The prognostic value of serum troponin T in unstable angina.

BACKGROUND. Cardiac troponin T is a regulatory contractile protein not normally found in blood. Its detection in the circulation has been shown to be a sensitive and specific marker for myocardial cell damage. We used a newly developed enzyme immunoassay for troponin T to determine whether its presence in the serum of patients with unstable angina was a prognostic indicator. METHODS. We screened 109 patients with unstable angina (25 with accelerated or subacute angina and 84 with acute angina at rest) for serum creatine kinase activity, creatine kinase isoenzyme MB activity, and troponin T every eight hours for two days after admission to the hospital. The outcomes of interest during the hospitalization were death and myocardial infarction. RESULTS. Troponin T was detected (range, 0.20 to 3.64 micrograms per liter; mean, 0.78; median, 0.50) in the serum of 33 of the 84 patients (39 percent) with acute angina at rest. Only three of these patients had elevated creatine kinase MB activity (two were positive for troponin T, and one was negative). Of the 33 patients who were positive for troponin T, 10 (30 percent) had myocardial infarction (3 after coronary-artery bypass surgery), and 5 of these died during hospitalization. In contrast, only 1 of the 51 patients with angina at rest who were negative for troponin T had an acute myocardial infarction (P less than 0.001), and this patient died (P = 0.03). Thus, 10 of the 11 patients with myocardial infarctions had detectable levels of troponin T; only 1 had elevated creatine kinase MB activity. Troponin T was not detected in any of the 25 patients with accelerated or subacute angina, and none of these patients died. CONCLUSIONS. Cardiac troponin T in serum appears to be a more sensitive indicator of myocardial-cell injury than serum creatine kinase MB activity, and its detection in the circulation may be a useful prognostic indicator in patients with unstable angina.     

Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium

BACKGROUND: Venous thromboembolism is a leading cause of morbidity and mortality during pregnancy and the puerperium. However, the role of mutations in the prothrombin and factor V genes and other thrombophilic abnormalities as risk factors for thromboembolism in women during pregnancy and the pueperium is not known. METHODS: In a study of 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women, we measured the activity of antithrombin, protein C, protein S, and lupus anticoagulant. We also performed genetic analyses to detect the G1691A mutation in the factor V gene (factor V Leiden), the G20210A mutation in the prothrombin gene, and the C677T mutation in the methylenetetrahydrofolate reductase gene. Blood samples were obtained at least three months post partum or after the cessation of lactation. RESULTS: Among the women with a history of venous thromboembolism, the prevalence of factor V Leiden was 43.7 percent, as compared with 7.7 percent among the normal women (relative risk of venous thromboembolism, 9.3; 95 percent confidence interval, 5.1 to 16.9); that of the G20210A prothrombin-gene mutation, 16.9 percent as compared with 1.3 percent (relative risk, 15.2; 95 percent confidence interval, 4.2 to 52.6); and that of both factor V Leiden and the G20210A prothrombin-gene mutation 9.3 percent as compared with 0 (estimated odds ratio, 107). Assuming an overall risk of 1 in 1500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2 percent, among carriers of the G20210A prothrombin-gene mutation, 0.5 percent, and among carriers of both defects, 4.6 percent, as calculated in a multivariate analysis. CONCLUSIONS: The G20210A prothrombin-gene mutation and factor V Leiden individually are associated with an increased risk of venous thromboembolism during pregnancy and the puerperium, and the risk among women with both mutations is disproportionately higher than that among women with only one mutation.     

Comparative effects ofβ 2-adrenoceptor agonists on intracranial self-stimulation,Sidman avoidance,and motor activity in rats

The effects of -adrenoceptor agonists were compared in various operant behavioral tasks, particularly intracranial self-stimulation (ICSS). Clenbuterol, salbutamol, and terbutaline all reduced responding by rats that lever-pressed for low stimulation intensities. The effects of clenbuterol in this test were completely reversed by propranolol, and those of salbutamol were partly reversed. Intermediate doses of clenbuterol and salbutamol slowed the initiation of rewarding brain stimulation in a shuttlebox but had little or no effect on the termination latencies. However, higher doses of both drugs lengthened the termination latencies. Motor activity was reduced at doses that attenuated ICSS responding. Complete tolerance occurred within 4 days to the effects of clenbuterol and salbutamol on leverpressing ICSS and to the effects of clenbuterol on motor activity. The apparent performance deficits induced by these drugs were overcome by more intense motivation. For example, even at high doses, clenbuterol reduced ICSS leverpressing only partially when animals bar-pressed for high rather than low stimulation intensities. Furthermore, all three drugs failed to alter Sidman avoidance responding at doses up to 100 times those that attenuated ICSS responding. It is concluded that although -adrenoceptor agonists cause apparent sedation in rats, this sedation is limited and shows rapid tolerance.     

Are long hours and hard work detrimental to end-clerkship examination scores?

BACKGROUND: Third-year medical students' complaints focus on the number of hours worked and subsequent lack of study time among three general surgery blocks. We hypothesize that this difference between the surgical blocks does not adversely influence student examination scores. METHODS: Student scores for the academic years 1996-97 to 1997-98 for the National Board of Medical Examiners (NBME) surgery subtests were compiled. A comparison of two "slow" general surgery blocks (B/C) with one "busy" block (A) was made using a two-tailed t test. A multiple regression analysis was also employed. Finally, United States Medical Licensing Examination (USMLE) part I scores were used to determine equivalency of groups. RESULTS: No significant difference existed between block A and blocks B/C in USMLE part I and NBME (P = 0.35 and 0.16 respectively). However, USMLE and rotation sequence influenced NBME scores (P < 0.001). CONCLUSION: The data suggest that no difference exists in examination scores between students assigned to a busy general surgery block versus those students assigned to slow blocks.     

Multiple single units and population responses during inhibitory gating of hippocampal auditory response in freely-moving rats

Paired clicks were presented to awake, freely-moving rats to examine neuronal activity associated with inhibitory gating of responses to repeated auditory stimuli. The rats had bundles of eight microwires implanted into each of four different brain areas: CA3 region of the hippocampus, medial septal nucleus, brainstem reticular nucleus, and the auditory cortex. Single-unit recordings from each wire were made while the local auditory-evoked potential was also recorded. The response to a conditioning stimulus was compared to the response to a test stimulus delivered 500 ms later: the ratio of the test response to the conditioning response provided a measure of inhibitory gating. Auditory-evoked potentials were recorded at all sites. Overall, brainstem reticular nucleus neurons showed the greatest gating of local auditory-evoked potentials, while the auditory cortex showed the least. However, except for the auditory cortex, both gating and non-gating of the evoked response were recorded at various times in all brain regions. Gating of the hippocampal response was significantly correlated with gating in the medial septal nucleus and brainstem reticular nucleus, but not the auditory cortex. Single-unit neuron firing in response to the clicks was most pronounced in the brainstem reticular nucleus and the medial septal nucleus, while relatively few neurons responded in the CA3 region of the hippocampus and the auditory cortex. Taken together, these data support the hypothesis that inhibitory gating of the auditory-evoked response originates in the non-lemniscal pathway and not in cortical areas of the rat brain.     

Differentiation of a unique macroglial cell type in the pecten oculi of the chicken

Glial cells in the CNS of vertebrates serve specialized functions in close interaction with surrounding neurons and blood vessels. In the avian eye, the neural tissue (retina) and the supporting vascular structure (pecten oculi) are spatially separated and comprise distinct glial cell types, i.e., the Müller glia and the pecteneal glia, respectively. In the present study we combined morphological and immunocytochemical investigations on the differentiation of the pecteneal glia in comparison to the retinal Müller glia, the retinal pigment epithelium, and the astrocytic cells of the optic nerve head in order to elucidate the nature, origin, and function of the pecteneal glia. Conventional transmission electron microscopy and freeze-fracture imaging revealed striking similarities between the pecteneal glia and retinal pigment epithelial cells at the transition zone to the optic nerve head. Immunofluorescence investigation identified specific labeling for vimentin and glutamine synthetase (GS) but not for glial fibrillary acidic protein (GFAP) in the mature pecteneal glia. Immunogold labeling confirmed the cellular specificity. GS labeling was weak during embryonic development but increasingly strong after hatching. Surprisingly, the intraneuroectodermal endothelial cells were highly immunopositive for GS throughout embryonic development and lost GS expression after hatching. GS expression in the pecteneal glia may participate in pH-regulation of the avian eye. Endothelial GS expression in the developing CNS may detoxify detrimental ammonium concentrations resulting from egg yolk degradation.     

Acute dyskinesias in monkeys elicited by halopemide,mezilamine and the “antidyskinetic” drugs,oxiperomide and tiapride

Oxiperomide and tiapride are dopamine receptor antagonists claimed to have antidyskinetic properties in animal models and in the clinic. Halopemide and mezilamine are other dopamine antagonists predicted to lack extrapyramidal side effects in man on the basis of animal studies. Acute dyskinesias, a neuroleptic-induced acute extrapyramidal syndrome, were elicited in squirrel monkeys by oxiperomide (1 mg/kg), tiapride (30 mg/kg), and halopemide (10 mg/kg). The dyskinesias were virtually indistinguishable from those caused by a standard behaviorally equivalent dose of haloperidol (1.25 mg/kg PO) in the same individual monkeys. Mezilamine (0.3 mg/kg) also induced dyskinesias, which appeared to be less pronounced than those following haloperidol. The antidyskinetic properties of oxiperomide and tiapride evidently do not confer protection against dyskinetic movements induced by dopamine antagonism.     

Recommendations for ICT use in Alzheimer’s disease assessment: Monaco CTAD expert meeting

Alzheimer disease (AD) and other related dementia represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments for assessing disease severity and disease progression to optimize patient’s care and support to care providers, and also provide better tools for clinical research. In this area, Information and Communication Technologies (ICT) are of particular interest. Such techniques enable accurate and standardized assessments of patients’ performance and actions in real time and real life situations. The aim of this article is to provide basic recommendation concerning the development and the use of ICT for Alzheimer’s disease and related disorders. During he ICT and Mental Health workshop (CTAD meeting held in Monaco on the 30th October 2012) an expert panel was set up to prepare the first recommendations for the use of ICT in dementia research. The expert panel included geriatrician, epidemiologist, neurologist, psychiatrist, psychologist, ICT engineers, representatives from the industry and patient association. The recommendations are divided into three sections corresponding to 1/ the clinical targets of interest for the use of ICT, 2/ the conditions, the type of sensors and the outputs (scores) that could be used and obtained, 3/ finally the last section concerns specifically the use of ICT within clinical trials.     

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib

Actual BCR-ABL kinase inhibition in vivo as determined by phospho-CRKL (pCRKL) monitoring has been recognized as a prognostic parameter in patients with chronic myelogenous leukemia treated with imatinib. We report a biomarker sub-study of the international phase I clinical trial of nilotinib (AMN107) using the established pCRKL assay in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. A minimum dose (200 mg) required for effective BCR-ABL inhibition in imatinib resistant/intolerant leukemia was determined. The pre-clinical activity profile of nilotinib against mutant BCR-ABL was largely confirmed. Substantial differences between peripheral blood baseline pCRKL/CRKL ratios were observed when comparing chronic myeloid leukemia with Ph+ acute lymphoblastic leukemia. Finally, rapid BCR-ABL-reactivation shortly after starting nilotinib treatment was seen in acute lymphoblastic leukemia patients with progressive disease carrying the P-loop mutations Y253H, E255K, or mutation T315I. Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib.