Kr-81m ventilation imaging: clinical utility in suspected pulmonary embolism

The results of Kr-81m/Tc-99m ventilation-perfusion (VP) lung scintigraphy were correlated with the results of pulmonary angiography for 74 patients suspected of having pulmonary embolism (PE). Among patients having a diagnostic scan, the sensitivity and specificity of scintigraphy were 91% and 94%, respectively. Also, 157 consecutive cases of Kr-81m/Tc-99m VP lung scintigraphy were reviewed, and the frequency of an indeterminate scan was found to be 22%. A similar frequency was found for VP scintigraphy with xenon-133. Of eight patients who had indeterminate scans due to the presence of a single VP mismatch, four were demonstrated to have PE by angiography. Kr-81m is an excellent agent for VP scanning in cases of suspected PE, offering accuracy in diagnosis as well as favorable physical properties.     

Depletion of somatostatin-like immunoreactivity in the rat central nervous system by cysteamine

Selective neurotoxins have been of value in providing a means for specifically interfering with the actions of endogenous neurotransmitter candidates. Others have shown cysteamine (CSH) to deplete the gastrointestinal tract and hypothalamus of rats of immunoreactive somatostatin, suggesting a toxic action of that compound directed against somatostatin-containing cells. The present study further defines the actions of cysteamine on somatostatin in the central nervous system. (CNS). Cysteamine hydrochloride administered subcutaneously results in a depletion of somatostatin-like immunoreactivity (SLI) in the retina, brain, and cervical spinal cord of rats. The effect is demonstrable at doses of 30 mg/kg of body weight and above, occurs within 2 to 4 hr of a single injection of the drug, and is largely reversible within 1 week. The mean depletion of SLI observed within the CNS varies from 38% in cerebral cortex to 65% in cervical spinal cord 24 hr following administration of CSH, 300 mg/kg of body weight, s.c. By gel permeation chromatography, all molecular weight forms of SLI are affected, with the largest reductions in those forms that co-chromatograph with synthetic somatostatin-14 and somatostatin-28. These results indicate that CSH has a generalized, rapid, and largely reversible effect in depleting SLI from the rat CNS.     

The MAP kinase pathway mediates transcytosis induced by TNF-alpha in an in vitro blood-brain barrier model

Cerebral capillary endothelial cells constitute the blood-brain barrier (BBB). In these highly specialized cells, transcellular transports rarely occur, and the presence of tight junctions between them leads to a low paracellular permeability. In order to understand the functions of this barrier, an in vitro model of the BBB has been developed and consists in a co-culture of primary cerebral capillary endothelial cells and glial cells. When these endothelial cells are subjected to an inflammatory agent, such as tumor necrosis factor-alpha (TNF-alpha), in vitro BBB permeability is increased, as indicated by the increase in holotransferrin transcytosis. However, no significant change in the paracellular permeability is observed. In order to understand the molecular mechanisms that underlie these transcytosis processes, we investigated the implication of the mitogen-activated protein kinase (MAPK) signalling pathway, as TNF-alpha is known to activate this kinase family. In the present study, an increase in the activation of p42-44 MAPK is observed after TNF-alpha treatment. Holotransferrin transcytosis as well as p42-44 MAPK activation are inhibited after addition of a p42-44 MAPK pathway inhibitor (UO126) during TNF-alpha challenge. These data suggest that the MAPK pathway is involved in the transcytosis regulation in endothelial cells from an in vitro BBB model.     

Denervation and repeated L-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons: implication of a dopamine D1-dependent mechanism

Motor complications induced through repeated L-DOPA treatment in patients with Parkinson's disease are thought to be the consequence of molecular adaptations that occur in response to repeated dopamine receptors stimulation. Here, we studied the molecular changes taking place in the denervated striatum of unilaterally 6-OHDA-lesioned rats repeatedly treated with L-DOPA alone or combined to the D1 receptor antagonist SCH23390. We looked at the territorial patterns of expression of neurotensin (NT), dynorphin (DYN), enkephalin (ENK) and Nur77 (also known as NGFI-B) mRNA expression in the striatum and contrasted these with markers of glutamatergic transport and dopaminergic receptor functions. The denervation process induced NT and Nur77 mRNA expression in ENK-positive cells. Subsequent repeated L-DOPA treatment led to a sensitization of L-DOPA-induced rotational response and produced a second surge of NT induction, this time limited to DYN-positive cells and preferentially restricted to the lateral striatum. In this specific territory, the number of Nur77-positive cells was decreased, in response to L-DOPA, when compared to the medial part of the lesioned striatum. L-DOPA treatment increased dopamine D3 receptor and glutamate transporter 1 (GLT1) mRNA expression in the lesioned striatum and that, specifically in an area overlapping one of Nur77 decrease and of NT/DYN induction. The concomitant administration of SCH23390 with repeated L-DOPA treatment blocked the development of behavioral sensitization and the appearance of all L-DOPA-induced molecular reorganizations reported above. Our results showed that repeated L-DOPA treatment produces, in a denervated striatum, a complex pattern of genes regulation in both the direct and the indirect striatal output pathways. This phenomenon is located preferentially in a striatal area receiving converging inputs from the thalamus and sensorimotor cortex and is dependent upon D1 receptor stimulation.     

Fluoxetine treatment of prepubescent rats produces a selective functional reduction in the 5-HT2A receptor-mediated stimulation of oxytocin

Various childhood mood disorders are being treated with serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine (Prozac(R)), yet limited data are available on their effects on serotonergic systems prior to maturation. This study investigated the effects of chronic fluoxetine treatment on 5-HT2A serotonin receptor-mediated neuroendocrine responses in young male rats. Prepubescent male rats were treated with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days, a treatment regimen producing maximal changes in postsynaptic 5-HT2A function in adults. Eighteen hours post-treatment, the rats received saline or increasing doses (0.5, 2.0, or 5.0 mg/kg, i.p.) of the 5-HT2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl ((+/-)-DOI). Trunk blood was obtained to determine changes in oxytocin, ACTH, corticosterone, and renin responses. Fluoxetine produced a small ( approximately 6%) but significant reduction in body weight gain, but no changes were observed in basal hormone levels. In both saline- and fluoxetine-treated rats, (+/-)-DOI increased plasma oxytocin levels in a dose-dependent manner. However, the magnitude of the oxytocin responses to all doses of (+/-)-DOI were markedly attenuated ( approximately 50%) in the fluoxetine-treated rats, indicating a functional reduction in the E(max) of 5-HT(2A) receptor-mediated oxytocin responses. In contrast, fluoxetine did not alter the (+/-)-DOI-induced increases in plasma ACTH, corticosterone, or renin. These data provide the first demonstration of selective neuroadaptive responses in 55-HT2A serotonin receptor function due to prepubescent treatment with fluoxetine. These data may be clinically relevant with respect to the use of selective serotonin reuptake inhibitors in children and adolescents.     

Impaired disengagement of attention in young children with autism

BACKGROUND: The present study examined the disengage and shift operations of visual attention in young children with autism. METHODS: For this purpose, we used a simple visual orienting task that is thought to engage attention automatically. Once attention was first engaged on a central fixation stimulus, a second stimulus was presented on either side, either simultaneously or successively. Latency to begin an eye movement to the peripheral stimulus served as the main dependent measure. The two stimulus conditions (simultaneous and successive) provided independent measures of disengaging and shifting attention, respectively. Performance of children with autism was compared to that of children with Down syndrome and a normal group. RESULTS: The main finding was that relative to both comparison groups, children with autism had marked difficulty in disengaging attention. Indeed, on 20% of trials they remained fixated on the first of two competing stimuli for the entire 8-second trial duration. Evidence is also provided for a more subtle problem in executing rapid shifts of attention. CONCLUSIONS: Our findings on disengagement in autism parallel those reported in normal 2-month-olds, in whom attention has been described as 'obligatory'. Discussion focuses on the potential role of general versus domain-specific processes in producing some of the core features of autism.     

Creating a useful vascular center: a statewide survey of what primary care physicians really want

OBJECTIVE: Multidisciplinary vascular centers (VCs) have been proposed to integrate vascular patient care. No studies, however, have assessed referring physician interest or which services should be provided. A statewide survey of primary care physicians (PCPs) was performed to answer these questions. METHODS: Questionnaires were mailed to 3711 PCPs, asking about familiarity with vascular disease, potential VC usage, and services VCs should provide. Univariate and multivariate analysis was used to determine which PCPs would refer patients, the services desired, and which patients would be referred. RESULTS: Of 1006 PCPs who responded, 66% would refer patients to a VC, especially patients younger than 50 years (P<.001) and those with lower extremity disease (P<.001) or abdominal aortic aneurysm (P<.001). PCPs practicing within 50 miles of a VC (P<.001), those in practice less than 5 years (P<.001), and those without specific training in vascular disease during residency (P=.004) were most likely to refer patients. Vascular surgery (97%), interventional radiology (90%), and a noninvasive vascular laboratory (82%) were considered the most important services, and physician educational services (62%) were also desirable. PCPs did not think cardiology, cardiac surgery, smoking cessation programs, or diabetes or lipid management are needed. Reasons for VC nonuse included travel distance (23%), sufficient local services (21%), and insurance issues (12%). Only 16% of PCPs believe that their patients with vascular disease currently receive optimal care. CONCLUSION: There is considerable interest in VCs among PCPs. In contrast to recently described models, VCs need not incorporate cardiology, cardiac surgery, smoking cessation programs, or diabetes or lipid management. VCs should include vascular surgery, interventional radiology, a noninvasive vascular laboratory, and physician educational services.     

Embryonic death and the creation of human embryonic stem cells

The creation of human embryonic stem cells through the destruction of a human embryo pits the value of a potential therapeutic tool against that of an early human life. This contest of values has resulted in a polarized debate that neglects areas of common interest and perspective. We suggest that a common ground for pursuing research on human embryonic stem cells can be found by reconsidering the death of the human embryo and by applying to this research the ethical norms of essential organ donation.     

Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock

OBJECTIVE: To determine whether pressor doses of vasopressin impair organ blood flow in endotoxic shock. DESIGN: Graded doses of vasopressin or phenylephrine, starting at the clinically recommended doses for pressure support in septic shock, were intravenously infused during endotoxic shock. SETTING: University hospital surgical research laboratory. SUBJECTS: Twelve random-bred female Yorkshire pigs. INTERVENTIONS: We measured mean arterial pressure, cardiac output, heart rate, pulmonary artery occlusion pressure, and carotid, mesenteric, renal, and iliac blood flows. MEASUREMENTS AND MAIN RESULTS: Low doses of vasopressin (typically used in the clinical management of septic shock) raised arterial pressure by increasing systemic vascular resistance without a significant preferential effect in the circulations measured. However, moderately greater doses of vasopressin had a very heterogeneous vasoconstrictor action; although there was no significant vasoconstriction in the carotid and iliac circulations, mesenteric and renal blood flows decreased markedly. Furthermore, at pressor doses vasopressin improved cerebral perfusion. CONCLUSIONS: The vasoconstrictor action of exogenous low-dose vasopressin in endotoxic shock does not impair blood flow to any of the vascular beds examined. However, moderately higher doses of vasopressin may induce ischemia in the mesenteric and renal circulations. The data indicate that the safe dose range for exogenous vasopressin in septic shock is narrow and support the current practice of fixed low-dose administration, generally 0.04 units/min and in no case exceeding 0.1 units/min.