Surface-bound heparin fails to reduce thrombin formation during clinical cardiopulmonary bypass

The hypothesis that heparin-coated perfusion circuits reduce thrombin formation and activity; fibrinolysis; and platelet, complement, and neutrophil activation was tested in 20 consecutive, randomized adults who had cardiopulmonary bypass. Twenty identical perfusion systems were used; in 10, all blood-contacting surfaces were coated with partially degraded heparin (Carmeda process; Medtronic Cardiopulmonary, Anaheim, Calif.). All patients received a 300 U/kg dose of heparin. Activated clotting times were maintained longer than 400 seconds. Cardiopulmonary bypass lasted 36 to 244 minutes. Blood samples for platelet count, platelet response to adenosine diphosphate, plasma beta-thromboglobulin, inactivated complement 3b, neutrophil elastase, fibrinopeptide A, prothrombin fragment F1.2, thrombin-antithrombin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, plasmin alpha 2-antiplasmin complex, and D-dimer were obtained at these times: after heparin was given, 5 and 30 minutes after cardiopulmonary bypass was started, within 5 minutes after bypass was stopped, and 15 minutes after protamine was given. After cardiopulmonary bypass, tubing segments were analyzed for surface-adsorbed anti-thrombin, fibrinogen, factor XII, and von Willebrand factor by radioimmunoassay. Heparin-coated circuits significantly (p < 0.001) reduced platelet adhesion and maintained platelet sensitivity to adenosine diphosphate (p = 0.015), but did not reduce release of beta-thromboglobulin. There were no significant differences between groups at any time for fibrinopeptide A, prothrombin fragment F1.2, or thrombin-antithrombin complex or in the markers for fibrinolysis: D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1, and alpha 2-antiplasmin complex. In both groups, concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex increased progressively and significantly during cardiopulmonary bypass and after protamine was given. Concentrations of D-dimer, alpha 2-antiplasmin complex, and plasminogen activator inhibitor-1 also increased significantly during bypass in both groups. Fibrinopeptide A levels did not increase during bypass but in both groups increased significantly after protamine was given. No significant differences were observed between groups for levels of inactivated complement 3b or neutrophil elastase. Radioimmunoassay showed a significant increase in surface-adsorbed antithrombin on coated circuits but no significant differences between groups for other proteins. We conclude that heparin-coated circuits used with standard doses of systemic heparin reduce platelet adhesion and improve platelet function but do not produce a meaningful anticoagulant effect during clinical cardiopulmonary bypass. The data do not support the practice of reducing systemic heparin doses during cardiac operations with heparin-coated extracorporeal perfusion circuitry.     

Moyamoya and Down syndrome. Clinical and radiological features

BACKGROUND AND PURPOSE: Moyamoya disease is a chronic occlusive cerebrovascular disorder characterized by progressive stenosis of the supraclinoid internal carotid artery, with the secondary development of enlarged basal collateral vessels. It may occur as a primary disease or as a syndrome in association with a variety of conditions, and its pathogenesis remains unexplained. There are relatively few reports describing the occurrence of moyamoya in Down syndrome. The aim of this study is to describe the clinical and radiological features of moyamoya syndrome associated with Down syndrome (MM-DS) and to explore theories of moyamoya pathogenesis in these patients. METHODS: Seven children with MM-DS underwent brain imaging, transfemoral angiography, and serial neurological exams. Neurological deficits, poststroke recovery, radiographic infarct characteristics, and angiographic abnormalities were reviewed. RESULTS: The clinical and radiological features of primary moyamoya disease overlap with those of MM-DS. Hemiplegia and aphasia were the most common presentations. Motor recovery was excellent in five of seven cases. Cerebral infarcts were superficial or deep and can occur in a watershed distribution. Angiography demonstrated involvement of the internal carotid artery and its branches bilaterally in all seven cases and the posterior cerebral arteries in four cases. CONCLUSIONS: The clinical and radiological features of MM-DS overlap with primary moyamoya disease. We postulate that a protein encoded on chromosome 21 may be related to the pathogenesis of moyamoya disease. Although the neuronal substrate is abnormal in Down syndrome patients, recovery from hemiplegic stroke in patients with MM-DS is comparable to recovery in patients with primary moyamoya.     

Peptide amidating activity in human bronchoalveolar lavage fluid

Monitoring respiratory epithelial biology may reveal individuals with incipient lung cancer. The expression of neuroendocrine (NE) markers in pulmonary epithelium is thought to be central to lung development, repair of injury and may contribute to carcinogenesis. In this study, we evaluate several candidate NE markers to determine the feasibility of prospective analysis of clinical specimens. The potential NE markers include the enzyme L-DOPA decarboxylase (DDC), the neuropeptide gastrin releasing peptide (GRP), and peptidyl-glycine alpha-amidating monooxygenase (PAM), the bifunctional enzyme responsible for the final bioactivation step of many neuropeptides. A comparison of PAM activity and DDC levels in 30 lung cancer cell lines indicated that peptide amidating activity may be an indicator of NE status. Bronchoalveolar lavage (BAL) fluid from subjects at risk of developing second primary lung cancer and from volunteers was obtained. The activity of the first PAM enzyme, peptidylglycine alpha-hydroxylating monooxygenase (PHM), ranged from not detectable to 507 pmol/h/mg protein in 57 specimens. The second PAM enzyme, peptidylamidoglycolate lyase (PAL), ranged from not detectable to 414 pmol/h/mg protein in 56 specimens. Using cluster analysis by the average linkage method, a group of enzyme values with PHM greater than 230 pmol/h/mg protein was determined. Long-term follow-up of these patients for new second primary lung cancers may help to determine the potential predictive value of PAM detected in the BAL fluid.     

Somatic mosaicism in a patient with neurofibromatosis type 1

Using loss of heterozygosity analysis, a method designed to detect moderate to large gene deletions, we have identified a new-mutation neurofibromatosis type 1 (NF1) patient who is somatically mosaic for a large maternally derived deletion in the NF1 gene region. The deletion extends at least from exon 4 near the 5' end of the gene to intron 39 near the 3' end. The gene-coding region is, therefore, mostly or entirely deleted, encompassing a loss of > or = 100 kb. We hypothesize that the deletion occurred at a relatively early developmental timepoint, since signs of NF1 in this patient are not confined to a specific body region, as seen in "segmental" NF, and since both mesodermally and ectodermally derived cells are affected. This report provides the first molecular evidence of somatic mosaicism in NF1 and, taken together with a recent report of germ-line mosaicism in NF1, adds credence to the concept that mosaicism plays an important role in phenotypic and genetic aspects of NF1 and may even be a relatively common phenomenon.     

Inflammatory polyarthritis in the community is not a benign disease: predicting functional disability one year after presentation

OBJECTIVE: To predict which patients with early inflammatory polyarthritis presenting to primary care will be functionally disabled one year after presentation, in order to inform treatment and referral decisions. METHODS: The study population consisted of 381 patients notified to the Norfolk Arthritis Register, a primary care based inception cohort of patients with inflammatory polyarthritis. Patients were regarded as functionally disabled if they had a Health Assessment Questionnaire (HAQ) score of one or more. Clinical, laboratory, and demographic variables easily measured at baseline were analyzed for their ability to predict future disability. Recursive partitioning was used to create a simple decision tree to predict those patients who would be disabled at one year. A logistic regression model was generated on a sample of 277 patients and tested on an independent sample of 104 patients. This was compared with other models, one of which consisted of the 1987 ARA criteria. RESULTS: 112 (29%) patients had a HAQ score of at least 1 at one year. The strongest predictors of future disability were a high baseline HAQ, large joint involvement, female sex, and longer disease duration. The decision tree predicted disability accurately in 67% of patients. CONCLUSION: It is possible to predict functional outcome at one year among patients with early inflammatory polyarthritis presenting to primary care using simple clinical variables measured at baseline. Satisfying the 1987 ARA criteria could not be used to predict future disability.     

Dose-rate sparing for micronucleus induction in lymphocytes of controls and ataxia-telangiectasia heterozygotes exposed to 60Co gamma-irradiation in vitro

We investigated the reproducibility of the cytochalasin B micronucleus (MN) assay in irradiated human lymphocytes to assess its suitability in predicting cancer predisposition and response to radiotherapy by virtue of defects in the processing of clastogenic lesions. G0 lymphocytes were exposed to 3.0 Gy 60Co gamma-rays at high (HDR) or low dose-rate (LDR). Six healthy donors were assayed three times each in nine experiments and compared with six ataxia-telangiectasia (A-T) heterozygotes. In controls, significant interexperiment variability in MN yields was observed at HDR and LDR, also in dose-rate sparing (i.e. reduction in MN yield at LDR compared with HDR). Significant inter-individual variability was seen at HDR, but not at LDR or for sparing. Average sparing was 66.4 +/- 4.8%. In spite of the experimental variability, a significant difference between controls and A-T heterozygotes was detected at LDR, and 5/6 heterozygotes had sparing values below the control range. This gives encouragement for the use of this assay in predictive testing if sources of experimental variability can be identified so as to improve discrimination between individuals. HDR and to a lesser extent LDR irradiation induced significant mitotic inhibition, seen as a reduction in binucleate cells after cytocholasin treatment. A positive correlation between mitotic inhibition and MN frequency suggests that similar lesions may be involved in these effects.     

Examination of the relationship between African American adolescents' condom use at sexual onset and later sexual behavior: implications for condom distribution programs

School-based condom distribution programs have generated considerable controversy across the country. In the present study 249 sexually active African American adolescents who did (n = 119) and did not (n = 130) use a condom during their initial sexual experience were compared to assess whether condom use at the onset of sexual activity was associated with later differences in sexual behavior. The results indicated that youths who used a condom from the onset of sexual activity were more likely to have used a condom in the most recent intercourse occasion, less likely to be diagnosed with a sexually transmitted disease (STD) or to combine substance use with sexual activity, endorsed more positive attitudes toward condoms, and were older when they initiated sexual activity. The findings have implications for condom availability programs and indicate that initial condom use was not associated with earlier onset of sexual activity and was associated with higher rates of precautionary behavior among sexually active minority adolescents.     

The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog

The protein Sonic hedgehog (Shh) controls patterning and growth during vertebrate development. Here we demonstrate that it binds Patched (vPtc), which has been identified as a tumour-suppressor protein in basal cell carcinoma, with high affinity. We show that Ptc can form a physical complex with a newly cloned vertebrate homologue of the Drosophila protein Smoothened (vSmo), and that vSmo is coexpressed with vPtc in many tissues but does not bind Shh directly. These findings, combined with available genetic evidence from Drosophila, support the hypothesis that Ptc is a receptor for Shh, and that vSmo could be a signalling component that is linked to Ptc.