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Biomedical subjects

K Nash

Publications and source records attributed to K Nash.

At least 19 recordsLinked to original sources
PubMed2006

Identifying the behavioural phenotype in Fetal Alcohol Spectrum Disorder: sensitivity, specificity and screening potential.

BACKGROUND: In most cases of Fetal Alcohol Spectrum Disorder (FASD), the pathognomonic facial features are absent making diagnosis challenging, if not impossible, particularly when no history of maternal drinking is available. Also because FASD is often comorbid with Attention Deficit Hyperactivity Disorder (ADHD), children with FASD are frequently improperly diagnosed and receive the wrong treatment. Since access to psychological testing is typically limited or non-existent in remote areas, other diagnostic methods are needed to provide necessary interventions. OBJECTIVES: To determine if a characteristic behavioural phenotype distinguishes children with FASD from typically developing children and children with ADHD and use this information to create a screening tool for FASD diagnosis. METHODS: Parents and caregivers completed the Child Behavior Checklist (CBCL), a well-established standardized tool for evaluating children's behavioural problems. Results from 30 children with Fetal Alcohol Syndrome or Alcohol-Related Neurodevelopmental Disability, 30 children with ADHD, and 30 typically developing healthy children matched for age and socioeconomic status with FASD were analyzed. Based on our previous work, 12 CBCL items that significantly differentiated FASD and control groups were selected for further analyses. Stepwise discriminant function analysis identified behavioural characteristics most strongly differentiating groups and Receiver Operating Characteristics (ROC) curve analyses determined sensitivity and specificity of different item combinations. RESULTS: Seven items reflecting hyperactivity, inattention, lying and cheating, lack of guilt, and disobedience significantly differentiated children with FASD from controls. ROC analyses showed scores of 6 or higher on these items differentiated groups with a sensitivity of 86%, specificity of 82%. For FASD and ADHD, two combinations of items significantly differentiated groups with high sensitivity and specificity (i) no guilt, cruelty, and acts young (sensitivity = 70%; specificity = 80% (ii) acts young, cruelty, no guilt, lying or cheating, steals from home, and steals outside (sensitivity = 81%; specificity = 72%). These items were used to construct a potential FASD screening tool. CONCLUSIONS: Our findings identifying the behavioural characteristics differentiating children with FASD from typically developing children or children with ADHD have the potential for development of an empirically derived tool for FASD tool to be used in remote areas where psychological services are not readily available. This technique may speed up diagnosis and intervention for children without ready access to formal assessments.

Attention Deficit Disorder with Hyperactivity↗
PubMed2000

High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response.

BACKGROUND: In pig-to-primate organ transplantation, hyperacute rejection can be prevented, but the organ is rejected within days by acute vascular rejection, in which induced high-affinity anti-Gal alpha1-3Gal (alphaGal) IgG and possibly antibodies directed against new porcine (non-alphaGal) antigenic determinants are considered to play a major role. We have explored the role of an anti-CD40L monoclonal antibody in modifying the humoral response to porcine hematopoietic cells in baboons pretreated with a nonmyeloablative regimen. METHODS: Porcine peripheral blood mobilized progenitor cells obtained by leukapheresis from both major histocompatibility complex-inbred miniature swine (n=7) and human decay-accelerating factor pigs (n=3) were transplanted into baboons. Group 1 baboons (n=3) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with ATG, complement depletion with cobra venom factor, short courses of cyclosporine, mycophenolate mofetil, porcine hematopoietic growth factors, and anti-alphaGal antibody depletion by immunoadsorption before transplantation of high doses (2-4 x 10(10)/cells/kg) of peripheral blood mobilized progenitor cells. In group 2 (n=5), cyclosporine was replaced by eight doses of anti-CD40L monoclonal antibodies over 14 days. The group 3 baboons (n=2) received the group 1 regimen plus 2 doses of anti-CD40L monoclonal antibodies (on days 0 and 2). RESULTS: In group 1, sensitization to alphaGal (with increases in IgM and IgG of 3- to 6-fold and 100-fold, respectively) and the development of antibodies to new non-alphaGal porcine antigens occurred within 20 days. In group 2, no sensitization to alphaGal or non-alphaGal determinants was seen, but alphaGal-reactive antibodies did return to their pre- peripheral blood mobilized progenitor cells transplant levels. In group 3, attenuated sensitization to alphaGal antigens was seen after cessation of cyclosporine and mycophenolate mofetil therapy at 30 days (IgM 4-fold, IgG 8-30-fold), but no antibodies developed against new porcine determinants. In no baboon did anti-CD40L monoclonal antibodies prevent sensitization to its own murine antigens. CONCLUSIONS: We believe these studies are the first to consistently demonstrate prevention of a secondary humoral response after cell or organ transplantation in a pig-to-primate model. The development of sensitization to the murine elements of the anti-CD40L monoclonal antibodies suggests that nonresponsiveness to cell membrane-bound antigen (e.g., alphaGal) is a specific phenomenon and not a general manifestation of immunological unresponsiveness. T cell costimulatory blockade may facilitate induction of mixed hematopoietic chimerism and, consequently, of tolerance to pig organs and tissues.

Animals↗
PubMed2000

Chronic anabolic-androgenic steroid treatment during adolescence increases anterior hypothalamic vasopressin and aggression in intact hamsters.

The present study examines the hypothesis that exposure to anabolic-androgenic steroids (AAS) during adolescent development predisposes hamsters to heightened levels of aggressive behavior by influencing the anterior hypothalamic-arginine vasopressin (AH-AVP) neural system. To test this, adolescent male hamsters (Mesocricetus auratus) were treated with high doses of AAS, tested for offensive aggression in the absence or presence of AH-AVP receptor antagonists, and then examined for changes in AH-AVP expression and neural organization. AAS exposure during adolescence significantly increased aggression intensity (number of attacks and bites) and initiation (latency to the first bite). Yet, only increases in aggression intensity were inhibited by AH-AVP receptor antagonism. Adolescent AAS-treated hamsters showed significant increases in AH-AVP fiber density and peptide content. However, no alterations in AH-AVP neuronal organization or mRNA expression were found. Together, these data suggest that adolescent AAS exposure increase aggression intensity by altering AH-AVP expression and activity, providing direct evidence for a causal role of AH-AVP expression and function in early onset AAS-stimulated aggression.

Aggression↗
PubMed2000

Validation of a life quality (LQ) test for asthma.

BACKGROUND: The American College of Allergy, Asthma, and Immunology (ACAAI) developed a questionnaire, the Life Quality (LQ) Test, for use in its Nationwide Asthma Screening Program. The test is intended as a tool to help individuals with breathing problems determine if they have asthma or, for those already diagnosed with asthma, if their asthma is under control. We attempted to assess whether the LQ Test was a valid tool for use in the screening program. OBJECTIVE: The objective of this study was to validate the LQ Test by determining whether a high score on the LQ Test is a positive predictor of a clinical diagnosis of asthma. METHODS: The 20-question LQ Test was prospectively distributed and self-administered to new patients on their first visit to an asthma and allergy clinic. Total LQ scores were recorded for each patient as the sum of all positive 'yes' responses to the test. All patients were subsequently diagnosed by an allergist as having asthma or not having asthma. The LQ Test also was administered to a group of individual patients who were seen in a dental office. This group of patients, who had no known breathing problems, served as a control. RESULTS: The clinic patients who were subsequently diagnosed with asthma had the highest average LQ score (9.31), 3.9 times higher than the average score for clinic patients diagnosed as not having asthma (2.39), and 8 times higher than the average score for the control group (1.15). CONCLUSION: Higher LQ scores correlate with a higher probability of a positive diagnosis, initially making the LQ Test questionnaire a valid tool to help predict which individuals are more likely to be diagnosed with asthma.

Adult↗
PubMed2000

Clarithromycin-resistant mycobacterium avium is still susceptible to treatment with clarithromycin and is virulent in mice.

Resistance to clarithromycin in breakthrough Mycobacterium avium complex (MAC) isolates typically occurs 3 to 4 months after the initiation of monotherapy in bacteremic AIDS patients. It has been suggested that continuation of clarithromycin therapy still results in clinical and microbiological improvement. To study this paradox, C57BL/6 beige mice were infected with a clarithromycin-resistant (MIC, > or =128 microg/ml) strain of MAC 101 (CLA-R MAC 101) and treated with 200 mg of clarithromycin per kg of body weight/day alone or in combination with ethambutol (100 mg/kg/day) for 2 weeks. Mice infected with a clarithromycin-susceptible strain of MAC 101 had bacterial loads reduced by 90% in the liver and 91% in the spleen (P<0.05, compared with the control). Clarithromycin treatment of CLA-R MAC 101 resulted in a 65% reduction of bacterial loads in the liver (P = 0.009) and a 71% reduction in the spleen (P = 0.009), compared with the results for the untreated control. CLA-R MAC 101 and MAC 101 (isogenic strains) had comparable growth rates in murine tissue, ruling out a loss of virulence of CLA-R MAC 101. Strains of MAC currently defined as macrolide resistant may still respond to treatment with an agent such as clarithromycin within infected tissues.

AIDS-Related Opportunistic Infections↗
PubMed1999

Comparison of inhibitor binding to feline and human immunodeficiency virus proteases: structure-based drug design and the resistance problem.

The design and synthesis of compounds targeted against human immunodeficiency virus 1 (HIV-1) protease have resulted in effective antiviral therapies. However, the rapid replication of the virus and the inherent mutability of the viral genome result in the outgrowth of resistant strains in the majority of patients. Thus, there is a continuing need to develop new antiprotease compounds that may bind more effectively to the resistant forms of protease. This contribution examines the binding of a single inhibitor to two different retroviral proteases, HIV-1 protease and feline immunodeficiency virus protease. Despite the overall similarity of the related retroviral enzymes, specific substitutions within the binding site cavity provide a distinctly different binding landscape that dramatically alters the affinity of compounds. Through this comparison, insights have been obtained into new strategies for drug design. New compounds based on these concepts have been tested against the two enzymes.

Animals↗
PubMed1999

Determinants of chronic infection with Staphylococcus aureus in patients with bronchiectasis.

Staphylococcus aureus is an uncommon pathogen in bronchiectasis not caused by cystic fibrosis (CF). The object of this study was to identify characteristics that cause patients to be prone to infection with S. aureus. The study population consisted of patients with bronchiectasis attending the authors' unit, excluding those with a diagnosis of overt CF. All patients had a high resolution computer tomographic scan (HRCT) of the thorax which demonstrated bronchiectasis. Cases that were currently chronically infected with S. aureus (isolated consecutively on more than two occasions >3 months apart) were identified (n = 12) and compared with 74 control patients who had not been chronically infected with S. aureus. Patients were carefully evaluated to determine the aetiology of their disease. Odds ratios (OR) and 95% confidence intervals (CI) as measures of the association between disease characteristics and chronic infection with S. aureus were calculated. The results for patients chronically infected by S. aureus demonstrated significant associations with allergic bronchopulmonary aspergillosis (ABPA; OR = 8.8, 95% CI 1.8-41.9), atypical variants of CF (OR = 12.0, 95% CI 1.8-81.7) or equivocal sweat sodium values (OR = 4.0, 95% CI 1.0-15.3). The associations persisted when the analysis was based on cases (n = 28) in whom S. aureus had ever been isolated from sputum. In the latter analysis there was also a significant association with predominant upper zone disease on HRCT. These results suggest that patients with bronchiectasis in whom S. aureus is isolated from sputum should be carefully evaluated to exclude allergic bronchopulmonary aspergillosis or atypical cystic fibrosis.

Adult↗
PubMed1999

Funding a school-based health center.

SBHCs have a positive impact on many health statistics. Yet many communities still do not have an SBHC. Nurse practitioners with grant writing and administrative experience are in a unique position to facilitate cost-effective primary care to children and youth in need. Once a clinic is established, community support is usually ongoing.

Child↗
PubMed1999

Peripheral blood progenitor cell mobilization and leukapheresis in pigs.

BACKGROUND AND PURPOSE: The pig is being investigated as an organ donor for humans. Induction of immunologic tolerance to pig tissues in primates would overcome the major immunologic barriers to xenotransplantation. A proven method of inducing tolerance to allografts is by the induction of mixed hematopoietic chimerism by bone marrow transplantation. We are therefore investigating induction of mixed hematopoietic chimerism in the pig-to-baboon model. METHODS: To obtain large numbers of pig hematopoietic cells, leukapheresis was used to collect blood cell products in miniature swine (n = 5) after progenitor cell mobilization by use of a course of hematopoietic growth factors (cytokines), consisting of porcine interleukin 3, porcine stem cell factor, and human granulocyte colony-stimulating factor. RESULTS: Cytokine therapy and leukapheresis were well tolerated. Cytokine therapy increased the total white blood cell count and allowed large numbers of leukocytes (60 x 10(10)) to be obtained by apheresis, of which approximately 0.1% were granulocyte-erythrocyte-monocyte-megakaryocyte colony-forming units (CFU-GEMMs), which are considered to be representative of hematopoietic progenitors with multi-lineage potential. CONCLUSIONS: The combination of cytokine therapy and leukapheresis enables hematopoietic progenitor cells to be obtained safely from miniature swine.

Animals↗
PubMed1997

Recombinant human and mouse purple acid phosphatases: expression and characterization.

The mammalian purple acid phosphatases (also called tartrate-resistant acid phosphatases) are expressed primarily in actively resorbing osteoclasts and activated macrophages. The enzymes are characterized by the presence of a binuclear iron center at the active site. Recent studies on transgenic mice lacking purple acid phosphatase implicate the osteoclast enzyme in both bone resorption and bone mineralization. To characterize the mammalian enzymes in more detail, particularly with respect to their substrate specificity at the low pH of the osteoclastic resorptive space (2.5-3), we have purified the recombinant human and mouse enzymes from baculovirus-infected insect cells. The properties of the recombinant mouse enzyme are compared with those of the nonrecombinant enzyme isolated from mouse spleen. The kinetics of hydrolysis of the substrates p-nitrophenyl phosphate, phosphotyrosine, and pyrophosphate and a phosphotyrosyl peptide by the recombinant human and mouse enzymes and the nonrecombinant mouse and pig enzymes were analyzed. For all the enzymes the ratio k(cat)/Km was typically approximately 10(6) M(-1) s(-1) and was higher at pH 2.5 than at 4.9. The increase was attributable to a large decrease in Km at the lower pH value. The results indicate that the enzyme exhibits high catalytic efficiency toward substrates such as pyrophosphate and acidic phosphotyrosine-containing peptides, particularly at low pH values typical of the bone resorptive space. The implications of the results for the physiological function of the enzyme are discussed.

Acid Phosphatase↗
PubMed1996

ECT-induced seizure durations.

Electroconvulsive therapy (ECT) efficacy is related to the stimulus intensity and clinically associated with the duration of the induced seizure. Convulsions lasting 30 to 60 seconds are conventionally considered to be of optimal length, and generally are achieved by applying routine ECT technique. An ictus slightly shorter or longer is usually also therapeutically satisfactory. In our study, seizures lasting between 30 and 60 seconds produced a favorable clinical outcome. A very similar effect was observed in all cases where the duration was within 16 to 120 seconds. However, subjects experiencing intal periods of less than 15 seconds and those over 120 seconds resulted in less favorable response. Detailed records as to medicinal and electrical stimulus doses, seizure timings, etc, were excellent guides for subsequent ECT to achieve appropriate convulsion durations and a safe, satisfactory outcome.

Adult↗
PubMed1995

A comparison of stereology and segmentation techniques for volumetric measurements of lateral ventricles in magnetic resonance imaging.

Lateral ventricular volumes were measured on magnetic resonance imaging (MRI) scans by independent raters in 18 subjects (11 psychotic patients and 7 healthy control subjects) with two different approaches: a point-counting stereological (PCS) technique and a computerized technique based on segmentation algorithms. The correlation between the two techniques was very high (r = 0.96), and phantom studies showed good validity for both approaches. These findings and the technical simplicity of the PCS technique support its potential use for MRI morphometric measurements.

Cerebral Ventricles↗
PubMed1994

Roles of Ca2+ influx and intracellular Ca2+ release in agonist-induced contractions in guinea pig trachea.

The contribution of receptor-operated Ca2+ channels (ROCs), voltage-operated Ca2+ channels (VOCs), and intracellular Ca2+ release to contractions induced by a range of stimuli in the guinea pig isolated trachea has been evaluated. In the presence of physiological Ca2+ (1.3 x 10(-3) M), tissue pretreatment with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (4 x 10(-3) M for 5 min) markedly inhibited (> 90%) the contractile responses to a range of agonists. Therefore, under physiological Ca2+ concentration, Ca2+ mobilization from internal stores appeared to make little contribution to maximum contractions. Nifedipine (10(-7) M) or verapamil (10(-5) M) abolished KCl-induced contractions but produced variable inhibition of contractions induced by other agonists. The ROC (and VOC) blocker, SK&F 96365 (10(-5)-10(-4) M), inhibited both KCl-induced contractions and the nifedipine-insensitive component of contractions induced by acetylcholine (ACh), U46619, or leukotriene D4 [half maximal inhibitory concentration (IC50) values 1.7-3.8 x 10(-5) M]. Ni2+, which has ROC- and VOC-blocking actions, also abolished nifedipine-insensitive contractions induced by ACh. When Ca2+ was replaced with Ba2+, the contraction induced by ACh was blocked by nifedipine. Also, under these conditions, ACh did not increase the KCl maximum contraction. These data are consistent with there being distinct ROC and VOC influx pathways in guinea pig trachea and with ROCs playing a significant role in smooth muscle contraction.

Animals↗
PubMed1993

Continuous and discontinuous assays for phosphotyrosyl protein phosphatase activity using phosphotyrosyl peptide substrates.

Assays for phosphotyrosyl protein phosphatase activity have been developed using the synthetic peptide Glu-Glu-Tyr(P)-Ala-Ala and its N alpha-fluorenylmethoxycarbonyl derivative (Fmoc-Glu-Glu-Tyr(P)-Ala-Ala) as substrates. Conditions for monitoring the phosphatase-catalyzed hydrolysis of the former peptide, either spectrophotometrically or fluorometrically, are reported. These continuous assays are similar in sensitivity to published assays using phosphotyrosine as substrate. A discontinuous HPLC-based assay using the intensely fluorescent Fmoc-peptide as substrate is also described. This assay is comparable in sensitivity to assays using 32P-labeled substrates and is suitable for assaying low levels of phosphotyrosyl protein phosphatase activity in crude tissue extracts.

Amino Acid Sequence↗
PubMed1992

Antibodies to soluble human T cell receptor beta chain recognize multiple epitopes on cell surface TcR.

The T cell receptor (TcR) is an integral membrane protein occurring as a disulfide linked heterodimer, non-covalently associated with CD3 on the surface of T lymphocytes. Antibodies to the TcR have been shown to be effective for treating autoimmune disorders in animals. We describe here a method for producing antibodies to cell surface determinants of the human TcR, using a soluble form of the receptor as antigen. Soluble V alpha 1.2, V beta 8.1, V beta 11 TcR chains are expressed from a construct in which the extracellular domains of the TcR are fused to the mouse gamma 2a heavy chain constant region lacking the CH1 domain. These chimeric molecules contain both immunoglobulin and TcR determinants, as revealed by antibody probes. Amino-terminal sequence analysis of a chimeric V beta 8.1 molecule indicates that the TcR leader peptide is correctly processed from the soluble form. Antibodies raised against the soluble human V beta 8.1 molecule recognize the native determinants on Jurkat cells, and on natural T cells derived from resting human peripheral blood lymphocytes. Epitope mapping studies using competitive binding assays suggest that the anti-V beta 8 antibodies produced using soluble antigen recognize multiple overlapping determinants on the cell surface form of the TcR.

Amino Acid Sequence↗