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Biomedical subjects

S Cook

Publications and source records attributed to S Cook.

At least 73 records · Page 4Linked to original sources
PubMed1999

Thalamic stimulation in patients with multiple sclerosis.

OBJECTIVE: To assess tremor control and side effects in patients with multiple sclerosis (MS) treated with chronic thalamic stimulation for relief of upper extremity tremor. METHODS: Five patients were studied before and after thalamic placement of a deep brain stimulation (DBS) system. Preoperative and postoperative evaluation included magnetic resonance imaging, Extended Disability Status Scale (EDSS), the Bain-Finchley visual analog scale for tremor, video recording and neuropsychological testing. Stereotactic targeting of the Vim nucleus was done using computed tomography; intraoperative testing was done under local anesthesia before permanent implantation. RESULTS: Functionally useful tremor suppression was obtained in 3/5 patients. Neuropsychological deficits of higher cortical function, memory and visuospatial coordination were observed in all patients before surgery; in 1 patient with improved postoperative visuospatial coordination, worsened memory was found. New brainstem plaque formation was seen several weeks after surgery in 1 patient who had an acute worsening of MS which improved after high-dose intravenous steroids. CONCLUSIONS: Chronic thalamic stimulation may help selected patients with MS-induced tremor. Given the complexity of their underlying illness, patients must be selected carefully, and long-term follow-up is vital to evaluate the true utility of DBS.

Adult↗
PubMed1998

Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome.

The purpose of this study was to determine the effect of exhaustive exercise on cognitive performance of patients with chronic fatigue syndrome (CFS) and sedentary healthy controls (CON). Subjects were 19 women with CFS and 20 CON. A test battery consisting of 4 cognitive tests (CTB) was given pre-, immediately post-, and 24 hours post-treadmill exercise to exhaustion. No differences were seen on the CTB pre-exercise. CFS patients improved at a slower rate than CON on the Symbol Digit Modalities Test (SDMT), Stroop Word Test (SWT), and Stroop Color Test (SCT). When compared with CON, a lower number of correct responses was seen for the CFS immediately postexercise on the SDMT (61 +/- 3 vs 66 +/- 2), SWT (137 +/- 6 vs 146 +/- 6), and SCT (99 +/- 4 vs 107 +/- 3), and 24 hours postexercise on the SDMT (64 +/- 3 vs 69 +/- 2), SWT (134 +/- 7 vs 148 +/- 5), and SCT (101 +/- 4 vs 106 +/- 3). We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.

Adult↗
PubMed1998

Acute opiate overdose: characteristics of 190 consecutive cases.

AIMS: To characterize the population of drug users consulting the Emergency Room (ER) of a university hospital with acute opiate overdose (AOO) and to assess rate of referral to specialized treatment programme. DESIGN: Survey of a 12-month sample of AOO patients. MEASUREMENTS: Medical and psychosocial features of the drug users, details of emergency treatment and referral by a mobile resuscitation team (SMUR) and the ER of our hospital (CHUV-Lausanne, Switzerland). In addition fatal AOO cases were collected by the Institute of Forensic Medicine (IFM) during the same period. FINDINGS: One hundred and eighty-four cases of AOO (134 patients) were treated. The files of the IFM detailed six additional deceased cases. This population of drug users was characterized by an over-representation of men (73%), by young age (27.4 years), by a high rate of multi-drugs use (90%) and by a high rate of multiple previous overdoses (2.6). Average length of stay was 20.1 hours but 41% of cases stayed less than 8 hours. Only one patient was readmitted within an 8-hour period. When discharged, 78% returned home. Unexpectedly, 67% of patients were not referred to any therapeutic programme for drug addiction. CONCLUSION: This study shows the low mortality of AOO when treated but also demonstrates the need to improve psychosocial evaluation and referral of drug addicts admitted with AOO.

Adolescent↗
PubMed1998

Membrane dipeptidase in the pig exocrine pancreas. Ultrastructural localization and secretion.

The GPI-anchored membrane dipeptidase is the major peptidase activity of the secretory granule membrane in the exocrine pancreas. The enzyme is also found in the granule content and in pancreatic secretions. Immunocytochemical localization confirmed its location in the granule membrane and in the acinar cell apical plasma membrane. In the endoplasmic reticulum and Golgi, membrane dipeptidase was strictly membrane-bound. There was no membrane dipeptidase in duct cells. The release of membrane dipeptidase from the membrane starts in the immature granule. To identify the mechanism responsible for its release, secretions were collected from cannulated conscious pig under basal conditions and atropine perfusion. The latter treatment caused complete inhibition of protein secretion but had a negligible effect on membrane dipeptidase activity in the secretions. In secretions, membrane dipeptidase partitioned into the detergent-rich phase on phase separation in Triton X-114, whereas treatment with bacterial phosphatidylinositol-specific phospholipase C caused the peptidase to partition into the aqueous phase, indicating that the secreted enzyme could come from shedding of membrane fragments at the apical surface or via the action of a previously characterized phospholipase A activity.

Animals↗
PubMed1998

Human papillomavirus screening in pediatric victims of sexual abuse.

OBJECTIVE: To evaluate for the presence of subclinical human papillomavirus (HPV) in cases of suspected sexual abuse in children. DESIGN: Prospective data collection via interviews, physical examination, colposcopic examination, and tissue sampling by a surface swab technique. SETTING: A total of 40 pediatric patients ranging in age from 1 to 16 years who were referred to the Special Assessment and Management Clinic at Cardinal Glennon Children's Hospital, St Louis, MO, for probable or confirmed sexual abuse. INTERVENTIONS: In addition to colposcopic examination for physical signs of abuse, the patients were screened for evidence of sexually transmitted diseases, including syphilis, gonorrhea, and Chlamydia. At that time, surveillance sampling of the throat, vaginal introitus, and/or rectum by a simple, rapid surface swab technique was performed to detect the presence of HPV. MEASUREMENTS: Template DNA was extracted from cotton swabs and analyzed using polymerase chain reaction analysis. RESULTS: Human beta-globin sequences were detected in 58 (83%) of 70 specimens obtained from 40 patients, indicating successful processing had occurred. Using a consensus L1 primer-probe set capable of detecting multiple HPV genotypes, 2 (3%) of 58 samples from 2 (5%) of 40 patients were positive for HPV 16. None of the other 56 specimens yielded evidence of HPV. Appropriate positive and negative controls were included in each assay. CONCLUSIONS: Our results suggest that subclinical HPV infection is possible, but not commonly associated with sexual abuse in children from St Louis, MO. In this group of children without condyloma, HPV 16 was the only type identified.

Adolescent↗
PubMed1997

Identification of membrane dipeptidase as a major glycosyl-phosphatidylinositol-anchored protein of the pancreatic zymogen granule membrane, and evidence for its release by phospholipase A.

Membrane dipeptidase (EC 3.4.13.19) enzyme activity that is inhibited by cilastatin has been detected in pancreatic zymogen granule membranes of human, porcine and rat origin. Immunoelectrophoretic blot analysis of human and porcine pancreatic zymogen granule membranes with polyclonal antisera raised against the corresponding kidney membrane dipeptidase revealed that the enzyme is a disulphide-linked homodimer of subunit mass 61 kDa in the human and 45 kDa in the pig. Although membrane dipeptidase was, along with glycoprotein-2, one of the only two major components of carbonate high pH-washed membranes, no enzyme activity or immunoreactivity was detected in the zymogen granule contents. Digestion with bacterial phosphatidylinositol-specific phospholipase C (PI-PLC), and subsequent recognition by antibodies specific for the cross-reacting determinant, revealed that membrane dipeptidase in human and porcine pancreatic zymogen granule membranes is glycosyl-phosphatidylinositol-anchored. Membrane dipeptidase was released from the pancreatic zymogen granule membranes by an endogenous hydrolase, and the released form migrated as a disulphide-linked dimer on SDS/PAGE under non-reducing conditions. Under reducing conditions it migrated with the same apparent molecular mass as the membrane-bound form, and was still a substrate for bacterial PI-PLC. Treatment of kidney microvillar membranes with phospholipase A2 resulted in the release of membrane dipeptidase in a form that demonstrated electrophoretic and cilastatin-Sepharose binding properties identical to those of the endogenously released form of the enzyme from zymogen granule membranes. These results indicate that the glycosyl-phosphatidylinositol anchor on the pancreatic membrane dipeptidase is cleaved by an endogenous hydrolase, probably a phospholipase A, and that this cleavage may promote the release of the protein from the membrane.

Animals↗
PubMed1997

Characterization of two alternately spliced forms of phospholipase D1. Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and Rho family monomeric GTP-binding proteins and protein kinase C-alpha.

We previously reported the cloning of a cDNA encoding human phosphatidylcholine-specific phospholipase D1 (PLD1), an ADP-ribosylation factor (ARF)-activated phosphatidylcholine-specific phospholipase D (Hammond, S. M., Tsung, S., Autschuller, Y., Rudge, S. A., Rose, K., Engebrecht, J., Morris, A. J., and Frohman, M. A. (1995) J. Biol. Chem. 270, 29640-29643). We have now identified an evolutionarily conserved shorter splice variant of PLD1 lacking 38 amino acids (residues 585-624) that arises from regulated splicing of an alternate exon. Both forms of PLD1 (PLD1a and 1b) have been expressed in Sf9 cells using baculovirus vectors and purified to homogeneity by detergent extraction and immunoaffinity chromatography. PLD1a and 1b have very similar properties. PLD1a and 1b activity is Mg2+dependent but insensitive to changes in free Ca2+ concentration. Phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate activate PLD1a and 1b but a range of other acidic phospholipids are ineffective. PLD1a and 1b are highly responsive to activation by GTP-gammaS-liganded ADP-ribosylation factor-1 (ARF-1) and can also be activated to a lesser extent by three purified RHO family monomeric GTP-binding proteins, RHO A, RAC-1, and CDC42. Activation of PLD1a and 1b by the RHO family monomeric GTP-binding proteins is GTP-dependent and synergistic with ARF-1. Purified protein kinase C-alpha activates PLD1a and 1b in a manner that is stimulated by phorbol esters and does not require ATP. Activation of PLD1a and 1b by protein kinase C-alpha is synergistic with ARF and with the RHO family monomeric GTP-binding proteins, suggesting that these three classes of regulators interact with different sites on the enzyme.

Adenosine Diphosphate Ribose↗
PubMed1997

Differential regulation of extracellular signal-regulated protein kinase 1 and Jun N-terminal kinase 1 by Ca2+ and protein kinase C in endothelin-stimulated Rat-1 cells.

The extracellular signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK) signalling cascades transduce signals from the cell cytoplasm to the nucleus, where they regulate gene expression. The activation of ERK1 by lysophosphatidic acid (LPA) and endothelin 1 (Et-1) was compared in Rat-1 cells. Both stimulated DNA synthesis to a similar degree but, in contrast with LPA, Et-1 did not stimulate sustained ERK1 activation, a signal that is thought to be important for the proliferation of fibroblasts. Et-1, but not LPA, was able to activate JNK1; pharmacological analysis revealed that the same EtA receptor mediates DNA synthesis, ERK1 and JNK1 activation. However, activation of JNK1 required higher concentrations of Et-1 than was required for stimulation of ERK1 or DNA synthesis. Signalling to ERK1 and JNK1 was partly inhibited by pertussis toxin, suggesting that both pathways are regulated in part by Gi or G0 proteins. Activation of JNK1 by Et-1 lagged behind ERK1 activation but was not dependent on it because PD98059, an inhibitor of mitogen-activated protein kinase (or ERK) kinase, was without effect on JNK1 activation. In contrast with recent studies, activation of protein kinase C (PKC) or Ca2+ fluxes inhibited activation of JNK1 but not ERK1; furthermore inhibition of PKC or sequestration of Ca2+ potentiated JNK1 activation by Et-1 but not by anisomycin, and again had little effect on ERK1 activation. These results demonstrate that the same G-protein-coupled receptor can activate both the ERK and JNK signal pathways but the two kinase cascades seem to be separate, parallel pathways that are differentially regulated by PKC and Ca2+. The results are discussed in terms of the role of ERK and JNK in proliferative signalling.

Animals↗
PubMed1997

Forebrain overgrowth (fog): a new mutation in the mouse affecting neural tube development.

Forebrain overgrowth, fog, is a spontaneous autosomal recessive mutation in the mouse producing forebrain, lumbo-sacral, and facial defects. The defects appear to result from excessive growth or cellular proliferation leading to abnormalities in neural tube closure. Three unique features of the mutant are: (1) the growth of telencephalon cells into the surrounding mesenchyme, (2) presence of an encephalocele through the midline cleft in some mutants, and (3) dissociation of the tail defect from the caudal neural tube defect. We used an intersubspecific intercross between mice carrying the fog mutation and mice from an inbred Mus musculus castaneus strain (CAST/Ei) to map the fog mutation to mouse Chromosome 10 near D10Mit262 and D10Mit230 in a region with several potential candidate genes.

Abnormalities, Multiple↗
PubMed1997

Expression of superoxide dismutase following axotomy.

Oxidative injury has been implicated in the pathophysiology of neuronal injury and neurodegenerative disease. Antioxidant proteins provide an endogenous defense against such oxidative injury and may yield important clues to mechanisms of cytoprotection and neuronal recovery. Axotomy is the simplest model of neuronal injury and lesioning the sciatic nerve allows concurrent study of both motor (spinal cord) and sensory (dorsal root ganglia, DRG) neurons affected by the same injury. This study was designed to examine the expression of superoxide dismutase (SOD), an essential antioxidant protein, in motor and sensory neurons following complete axotomy of peripheral nerve. Immunocytochemical, quantitative immunoblot, and enzymatic activity assay techniques are used. By 12 days after axotomy, immunocytochemical expression of Mn-SOD is markedly increased in affected DRG and spinal cord. A similar increase in Cu/Zn-SOD is not seen in DRG or spinal cord. This immunocytochemical staining is associated with a significant increase in specific activity and Mn-SOD protein content as measured on quantitative immunoblots. This report suggests, for the first time, that Mn-SOD and not Cu/Zn-SOD increases in sensory neurons of the DRG and motor neurons of the spinal cord following distal axotomy of the sciatic nerve. Quantitative measurements of Mn-SOD following axotomy reveals that the increase in immunocytochemical reactivity is associated with an approximately 30% increase in specific activity when comparing lesioned and contralateral spinal cord samples. These data suggest that Mn-SOD may have a more significant role in the pathophysiology of neuronal injury than Cu/Zn-SOD.

Animals↗
PubMed1997

Cell death and birth in multiple sclerosis brain.

The hallmark of the brain pathology in multiple sclerosis is the white matter plaque, characterized by myelin destruction and oligodendrocyte loss. To examine the role that cell death plays in the development of MS lesions, we used the in situ TUNEL technique, a method that sensitively detects DNA fragmentation associated with death at the single cell level. We found that patchy areas within acute MS lesions have massive numbers of inflammatory and glial cells undergoing cell death. The punched out areas of some long-standing chronic lesions also had labeled glial cells showing that the attack was not a single event. Immunocytochemical identification of the dying cells with glial specific marker co-labeling showed that 14-40% were the myelin-sustaining oligodendroglial cell. Confocal microscopic evaluation of fluorescein-labeled TUNEL positive cells revealed nuclei with morphologic characteristics of apoptosis, and electrophoresed MS brain DNA produced a ladder characteristic of apoptotic DNA cleavage confirming that substantial numbers of labeled cells, but not necessarily all, were dying by apoptotic mechanisms rather than cell necrosis. Companion studies using a marker for cell proliferation on MS lesions revealed that unexpectedly large populations of perivascular inflammatory cells and parenchymal glial cells had entered the cell proliferation cycle. These findings establish that two opposing glial cell responses - relentless cell death and coincident brisk cellular proliferation - are important features of MS pathology. In the end, however, glial cell loss prevails, and we suspect apoptosis may be the critical death mechanism responsible for the depletion of myelin observed in this condition.

Animals↗
PubMed1997

Bacterial keratitis in the critically ill.

BACKGROUND: In the 4 year period (1988-91 there were nine cases of bacterial keratitis in five critically ill patients on an intensive care unit ('unit A'), all except one due to Pseudomonas aeruginosa. Many of these patients had serious ocular complications requiring surgery and all surviving patients were left with significant visual deficits. One further case of keratitis due to P aeruginosa occurred on unit A in April 1993. The problem of keratitis in ventilated patients is not unique to this unit as a further four cases in three patients from additional units in this area have been treated. METHODS: Predisposing factors in unit A were established through subsequent investigations. It was found, in particular, that all the ocular infections were preceded by colonisation of the respiratory tract with the pathogenic organism. Recommendations concerning eye care and tracheal suctioning were adopted by unit A in 1991. RESULTS: In the subsequent 4 years (1991-5), the frequency of isolation of pseudomonas from the respiratory tract per patient treated in unit A remained relatively high at 3.8% (153/4032). However, the conjunctival pseudomonas isolation rate has decreased significantly (p < 0.001) from 0.8% (19/2430) to 0.05% (2/4032). CONCLUSIONS: Ventilated patients may be at risk from inoculation of pathogens into the eyes. The principal risk factor for bacterial keratitis in this series was corneal exposure secondary to conjunctival chemosis or lid damage. The adoption of simple preventative measures on unit A had a significant impact on the incidence of eye infections due to pseudomonas, despite the high proportion of patients whose respiratory tracts were colonised with the same organism. There is a need for additional research into the most effective method of eye care for ventilated patients in order to reduce the frequency of this avoidable condition.

Critical Care↗
PubMed1997

Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

PURPOSE: Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS: Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS: The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION: N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.

Adult↗
PubMed1997

The PATHWAYS church-based weight loss program for urban African-American women at risk for diabetes.

OBJECTIVE: This study was carried out to test the effectiveness of PATHWAYS, a weight loss program designed specifically for urban African-American women, when administered in urban churches by trained lay facilitators. RESEARCH DESIGN AND METHODS: Thirty-nine obese women were recruited from three urban African-American churches. After randomization and the collection of baseline data on weight and lifestyle practices, subjects in the experimental group (n = 19) were assigned to receive a 14-week weight loss program (PATHWAYS) conducted by trained lay volunteers; control group subjects (n = 20) were put on a waiting list to receive the program at the conclusion of the study period. RESULTS: Of the 39 women enrolled, 15 experimental group subjects and 18 control group subjects were available for posttreatment data collection. After completing the program, PATHWAYS participants lost an average of 10.0 lb, and the control group subjects gained an average of 1.9 lb. Posttreatment difference in weight loss between the groups was statistically significant (P < 0.0001). Waist circumference among PATHWAYS participants decreased 2.5 inches, while waist circumference among control group subjects remained relatively the same. This difference between the groups was statistically significant (P < 0.05). CONCLUSIONS: A weight loss program administered by trained lay volunteers was effective in producing significant and clinically meaningful weight loss among African-American women who often do not benefit from typical weight loss programs. Ongoing research is focusing on whether the weight loss can be maintained or enhanced through monthly reinforcement sessions.

Black or African American↗
PubMed1996

Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain.

Immunohistochemical methods were used to search for Fas receptor/Fas ligand system involvement in multiple sclerosis (MS) white matter brain lesions. We found large numbers of Fas ligand (Fas-L)-bearing cells present in two acute lesions and 12 of 16 chronic MS lesions, and very few positive cells in non-inflammatory controls. Four of six brains from non-MS neuropathologic conditions associated with inflammation and white matter disease were, however, also positive for Fas-L. Double staining with cell-specific markers revealed that the pattern of ligand-positive cells in chronic MS lesions was complex and composed of several different cell types which were primarily resident glial cells with a small overlay of macrophages. Fas/APO 1 (CD95) receptor expression in MS tissue was also evaluated and marked upregulation of the receptor was found. In addition, Fas receptor was induced, but to a lesser extent, in numerous control brains. The observations that TUNEL-positive dying cells were present in MS lesions and showed excellent co-localization with Fas-L, indicate that the Fas death system may contribute to plaque pathogenesis and could lead to the development of a new category of therapeutic agents for MS.

Biological Specimen Banks↗