The effect of an inhibitor of adenylate cyclase on the development of pyrogen,prostaglandin and cyclic AMP fevers in the rabbit

Summary An exotoxin of Bacillus thuringiensis known to inhibit adenylate cyclase in vitro has been used to investigate the role of cyclic AMP in the pathogenesis of fever in the rabbit. Intra-hypothalamic microinjections of the exotoxin are non-pyrogenic and significantly attenuate the hyperthermia caused by intrahypothalamic microinjections of both bacterial pyrogen (endotoxin) and prostaglandin E₁. The hyperthermia produced by dibutyryl cyclic AMP is not affected by the exotoxin. These results support the idea that adenylate cyclase is activated during the development of fever in the rabbit.     

Direct cardiac and vascular actions of adrenomedullin in conscious sheep

1. Adrenomedullin (ADM) is a recently characterized circulating hormone which affects haemodynamic, renal and pituitary function in mammals. We have shown previously that in sheep, ADM produces vasodilatation together with increases in cardiac output and contractility. However, whether these effects are direct or mediated by autonomic reflexes is unclear. The present study examined the cardiovascular actions of an intravenous infusion of ADM in conscious, chronically instrumented sheep with either sympathetic, parasympathetic or autonomic ganglion blockade, to determine the role of the autonomic nervous system in mediating these cardiovascular changes.
2. Human ADM (1–52) was infused for 60 min at 2 μg kg⁻¹ h⁻¹ following: (1) saline control, (2) combined α/β-adrenoceptor (sympathetic) blockade (proporanolol 0.4 mg kg⁻¹ h⁻¹+phentolamine 0.15 mg kg⁻¹ h⁻¹ for 20 h), (3) muscarinic (parasympathetic) blockade (methscopolamine 0.05 mg kg⁻¹ h⁻¹ for 20 h) or (4) ganglion blockade (hexamethonium 3 mg kg⁻¹ h⁻¹ for 4 h). Measurements were made of mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), maximal aortic flow (Fmax) and maximal rate of change of aortic flow (dF/dt).
3. ADM reduced MAP by 3±1 mmHg, and increased CO (1.2±0.2 l min⁻¹), HR (14±2 beats min⁻¹), TPC (21±3 ml min⁻¹ mmHg⁻¹), Fmax (2.3±0.8 l min⁻¹) and dF/dt (86±21 l min⁻¹ s⁻¹) in normal sheep. In animals with α/β blockade, similar changes were observed with ADM. However, during muscarinic blockade, the increases in HR (32±4 beats min⁻¹), CO (2.1±0.4 l min⁻¹), TPC (31±4 ml min⁻¹ mmHg⁻¹), Fmax (4.0±0.6 l min⁻¹), and dF/dt (150±12 l min⁻¹ s⁻¹) produced by ADM were enhanced. During ganglion blockade, ADM produced a greater reduction in MAP (−10±2 mmHg) compared to controls (−3±1 mmHg). However, there was no increase in HR. The changes in CO, TPC and contractility were similar to those observed in control animals.
4. These results suggest that the vasodilator effects of ADM on the periphery and its ability to increase CO and cardiac contractility are not mediated by the autonomic nervous system, but are probably the result of direct actions of ADM on the heart and vasculature.

     

The regulation by phosphorylation of ‘priming' of phospholipase A2 activity in the neutrophil model system,differentiated HL60 cells

1. Differentiated HL60 cells have been utilized as a model system to examine the ‘priming'' of neutrophil phospholipase A₂ activity. In control cells activation of phospholipase A₂ by a 5 min stimulation with the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (100 nM) was essentially undetectable. When cells were primed by preincubation with 5 μM cytochalasin B for 5 min arachidonate release, a measure of phospholipase A₂ activation, was observed within 20 s.
2. Priming by cytochalasin B did not involve or require a change in intracellular free calcium concentration.
3. Priming was associated with an increase in general protein tyrosine phosphorylation and could also be induced by the receptor tyrosine kinase agonist granulocyte macrophage colony-stimulating factor (GM-CSF, 20 ng ml⁻¹) and be mimicked by treatment with the phosphotyrosine phosphatase inhibitor perhydrovanadate (0.5 mM). However, an increase in MAP kinase activity was not involved in the priming process.
4. Western blot analysis demonstrated that phospholipase A₂ was phosphorylated in both control and primed cells, but that an increase in the amount of membrane associated enzyme was found in the primed cells.
5. Thus priming appears to be due to membrane association of the phospholipase and this may be regulated by tyrosine kinase activities.

     

Persistence of effects of nitric oxide synthase inhibitors: Comparisons on blood flow and plasma exudation in guinea pig skin

Plasma protein extravasation has been measured in guinea pig skin using

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-albumin and blood flow using

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enon (

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e) clearance. The nitric oxide (NO) synthase inhibitors N^G-nitro-

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-arginine methyl ester (

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-NAME), N^G-monomethyl-

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-arginine (l

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NMMA) and N^G-nitro-

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-arginine (

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-NOArg) and the α-adrenoceptor agonist, phenylephrine, inhibited bradykinin induced plasma protein extravasation when co-injected with the peptide. The inhibitory effects of

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-NAME and

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-NOArg lasted for up to 8 and 4 h, respectively, whereas phenylephrine and

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-NMMA had no persistent inhibitory effects. When co-injected with

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e,

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-NAME,

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-NMMA,

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-NOArg and phenylephrine, but not

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-NAME, produced significant reductions in skin blood flow. When injected prior to

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e,

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-NAME and

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-NOArg, but not phenylephrine or

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-NMMA, significantly reduced flow. The effect of

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-NAME on flow was not significant at 8 h. Thus, although the inhibitory effects of the NO synthase inhibitors on mediator induced plasma protein extravasation show correlations with their effects on blood flow, the persistent effect of

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-NAME on exudation appears to extend beyond its effect on flow.     

The role of the principal clinical coordinator in the Health Care Financing Administration's Health Care Quality Improvement Initiative

The Health Care Quality Improvement Initiative (HCQII) is the Health Care Financing Administration's latest approach to quality management by peer review organizations (PROs) of the health care delivered to Medicare beneficiaries. The principal clinical coordinator (PCC) of each PRO, a physician with both clinical and methodological expertise, has the overall responsibility for all HCQII-related activities. The PCC works with a clinical coordinating team to analyze patterns of care and provide feedback about these patterns to the medical community for the purpose of improving the quality of care. Each PRO provides its PCC with the necessary infrastructure and expertise to conduct pattern analyses and implement the dissemination process. However, the effectiveness of the HCQII will depend largely on the PCC's ability to maintain the full support and cooperation of the local medical community. The success of the PCC role under the HCQII may enable it to serve as a useful model of physician leadership in the quality oversight organizations that will accompany national health care reform.     

Competencies and problems reported by parents of Greek and American children,ages 6–11

This study compared parent-reported competencies and behavioral/emotional problems in demographically-matched samples of Greek and American children, ages 6–11. Parents of 356 children of each nationality completed the Child Behavior Checklist (CBCL). Competence scores were higher for American children, except on Academic Competence, where scores were higher for Greek children. Greek scores were significantly higher than American scores on the Withdrawn, Anxious/Depressed, Attention Problems, Delinquent Behavior, Aggressive Behavior, Internalizing, Externalizing, and Total Problem scales. On the Anxious/Depressed syndrome, nationality accounted for 14% of the variance. There were few main effects for sex and age and fewer interactions. The higher problem scores in the Greek sample were partly due to the tendency of Greek parents to use extreme item scores. When items were scored present v. absent, Greek scores were higher only on Withdrawn, Anxious/Depressed, Internalizing, and Total Problems, while American scores were higher on Somatic Complaints and Thought Problems. Nationality differences in rates of referral for mental health services and sample differences in exclusion criteria for prior mental health services may have contributed to differences in problem scores. Results are compared to findings from other cross-cultural studies.

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Zusammenfassung Diese Studie vergleicht die Fähigkeiten und Verhaltens- bzw. emotionalen Auffälligkeiten in demographisch parallelisierten Stichproben von griechischen und amerikanischen Kindern im Alter von 6-11 Jahren. Die Eltern von 356 Kindern der beiden Nationalitäten füllten die Child Behavior Checklist (CBCL) aus. Die Kompetenzwerte waren bei den amerikanischen Kindern mit Ausnahme der akademischen Fähigkeiten höher. Die griechischen Werte waren signifikant höher als die amerikanischen im Hinblick auf die Skalen Zurückhaltung, ängstlich/depressiv, Aufmerksamkeitsstörungen, delinquentes Verhalten, aggressives Verhalten, Internalisation, Externalisation und Gesamtauffälligkeiten. Im Hinblick auf das ängstlich/depressive Syndrom war die Nationalität für 14% der Varianz verantwortlich. Nur vereinzelt wurden Haupteffekte im Hinblick auf Geschlecht und Alter und eine geringere Anzahl Interaktionen festgestellt. Die höheren Problemwerte in der griechischen Stichprobe waren teilweise durch die Tendenz der griechischen Eltern bedingt, extreme Werte anzukreuzen. Bei den Items, die als vorhanden bzw. nicht vorhanden gewertet werden mußten, waren die griechischen Werte nur bei den Skalen Zurückhaltung, ängstlich/depressiv, Internalisation und Gesamtprobleme höher, während amerikanische Werte für die Skalen körperliche Beschwerden und Denkstörungen höher lagen. Nationalitätsunterschiede der Zuweisungsraten zu psychosozialen Diensten und Stichprobenunterschieden im Hinblick auf die Ausschlußkriterien für vorangegangene Inanspruchnahme psychosozialer Dienste könnten zu den unterschiedlichen Problemwerten beigetragen haben. Die Ergebnisse werden verglichen mit anderen transkulturellen Studien.

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Résumé Cette étude a comparé les compétences et les problèmes de comportement et affectifs rapportés par les parents d'un échantillon d'enfants grecs et américains âgés de 6 à 11 ans appariés démographiquement. Les parents de 356 enfants de chaque nationalité ont rempli la Child Behavior Checklist (CBCL). Les scores de compétence étaient plus élevés pour les enfants américains excepté pour la compétence scolaire pour laquelle les scores étaient plus élevés chez les enfants grecs. Les scores grecs étaient significativement plus hauts que les scores américains quant au retrait, l'anxiété-dépression, les problèmes d'attention, le comportement délinquant, le comportement agressif, les échelles d'internalisation, d'externalisation et de problèmes totaux. Pour le syndrome anxiodépressif, la nationalité intervenait pour une variance de 14%. Il y avait peu d'effets principaux en ce qui concerne le sexe et l'âge. Les scores de problèmes les plus élevés dans les échantillons grecs étaient en partie dûs à la tendance des parents grecs à utiliser des items extrêmes. Quand les items étaient cotés présents versus absents, les scores grecs étaient plus élevés seulement en ce qui concerne le retrait, l'anxiété-dépression, l'internalisation et les problèmes totaux tandis que les scores américains étaient plus hauts en ce qui concerne les plaintes somatiques et les problèmes de pensée. Les différences de nationalité en ce qui concerne les taux de référence à des services de santé mentale et les différences des échantillons dans les critères d'exclusion pour l'utilisation antérieure de services de santé mentale, peuvent avoir contribué aux différences dans les scores de problèmes. Les résultats sont comparés aux autres études transculturelles.

     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

Predictive coding in the visual cortex: a functional interpretation of some extra-classical receptive-field effects

We describe a model of visual processing in which feedback connections from a higher- to a lower-order visual cortical area carry predictions of lower-level neural activities, whereas the feedforward connections carry the residual errors between the predictions and the actual lower-level activities. When exposed to natural images, a hierarchical network of model neurons implementing such a model developed simple-cell-like receptive fields. A subset of neurons responsible for carrying the residual errors showed endstopping and other extra-classical receptive-field effects. These results suggest that rather than being exclusively feedforward phenomena, nonclassical surround effects in the visual cortex may also result from cortico-cortical feedback as a consequence of the visual system using an efficient hierarchical strategy for encoding natural images.     

Medial temporal lobe atrophy on MRI in dementia with Lewy bodies

OBJECTIVE: To investigate whether medial temporal lobe atrophy (MTA) on MRI is less frequent in dementia with Lewy bodies (DLB) compared with AD and vascular dementia (VaD), and to determine the diagnostic utility of MTA in the differential diagnosis of dementia. METHOD: Coronal T1-weighted 1.0-T MR images were acquired in patients with DLB (consensus criteria; n = 26; mean age, 75.9 years), AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association; n = 28; mean age, 77.4 years), VaD (National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences; n = 24; mean age, 76.9 years), and normal control subjects (n = 26; mean age, 76.2 years). Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized scale. RESULTS: MTA was more frequent and severe in all dementia groups compared with control subjects (AD, 100%; VaD, 88%; DLB, 62%; control subjects, 4%; p < 0.001). Comparing dementia groups, MTA scores were significantly lower in DLB than AD (p = 0.002), with a trend toward less atrophy in DLB compared with VaD (p = 0.07). The absence of MTA had a specificity of 100% and 88% for separating DLB from AD and VaD respectively, and a sensitivity of 38%. In patients with DLB, MTA increased with age (r = 0.58, p = 0.002), and in all dementia patients MTA correlated with memory impairment (combined memory score, r = -0.34, p = 0.003) but not total CAMCOG score or other subscales. CONCLUSION: Patients with DLB have significantly greater MTA than control subjects but significantly less than those with AD. The authors confirmed that the presence of MTA is useful in detecting AD but less useful in differentiating between dementias. However, in the differentiation of DLB from AD and VaD, the absence of MTA is highly suggestive of a diagnosis of DLB.