In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

Functional Anatomy of Visuomotor Skill Learning in Human Subjects Examined with Positron Emission Tomography

The present study was designed to examine patterns of regional cerebral blood flow (CBF) associated with the learning of a repeated visuomotor sequence both in the early and late phases of the acquisition process. In addition, changes in blood flow related to the implicit versus explicit aspects of learning such a skill were investigated. Fourteen normal control subjects were scanned while performing the task (i) in both early and advanced learning stages of the visuomotor sequence; (ii) after having acquired explicit knowledge of the sequences; and (iii) in two control conditions (perceptual and random sequence). Subtraction of the random condition from the highly learned condition revealed specific areas of activity in the right ventral striatum and dentate nucleus of the cerebellum. Blood flow changes in the right hemisphere were also seen in the medial posterior parietal and prestriate regions, as well as in the anterior cingulate cortex. Finally, once the subjects had acquired explicit knowledge of the embedded sequence that was presented in the highly learned condition, increased CBF activity was observed only in the mid-ventrolateral frontal area in the right hemisphere. These findings confirm that both the striatum and the cerebellum are involved in the implicit acquisition of a visuomotor skill, especially in the advanced stages of the learning process, and furthermore that the ventrolateral prefrontal cortex contributes preferentially to the declarative aspect of this task.     

Systemic amyloidosis: diagnosis before treatment.

Familial amyloidotic polyneuropathy is a systemic amyloidosis with a dismal prognosis for which a surgical treatment exists. Awareness of the clinical characteristics of the disease is critical for early genetic diagnosis and timely referral for liver transplantation. In this report we describe the history of a 49-year-old man in whom non-AA amyloidotic infiltration of the heart and the intestinal tract was diagnosed. Initially, inappropriate identification of the etiology of the disease led to maltreatment.     

Lutzomyia longipalpis salivary gland homogenate impairs cytokine production and costimulatory molecule expression on human monocytes and dendritic cells

In this report, we describe an investigation of the effects of Lutzomyia longipalpis sand fly salivary gland homogenates (SGH) on cytokine production and expression of costimulatory molecules on human monocytes, macrophages (Ms), and dendritic cells (DCs). SGH of L. longipalpis induced an increase in interleukin-6 (IL-6), IL-8 and IL-12p40 production but a decrease in tumor necrosis factor alpha and IL-10 production by lipopolysaccharida (LPS)-stimulated monocytes. We also examined the expression of costimulatory molecules on the surface of monocytes, Ms, and DCs. Whereas SGH affected the expression of these molecules on monocytes and Ms, it had little effect on these molecules on DCs. However, when DCs were generated from human monocytes in the presence of SGH, SGH inhibited the expression of costimulatory molecules. In addition, a decrease in the maturation of DCs induced by CD40L was observed in the presence of SGH. Finally, preincubating SGH with human sera containing anti-SGH-specific antibodies abolished the effects of SGH on cytokine production by LPS-stimulated monocytes.     

Aboriginal status is a prognostic factor for mortality among antiretroviral naïve HIV-positive individuals first initiating HAART

Background  

Although the impact of Aboriginal status on HIV incidence, HIV disease progression, and access to treatment has been investigated previously, little is known about the relationship between Aboriginal ethnicity and outcomes associated with highly active antiretroviral therapy (HAART). We undertook the present analysis to determine if Aboriginal and non-Aboriginal persons respond differently to HAART by measuring HIV plasma viral load response, CD4 cell response and time to all-cause mortality.     

Increased chloride permeability of amphibian epithelia treated with aldosterone

The transepithelial flux of chloride was increased by aldosterone treatment of amphibian skin and bladder and this was reflected by increased shunt conductance. The hormonal effect depended on the presence of chloride on the epithelial side of the preparation. These changes in tissue conductance and chloride permeability appear to be a direct effect of aldosterone as they did not occur when sodium transport was stimulated with vasopressin or hypotonicity.Chloride efflux was reduced in magnitude by indacrinone and DIDS, as well as after removal of chloride from the solution on the epithelial side of the preparations. These results suggest that, rather than merely diffusing along (a) paracellular pathway(s), chloride flows through (a) cellular structure(s), notably mitochondria-rich cells. These cells can therefore be considered as targets for aldosterone.Presented in part before the Belgian Physiological Society (Beauwens et al. 1985)     

Cesarean Delivery and Risk of Excess Weight Among Brazilian Preschool Children

Maternal and Child Health Journal - To study the relationship between cesarean Delivery (CD) and overweight in preschool children, considering the presence of birth aspects and demographic...     

Comparative study of rest technetium-99m sestamibi SPET and low-dose dobutamine stress echocardiography for the early assessment of myocardial viability after acute myocardial infarction: importance of the severity of the infarct-related stenosis

Rest technetium-99m sestamibi single-photon emission tomography (SPET) has been shown to under-estimate viability in some patients with chronic ischaemic myocardial dysfunction. The present study was designed to appraise the value of^99mTc-sestamibi as a viability tracer in patients with a recent myocardial infarction and to determine factors that might influence its accuracy in assessing infarct size. Therefore, rest^99mTc-sestamibi SPET, low-dose dobutamines stress echocardiography and quantitative coronary angiography were performed in 51 patients with a recent myocardial infarction. Perfusion activity and regional wall motion were scored semi-quantitatively using the same segmental division of the left ventricle. Assessment of^99mTc-sestamibi uptake as a marker of viability was performed by comparing a binary uptake score (viable=>50% vs necrotic =50% of the maximal tracer activity) with a binary wall motion classification during low-dose dobutamine infusion (viable=normal/hypokinetic vs necrotic=akinetic/dyskinetic). Infarct size, expressed as the number of segments with evidence of necrotic tissue, was significantly greater in the scintigraphic study than in the echocardiographic study (2.8±1.5 vs 2.2±1.3,P=0.006). This overestimation of infarct size by^99mTc-sestamibi was present only in patients with a severe infarct-related stenosis (% diameter stenosis 65%–100%) and particularly those with late reperfusion therapy (time delay 180 min). In patients without a severe infarct-related stenosis,^99mTc-sestamibi was able to accurately distinguish viable from necrotic segments. Thus, rest^99mTc-sestamibi scintigraphy early after acute myocardial infarction may underestimate residual viability within the infarct region, particularly in patients with low flow state coronary anatomy, as a result of a severe infarct-related stenosis and/or late reperfusion therapy.This paper was presented in part at the European Nuclear Medicine Congress, Brussels, Belgium, August 1995