linkage with cell surface proteins (possibly H-2- controlled products) is important for immunological function. Furthermore, these observations do not favor the dual receptor model for H-2-restricted syngeneic CML if it is assumed in such a model that one receptor is specific for the TNP moiety and the second for unmodified self major histocompatibility products.
Electrocardiographic Effects of Changing the Nature of the Contact Between the Exposed Heart and the Body
Authors: JOHN J. SAYEN, AARON H. KATCHER, GEORGE PEIRCE
Journal: Circulation Research (1961)

In dog studies designed to improve the accuracy of direct extracellular heart-body leads, the electrocardiographic representation of the heart when maximally insulated (connected to the body only by its vascular pedicdc) was compared with common open-chest experimental situations in which portions of the normally behaving ventricular surface are allowed to remain in contact with the body. The addition of any ventricular surface to the heart-body contact area (by removal of insulation) lowered the R-wave amplitude in all. direct heart-body leads from the ventricular surface or wall. The effects of locally altering the physiological behavior of portions of the left ventricle were also studied. Any portion of the ventricular surfaces of maximally insulated hearts could be altered by locally applied agents to show heart-body lead changes entirely confined to the area of demonstrably local physiological disturbance. Small- or medium-sized areas of transmural regional is chemia likewise produced electrocardiographic changes only in the vicinity of the ischeniic muscle. In the case of less completely in Sn lated hearts, direct heart-body lead changes consequent to localized physiological change
Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway
Authors: Mikio Shimada, Ruri Sagae, Junya Kobayashi, Toshiyuki Habu, Kenshi Komatsu
Journal: Cancer Research (2009)

Nijmegen breakage syndrome is characterized by genomic instability and a predisposition for lymphoma and solid tumors. Nijmegen breakage syndrome 1 (NBS1), the protein which is mutated in these patients, functions in association with BRCA1 and ATR as part of the cellular response to DNA double-strand breaks. We show here that NBS1 forms foci at the centrosomes via an interaction with gamma-tubulin. Down-regulation of NBS1 by small interfering RNA induces supernumerary centrosomes, and this was confirmed with experiments using Nbs1 knockout mouse cells; the introduction of wild-type NBS1 (wt-NBS1) cDNA into these knockout mouse cells reduced the number of supernumerary centrosomes to normal levels. This phenotype in NBS1-deficient cells is caused by both centrosome duplication and impaired separation of centrioles, which have been observed in BRCA1-inhibited cells. In fact, supernumerary centrosomes were observed in Brca1 knockout mouse cells, and the frequency was not affected by NBS1 down-regulation, suggesting that NBS1 maintains centrosomes via a common pathway with BRCA1. This is consistent with findings that NBS1 physically interacts with BRCA1 at the centrosomes and is required for BRCA1-mediated ubiquitination of gamma-tubulin. Moreover, the ubiquitination of gamma-tubulin is compromised by either ATR depletion or an NBS1 mutation in the ATR interacting (FHA) domain, which is essential for ATR activation. These results suggest that, although centrosomes lack DNA, the NBS1/ATR/BRCA1 repair machinery affects centrosome behavior, and this might be a crucial role in the prevention of malignances.
Collapsing Focal Segmental Glomerulosclerosis Following Treatment with High-Dose Pamidronate
Authors: GLEN S. MARKOWITZ, GERALD B. APPEL, PAUL L. FINE, ANDREW Z. FENVES, NICHOLAS R. LOON, SUNDAR JAGANNATH, JOSEPH A. KUHN, ADAM D. DRATCH, VIVETTE D. D'AGATI
Journal: Journal of the American Society of Nephrology (2001)

Collapsing focal segmental glomerulosclerosis (FSGS) is a distinct clinicopathologic entity seen most commonly in young African American patients who present with renal insufficiency and nephrotic syndrome. The only epidemiologic factor previously linked to collapsing FSGS is HIV infection. Here clinicopathologic findings are reported for a distinctive population of seven patients, who were older, Caucasian, and HIV negative and developed collapsing FSGS during active treatment of malignancy (multiple myeloma in six patients and metastatic breast carcinoma in one). Although oncologic treatment regimens included vincristine for four patients, doxorubicin for five patients, cisplatin for two patients, and total-body irradiation for one patient, the only agent common to all patients was pamidronate (Aredia). All patients had normal renal function before the administration of pamidronate. Patients began therapy with pamidronate at or below the recommended dose of 90 mg, intravenously, monthly, which was increased to 180 mg monthly in two patients and 360 mg monthly in three patients. Patients received pamidronate for 15 to 48 mo before presentation with renal insufficiency (mean serum creatinine, 3.6 mg/dl) and full nephrotic syndrome (mean 24-h urinary protein excretion, 12.4 g/d). Pamidronate, which is a member of the class of bisphosphonates, is widely used in the treatment of hypercalcemia of malignancy and osteolytic metastases. At the recommended dose of 90 mg, intravenously, monthly, renal toxicity is infrequent; however, higher doses have produced nephrotoxicity in animal models. The temporal association between pamidronate therapy and the development of renal insufficiency, the use of escalating doses that exceed recommended levels, and the distinctive pattern of glomerular and tubular injury strongly suggest a mechanism of drug-associated podocyte and tubular toxicity. These data provide the first association of collapsing FSGS with toxicity to a therapeutic agent.
Protein kinase C agonists inhibit bile secretion independently of effects on the microcirculation in the isolated perfused rat liver
Authors: James G. Corasanti, Neil D. Smith, Ellen R. Gordon, James L. Boyer
Journal: Hepatology (1989)

The role of hormones in the regulation of bile secretion is not known; however vasoactive agents, which act via the phosphoinositide signal transduction pathway, may mediate changes in bile flow by altering the hepatic microvasculature. We therefore examined the effects of phorbol esters and diacylglycerol, agonists of the protein kinase C branch of the phosphoinositide cascade, on perfusion pressure and bile flow in a single-pass, hemoglobin-free, isolated perfused rat liver system with constant perfusate flow. The active phorbol ester, 12,13-phorbol dibutyrate, produced a dose-dependent (maximal effect at 10 −6 M ), sustained and reversible decrease in bile flow from 1.09 ± 0.18 to 0.61 ± 0.09 μl per min per gm liver (37.2 ± 5.9%) while simultaneously increasing perfusion pressure from 12.3 ± 0.7 to 21.5 ± 2.5 cm H 2 O (74.0 ± 4.3%). Both effects were inhibited by the synthetic protein kinase C antagonist H-7. 1,2-Dioctanoyl- sn -glycerol, a diacylglycerol, produced changes in bile flow and perfusion pressure that were similar to, but more marked than, those caused by 12,13-phorbol dibutyrate, whereas the inactive phorbol ester 4α-phorbol didecanoate and the vehicle dimethyl sulfoxide had no effects on either parameter. 12,13-Phorbol dibutyrate infusion resulted in reversible decreases in oxygen consumption (23.3%) and a reversible vascular redistribution of trypan blue dye but did not alter hepatic venous effluent concentrations of K + . Increases in perfusion pressure produced by mechanical constrictions of the hepatic venous cannulae did not reproduce phorbol-induced changes in bile flow, suggesting that the cholestasis is not mediated by postsinusoidal increases in hepatic outflow resistance. Furthermore, the nonspecific vasodilators sodium nitroprusside (10 −3 M ) and papaverine (40 μ M ) prevented the phorbol-induced increases in perfusion pressure (p &lt; 0.01) but did not block 12,13-phorbol dibutyrate’s cholestatic effects. We conclude from this study that protein kinase C agonists have both vascular and nonvascular effects in the isolated perfused rat liver and that the cholestasis caused by these agents is independent of effects on the hepatic microcirculation.
Study of Paclitaxel, Etoposide, and Cisplatin Chemotherapy Combined With Twice-Daily Thoracic Radiotherapy for Patients With Limited-Stage Small-Cell Lung Cancer: A Radiation Therapy Oncology Group 9609 Phase II Study
Authors: David S. Ettinger, Brian A. Berkey, Ross A. Abrams, James Fontanesi, Mitchell Machtay, Philip J. Duncan, Walter J. Curran, Benjamin Movsas, Roger W. Byhardt
Journal: Journal of Clinical Oncology (2005)

Purpose To determine the response rate, progression-free survival and overall survival, and toxicity of paclitaxel, etoposide, and cisplatin combined with accelerated hyperfractionated thoracic radiotherapy in patients with limited-disease (LD) small-cell lung cancer (SCLC). Patients and Methods LD-SCLC patients with measurable disease, Karnofsky performance score of ≥ 70, and adequate organ function who were previously untreated were eligible for the study. Treatment was as follows. In cycle 1 of chemotherapy, concurrent thoracic radiation therapy was administered. In cycles 2 to 4, chemotherapy was administered alone. In cycle 1, chemotherapy consisted of paclitaxel 135 mg/m 2 intravenous over 3 hours on day 1, etoposide 60 mg/m 2 intravenous on day 1 and 80 mg/m 2 orally on days 2 and 3, and cisplatin 60 mg/m 2 intravenous on day 1. In cycles 2 to 4, the paclitaxel dose was increased to 175 mg/m 2 , with the etoposide and cisplatin doses remaining the same as in cycle 1. The thoracic radiation therapy consisted of 1.5 Gy in 30 fractions (total dose, 45 Gy) administered 5 days a week for 3 weeks. Results Fifty-five patients were enrolled onto the study, and 53 were assessable. The major toxicities included grade 3 and 4 acute neutropenia (32% and 43%, respectively) and grade 3 and 4 esophagitis (32% and 4%, respectively). Two patients died as a result of therapy (one died of acute respiratory distress syndrome, and one died of sepsis). There was one late fatal pulmonary toxicity. The median survival time was 24.7 months. The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months, with a 2-year progression-free survival rate of 26.4%. Conclusion Although this therapeutic regimen is effective in the treatment of patients with LD-SCLC, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times compared with the etoposide plus cisplatin chemotherapy regimen with thoracic radiation therapy in LD-SCLC patients.
The goal of treatment for motor impairment is not to “normalize” but to “functionalize” through facilitative modulation and enabling context
Authors: Gary Goldberg, Nathaniel H. Mayer
Journal: Behavioral and Brain Sciences (1996)

Abstract Adaptations occurring in the central nervous system (CNS) in the presence of pathology are not uniformly “good” for the organism when viewed in a functional context. A functional reordering of CNS priorities can be produced by allowing restructuring of the external context or through modification of neuromuscular physiology or anatomy designed to reduce the inherent restriction of functional movement in upper motor neuron syndrome. In fact, volitional control can often be “unmasked” through such interventions. Therapeutic interventions should not be directed toward “normalization” of motor patterns but should permit a functional reordering of CNS priorities that would otherwise not be possible.
Expression of IL-16 in allergen-induced late-phase nasal responses and relation to topical glucocorticosteroid treatment
Authors: Sophie Laberge, Stephen R. Durham, Omar Ghaffar, Sabina Rak, David M. Center, Mikila Jacobson, Qutayba Hamid
Journal: Journal of Allergy and Clinical Immunology (1997)

Allergen-induced late nasal responses (LNRs) are associated with a cellular infiltrate in which CD4+ cells are prominent. These cells have been shown to be the major cellular source of Th2-type cytokines. Mechanisms responsible for the local accumulation of CD4+ cells in the nasal mucosa after allergen exposure are unclear. IL-16 is a potent chemoattractant for CD4+ cells in vitro and may play a significant role in recruiting CD4 cells in LNRs. We investigated the expression of IL-16 messenger RNA and immunoreactivity in nasal biopsy specimens from 17 subjects with allergic rhinitis. A biopsy specimen of the nasal inferior turbinate was obtained before and 24 hours after local nasal provocation with grass pollen extract after 6 weeks of treatment with either topical fluticasone propionate (n = 9) or placebo (n = 8) nasal spray twice daily. IL-16 mRNA–positive cells and IL-16-immunoreactive cells were identified in both the epithelium and the subepithelial tissue at baseline. Within the placebo-treated group, the numbers of epithelial and subepithelial IL-16 mRNA–positive cells and IL-16-immunoreactive cells were significantly increased 24 hours after challenge compared with baseline (p < 0.001). Topical glucocorticoid therapy resulted in a decrease in allergen-induced epithelial immunoreactive cells and subepithelial IL-16 mRNA–positive cells. The numbers of CD4+ cells increased after antigen challenge compared with baseline (p < 0.05), and this increase was inhibited by glucocorticoid treatment. There were significant correlations between epithelial and subepithelial IL-16 immunoreactivity and CD4+ cell infiltration after antigen challenge. The upregulation of IL-16 expression in allergic nasal mucosa after antigen challenge may have critical implications in the accumulation of CD4+ cells in response to antigen exposure. Steroid-mediated inhibition of IL-16 may be partly responsible for the decrease in local CD4+ cells after topical glucocorticoid therapy. (J Allergy Clin Immunol 1997;100:569-74.)
Driving simulator and neuropyschological testing in OSAS before and under CPAP therapy
Authors: M. Orth, H-W. Duchna, M. Leidag, W. Widdig, K. Rasche, T. T. Bauer, J. W. Walther, J. de Zeeuw, J-P. Malin, G. Schultze-Werninghaus, S. Kotterba
Journal: European Respiratory Journal (2005)

Patients with obstructive sleep apnoea syndrome (OSAS) have an increased car accident rate. Investigations on accident frequency are based on case history, insurance reports and driving simulator studies. The present study combines neuropsychological testing of different attention aspects engaged in driving a car and driving simulation to evaluate a suitable instrument for assessing therapeutic effects of continuous positive airway pressure (CPAP). Driving simulator investigation and neuropsychological testing of alertness, vigilance and divided attention were performed in 31 patients with polysomnographically confirmed OSAS (apnoea–hypopnoea index 24.8±21.5·h −1 ) before, and 2 and 42 days after initiation of CPAP. Divided attention and alertness improved significantly during CPAP, whereas vigilance remained unchanged. However, accident frequency (OSAS before therapy: 2.7±2.0; 2 days after CPAP: 1.5±1.4; 42 days after CPAP: 0.9±1.3) and frequency of concentration faults (OSAS before therapy: 12.4±5.1; 2 days after CPAP: 6.5±3.9; 42 days after CPAP: 4.9±3.3) decreased in the simulated driving situation after 2 and 42 days of therapy. There was no relation between accident frequency, concentration faults and daytime sleepiness, as measured by the Epworth Sleepiness Scale, and polysomnographic or neuropsychological findings, respectively. In conclusion, the present results suggest that driving simulation is a possible benchmark parameter of driving performance in obstructive sleep apnoea syndrome patients.
Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3
Authors: Sophie Sokolow, Mario Manto, Philippe Gailly, Jordi Molgó, Clarisse Vandebrouck, Jean-Marie Vanderwinden, Andre Herchuelz, Stéphane Schurmans
Journal: Journal of Clinical Investigation (2004)

We produced and analyzed mice deficient for Na/Ca exchanger 3 (NCX3), a protein that mediates cellular Ca2+ efflux (forward mode) or Ca2+ influx (reverse mode) and thus controls intracellular Ca2+ concentration. NCX3-deficient mice (Ncx3–/–) present a skeletal muscle fiber necrosis and a defective neuromuscular transmission, reflecting the absence of NCX3 in the sarcolemma of the muscle fibers and at the neuromuscular junction. The defective neuromuscular transmission is characterized by the presence of electromyographic abnormalities, including low compound muscle action potential amplitude, a decremental response at low-frequency nerve stimulation, an incremental response, and a prominent postexercise facilitation at high-frequency nerve stimulation, as well as neuromuscular blocks. The analysis of quantal transmitter release in Ncx3–/– neuromuscular junctions revealed an important facilitation superimposed on the depression of synaptic responses and an elevated delayed release during high-frequency nerve stimulation. It is suggested that Ca2+ entering nerve terminals is cleared relatively slowly in the absence of NCX3, thereby enhancing residual Ca2+ and evoked and delayed quantal transmitter release during repetitive nerve stimulation. Our findings indicate that NCX3 plays an important role in vivo in the control of Ca2+ concentrations in the skeletal muscle fibers and at the neuromuscular junction.
Ultrasound guided electrocoagulation in patients with chronic non-insertional Achilles tendinopathy: a pilot study
Authors: M Ilum Boesen, S Torp-Pedersen, M Juhl Koenig, R Christensen, H Langberg, P Hölmich, M Bachmann Nielsen, H Bliddal
Journal: British Journal of Sports Medicine (2006)

Background: High resolution colour Doppler ultrasound shows intratendinous Doppler activity in patients with chronic Achilles tendinopathy. Treatment of this neovascularisation with sclerosing therapy seems to relieve the pain. However, the procedure often has to be repeated. Objective: To investigate the effect of electrocoagulation of the neovessels on tendon pain and tendon vascularity in patients with chronic Achilles tendinopathy. Methods: Colour Doppler ultrasound guided electrocoagulation was used on vessels in the ventral portion of the Achilles tendon in 11 patients (seven men, four women, mean age 41 years) with painful chronic mid-portion Achilles tendinosis. A unipolar coagulation device was used. Results: One patient dropped out after two months (dissatisfied with the results). The remaining 10 patients (91%) were satisfied. These 10 patients were still satisfied at six months of follow up and had returned to their previous level of activity. All 10 patients were “cured” after one treatment. The patient who dropped out received two treatments because of lack of progress. There was significantly reduced pain (Likert pain scale, 0–10) during activity, from a median of 7 (range 4 to 10) at baseline to 0 (0 to 8) at six months’ follow up (p&lt;0.005); and at rest, from 1.5 (1 to 5) to 0 (0 to 8) (p = 0.005). In all patients, vascularisation was unchanged at the six months follow up, with no significant change in semiquantitative or quantitative colour scoring. Conclusions: Coagulation in the area with vessels entering the tendon appears to be effective treatment for painful chronic mid-tendinous Achilles tendinopathy. No effect on the intratendinous Doppler activity could be detected, suggesting that the effect is independent of changes in blood flow. Localisation of hyperaemia appears to be the key to the pathology and for targeting the treatment. One explanation could be that the effect is obtained by destruction of nerves accompanying the vessels.
Accuracy of transbronchial needle aspiration for mediastinal staging of non-small cell lung cancer: a meta-analysis
Authors: J-E C Holty
Journal: Thorax (2005)

<b>Background:</b> The reported accuracy of transbronchial needle aspiration (TBNA) for mediastinal staging in non-small cell lung cancer (NSCLC) varies widely. We performed a meta-analysis to estimate the accuracy of TBNA for mediastinal staging in NSCLC. <b>Methods:</b> Medline, Embase, and the bibliographies of retrieved articles were searched for studies evaluating TBNA accuracy with no language restriction. Meta-analytical methods were used to construct summary receiver-operating characteristic curves and to pool sensitivity and specificity. <b>Results:</b> Thirteen studies met inclusion criteria, including six studies that surgically confirmed all TBNA results and enrolled at least 10 patients with and without mediastinal metastasis (tier 1). Methodological quality varied but did not affect diagnostic accuracy. In tier 1 studies the median prevalence of mediastinal metastasis was 34%. Using a random effects model, the pooled sensitivity and specificity were 39% (95% CI 17 to 61) and 99% (95% CI 96 to 100), respectively. Compared with tier 1 studies, the median prevalence of mediastinal metastasis (81%; p = 0.002) and pooled sensitivity (78%; 95% CI 71 to 84; p = 0.009) were higher in non-tier 1 studies. Sensitivity analysis confirmed that the sensitivity of TBNA depends critically on the prevalence of mediastinal metastasis. The pooled major complication rate was 0.3% (95% CI 0.01 to 4). <b>Conclusions:</b> When properly performed, TBNA is highly specific for identifying mediastinal metastasis in patients with NSCLC, but sensitivity depends critically on the study methods and patient population. In populations with a lower prevalence of mediastinal metastasis, the sensitivity of TBNA is much lower than reported in recent lung cancer guidelines.