Chemokine and Chemokine Receptor Dynamics during Genital Chlamydial Infection

Current design strategies for vaccines against certain microbial pathogens, including Chlamydia trachomatis, require the induction and targeting of specific immune effectors to the local sites of infection known as the mucosal effector sites. Chemokines and their receptors are important mediators of leukocyte trafficking and of the controlled recruitment of specific leukocyte clonotypes during host defense against infections and during inflammation. We analyzed the dynamics of chemokine and chemokine receptor expression in genital mucosae during genital chlamydial infection in a murine model to determine how these molecular entities influence the development of immunity and the clearance of infection. A time course study revealed an increase of up to threefold in the levels of expression of RANTES, monocyte chemotactic protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), macrophage inflammatory protein 1alpha (MIP-1alpha), and intercellular adhesion molecule type 1 (ICAM-1) after genital infection with the C. trachomatis agent of mouse pneumonitis. Peak levels of expression of RANTES, MCP-1, and MIP-1alpha occurred by day 7 after primary infection, while those of IP-10 and ICAM-1 peaked by day 21. Expression levels of these molecules decreased by day 42 after primary infection, by which time all animals had resolved the infection, suggesting an infection-driven regulation of expression. A rapid upregulation of expression of these molecules was observed after secondary infection. The presence of cells bearing the chemokine receptors CCR5 and CXCR3, known to be preferentially expressed on Th1 and dendritic cells, was also synchronous with the kinetics of immune induction in the genital tract and clearance of infection. Results demonstrated that genital chlamydial infection is associated with a significant induction of chemokines and chemokine receptors that are involved in the recruitment of Th1 cells into the site of infection. Future studies will focus on how selective modulation of chemokines and their receptors can be used to optimize long-term immunity against CHLAMYDIA:     

Development of a nucleic acid sequence-based amplification assay that uses gag-based molecular beacons to distinguish between human immunodeficiency virus type 1 subtype C and C' infections in Ethiopia

A gag-based molecular beacon assay utilizing real-time nucleic acid sequence-based amplification technology has been developed to differentiate between the two genetic subclusters of human immunodeficiency virus type 1 (HIV-1) subtype C (C and C') circulating in Ethiopia. Of 41 samples, 36 could be classified as C or C' by sequencing of the gag gene. All 36 isolates were correctly identified by the gag beacon test. Three isolates with genomes that were recombinant in gag were unambiguously typed as belonging to the C' subcluster. Further analysis revealed that these contained the most sequence homology with a reference subcluster C' sequence in the target region of the beacon and hence were correct for the analyzed region. For one sample, sequencing and gag molecular beacon results did not match, while another isolate could not be detected at all by the beacon assay. Overall, high levels of sensitivity and specificity were achieved for both beacons (90.5% sensitivity and 100% specificity for the C beacon and 100% sensitivity and 95.2% specificity for the C' beacon). The availability of a diagnostic test which can quickly and reliably discriminate between C and C' HIV-1 infections in Ethiopia is an important first step toward studying their respective biological characteristics. As the assay is specific to the Ethiopian HIV-1 subtype C epidemic, it will contribute to characterizing the circulating viruses in this population, thereby generating the information necessary for the development of a potential efficacious HIV-1 vaccine appropriate for the Ethiopian context.     

The effect of seizure focus on regional language processing areas

Purpose: To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance. Methods: In this cross‐sectional study we investigated 90 patients (mean age 23.3 ± 12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 ± 8.3 years). Eighteen patients had a frontal lobe focus and 72 had a temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3 Tesla blood oxygen level dependent (BOLD) EPI functional magnetic resonance imaging (fMRI). Data were analyzed in SPM2. Regional laterality indices (LIs) for inferior frontal gyrus (IFG), and Wernicke’s area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed. Key Findings: Mean WA LI was lower for subjects with a mesial temporal focus compared with a frontal focus (p = 0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared with a frontal focus (χ² = 4.37, p = 0.04). WA LI did not differ for subjects with a neocortical focus compared with a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r = ?0.18, p = 0.10), but not IFG LI. Significance: Temporal lobe foci have wide‐ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas.     

Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.     

Corrosive esophageal injuries in children. A shortlived experience in Sierra Leone

OBJECTIVE: Children with caustic ingestions in developing countries are often treated at home, sometimes by traditional healers, or are referred, frequently late, to tertiary hospitals, which only seldom offer adequate endoscopic and dilatation facilities. Therefore, when dilatations are performed, the stricture is often already well established, making dilatation more difficult. The aim of this paper is to report our experience in the management of corrosive injuries in a group of children of Sierra Leone, all complaining accidental ingestion of caustic soda, many of them treated months after the ingestion. METHOD: We considered all children admitted after corrosive ingestion, from November 2001 to November 2005, to the "Emergency" Surgical Center in Goderich-Freetown, Sierra Leone. In December 2005 the hospital was supplied with endoscopes and dilatation devices. The children still followed up clinically were recalled to submit them to an endoscopic follow-up and to a dilatation, if needed. RESULTS: Forty children were admitted (mean age: 4.5 years): 16 (group A) after an esophageal perforation during dilatation performed elsewhere (death rate: 56%). Twenty-four children (group B) were observed after ingestion, 58% being submitted to a surgical gastrostomy. Death rate after ingestion was nil. The mean interval between ingestion and endoscopy was 8.8 months. Fifty-three dilatations were carried out in 17 children over a 3 months period. We report three perforations (17.6%) and a death rate of 5.8% (1/17). Two patients were lost to follow-up. Three patients (17.6%) did not show any improvement. Four children complained recurrent dysphagia after the first dilatation cycle. Overall, 10 children (58.8%) showed a clear-cut improvement at 6 months. CONCLUSIONS: The majority of treated strictures were late, therefore difficult to dilate and at higher risk of perforation. Dilatation with Savary bougies seems safer than with balloon catheters. Recurrent strictures and a long-term dilatation treatment should be expected. Retrograde dilatations through gastrostomies should be the preferred method of treatment and surgical gastrostomies should be performed without hesitation. Esophageal replacement is unlikely in these countries, except in very few referral centres. Therefore, any effort should be made to treat caustic strictures by timely dilatation programs.