SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Adaptation of adherent-invasive E. coli to gut environment: Impact on flagellum expression and bacterial colonization ability

ABSTRACT

The pathogenesis of Crohn's disease (CD) is multifactorial and involves genetic susceptibility, environmental triggers and intestinal microbiota. Adherent-invasive Escherichia coli (AIEC) are flagellated bacteria more prevalent in CD patients than in healthy subjects and promote chronic intestinal inflammation. We aim at deciphering the role of flagella and flagellin modulation by intestinal conditions. AIEC flagellum expression is required for optimal adhesion to and invasion of intestinal epithelial cells. Interestingly, differential flagellin regulation was observed between commensal E. coli (HS) and AIEC (LF82) strains: flagellum expression by AIEC bacteria, in contrast to that of commensal E. coli, is enhanced under intestinal conditions (the presence of bile acids and mucins). Flagella are involved in the ability of the AIEC LF82 strain to cross a mucus layer in vitro and in vivo, conferring a selective advantage in penetrating the mucus layer and reaching the epithelial surface. In a CEABAC10 mouse model, a non-motile mutant (LF82-ΔfliC) exhibits reduced colonization that is restored by a dextran sodium sulfate treatment that alters mucus layer integrity. Moreover, a mutant that continuously secretes flagellin (LF82-ΔflgM) triggers a stronger inflammatory response than the wild-type strain, and the mutant's ability to colonize the CEABAC10 mouse model is decreased. Overexpression of flagellin in bacteria in contact with epithelial cells can be detrimental to their virulence by inducing acute inflammation that enhances AIEC clearance. AIEC pathobionts must finely modulate flagellum expression during the infection process, taking advantage of their specific virulence gene regulation to improve their adaptability and flexibility within the gut environment.     

Limitations of IL-2 and Rapamycin in Immunotherapy of Type 1 Diabetes

Administration of low-dose interleukin-2 (IL-2) alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent-onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (T_reg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000–500,000 IU daily) as well as low-dose IL-2 (25,000 IU daily) and RAPA (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of T_reg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on T_reg cells, failed to control IL-2–boosted NK cells, and broke IL-2–induced tolerance in a reversible way. Notably, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.In type 1 diabetes (T1D), the immune system destroys the pancreatic β-cells (1). At clinical onset, ∼30% of β-cells are still able to produce insulin (2), thus stopping autoimmune destruction, which at this stage is a promising approach (3). Along the same lines, there is a growing list of phase I/II clinical trials based on immunomodulation that are currently being conducted in T1D patients (4).NOD mice, which develop spontaneous T1D, represent an accepted model for testing new therapies (5), the gold standard being that treatments that cure overt hyperglycemia in these mice may be most appropriate for translation into the clinic, as was the case for anti-CD3 antibodies (Abs) (6), which have been tested in patients with promising results (7). In addition, results from our own group showing that low-dose interleukin-2 (IL-2) can prevent (8) and revert disease in NOD mice (9) have led to the translation of this strategy into clinical trials in T1D patients (clinical trial reg. no. {"type":"clinical-trial","attrs":{"text":"NCT01353833","term_id":"NCT01353833"}}NCT01353833, clinicaltrials.gov).We have shown that in NOD mice, administration of low-dose IL-2 for 5 days induced the remission of new-onset T1D by specifically boosting regulatory T cells (T_reg cells) in the pancreas without activating pathogenic effector T cells (T_eff cells). However, remission was obtained in only 60% of treated mice, and half of them became diabetic again during the following months (9). Consequently, improving IL-2 therapy by optimizing dosing or combining IL-2 with other immunomodulatory drugs, such as rapamycin (RAPA), could be of great importance for the goal of translating this therapy to humans.RAPA has been used in clinical transplantation for many years (10), and it has been safely administered to T1D patients during islet transplantation (11,12). In mice, RAPA monotherapy can prevent T1D development (13); however, it is unable to induce disease reversal (14). Moreover, RAPA and IL-2 were found to be synergistic for the prevention of diabetes in NOD mice (13). Consequently, we decided to test whether RAPA could synergize with short-term IL-2 therapy to reverse T1D and reinforce the development of long-term tolerance.In this work, we have further studied the mechanisms of action of IL-2 and RAPA alone or in combination in the NOD model of T1D.     

Significance of T wave normalization in the electrocardiogram during exercise stress test

Although normalization of previously inverted T waves in the ECG is not uncommon during exercise treadmill testing, the clinical significance of this finding is still unclear. This was investigated in 45 patients during thallium-201 exercise testing. Patients with secondary T wave abnormalities on the resting ECG and ischemic exercise ST segment depression were excluded. On the thallium-201 scans, the left ventricle was divided into anterior-septal and inferior-posterior segments; these were considered equivalent to T wave changes in leads V1 and V5, and aVF, respectively. A positive thallium-201 scan was found in 43 of 45 (95%) patients and in 49 of 52 (94%) cardiac segments that showed T wave normalization. When thallium scans and T wave changes were matched to sites of involvement, 76% of T wave normalization in lead aV, was associated with positive thallium scans in the inferior-posterior segments, and 77% of T wave normalization in V1 and V5 was associated with positive thallium scans in the anterior-septal segments. These site correlations were similar for reversible and fixed thallium defects, and for patients not on digoxin therapy. Similar correlations were noted for the sites of T wave changes and coronary artery lesions in 12 patients who had angiography. In patients with a high prevalence for coronary artery disease, exercise T wave normalization is highly specific for the presence of the disease. In addition, it represents predominantly either previous injury or exercise-induced ischemic changes over the site of ECG involvement, rather than reciprocal changes of the opposite ventricular wall.     

Non-traumatic coma in young children in Benin: are viral and bacterial infections gaining ground on cerebral malaria?

Background::While malaria morbidity and mortality have declined since 2000, viral central nervous system infections appear to be an important, underestimated ca...     

Dramatically decreased therapeutic efficacy of chloroquine and sulfadoxine-pyrimethamine, but not mefloquine, in southern Benin

OBJECTIVE: To evaluate the in vivo therapeutic efficacy of chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and mefloquine (MQ) in children presenting with uncomplicated malaria in Benin. METHODS: Drug efficacy was tested according to the WHO in vivo 28-day protocol. For failures that occurred after 7 days of follow-up, paired pre- and post-treatment blood samples were genotyped at msp1 and msp2 loci to distinguish new infections and recrudescent strains. Children enrolled were randomly assigned to a therapeutic group (CQ, n=14; SP, n=42; MQ, n=44). The number of CQ treatment was intentionally restricted after 1 month, as its use was considered to constitute a danger for children. RESULTS: Chloroquine and SP showed very high failure rates (85.7% and 50%, respectively), whereas MQ treatment was successful in 97.5%. The molecular tool allowed to re-evaluate two new infections previously considered as failures. CONCLUSIONS: Chloroquine should no longer be used to treat children presenting with Plasmodium falciparum malaria in Benin.     

SPECT brain imaging in Alzheimer's disease during treatment with oral tetrahydroaminoacridine and lecithin.

Quantitative SPECT brain imaging was performed in five normal subjects and in six ambulatory patients with Alzheimer's disease before the initiation of treatment with tetrahydroaminoacridine (THA) and lecithin. Imaging data were acquired with a single-head SPECT camera and a high-resolution collimator after the intravenous injection of 5 mCi of (p,5n) I-123 IMP. Uptake per pixel in 28 regions of interest in the transverse projection of each study was normalized to uptake per pixel in the cerebellum. Perfusion in the patients with Alzheimer's disease was decreased compared with that of the subjects. Perfusion was decreased greater than 2 SD below the mean in the posterior parietal cortex of 5/6 patients, in the temporal cortex of 3/6 patients, and in the frontal cortex of 2/6 patients with Alzheimer's disease. SPECT imaging was repeated in the six patients after initial titration to peak therapy with oral THA (75 to 200mg per day). The same abnormalities were again seen in the same patients. No dramatic clinical or behavioral change in cerebral perfusion was observed from initial treatment of Alzheimer's disease with THA and lecithin.     

Genetic diversity of influenza A(H3N2) viruses in Northern Cameroon during the 2014-2016 influenza seasons

In Cameroon, genome characterization of influenza virus has been performed only in the Southern regions meanwhile genetic diversity of this virus varies with respect to locality. The Northern region characterized by a Sudan tropical climate might have distinct genetic characterization. This study aimed to better understand the genetic diversity of influenza A(H3N2) viruses circulating in Northern Cameroon. Sequences of three gene segments (hemagglutinin (HA), neuraminidase (NA) and matrix (M) genes) were obtained from 16 A(H3N2) virus strains collected during the 2014 to 2016 influenza seasons in Garoua. The HA gene segments were analysed with respect to reference strains while the NA and M gene was analysed for reported genetic markers of resistance to antivirals. Analysis of the HA sequences revealed that majority of the virus strains grouped together with the 2016-2017 vaccine strain (3C.2a-A/Hong Kong/4801/2014) while 3/5 (60%) of the 2015 viral strains grouped together with the 2015-2016 vaccine strain 3C.3a-A/Switzerland/9715293/2013. Within clade 3C.2a, Northern Cameroon sequences mostly grouped in sub-clade A3 (10/16). Analysis of the coding regions of the NA and M genes showed that none had genetic markers of resistance to neuraminidase inhibitors but all strains possessed the S31N substitution of resistance to amantadine. Due to some discrepancies observed in this region with respect to the Southern regions of Cameroon, there is necessity of including all regions within a country in the sentinel surveillance of influenza. These data will enable to track changes in influenza viruses in Cameroon.