Parasite-host interaction in malaria: genetic clues and copy number variation

In humans, infections contribute highly to mortality and morbidity rates worldwide. Malaria tropica is one of the major infectious diseases globally and is caused by the protozoan parasite Plasmodium falciparum. Plasmodia have accompanied human beings since the emergence of humankind. Due to its pathogenicity, malaria is a powerful selective force on the human genome. Genetic epidemiology approaches such as family and twin studies, candidate gene studies, and disease-association studies have identified a number of genes that mediate relative protection against the severest forms of the disease. New molecular approaches, including genome-wide association studies, have recently been performed to expand our knowledge on the functional effect of human variation in malaria. For the future, a systematic determination of gene-dosage effects and expression profiles of protective genes might unveil the functional impact of structural alterations in these genes on either side of the host-parasite interaction

Genetic Evidence of Functional Ficolin-2 Haplotype as Susceptibility Factor in Cutaneous Leishmaniasis

Background: Ficolin-2 coded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity. In this study, we analyzed five functional polymorphisms of the FCN2 gene for their possible association with cutaneous leishmaniasis. Methods: Initially we screened 40 Syrian Arabs for the entire FCN2 gene. We investigated the contribution of FCN2 functional variants in 226 patients with cutaneous leishmaniasis and 286 healthy controls from Syria. Polymorphisms in the promoter regions (2986G/A, 2602G/A, 24A/G) of the FCN2 gene were assessed by TaqMan real time PCR, whereas polymorphisms in exon8 (+6359C/T and +6424G/T) were assessed by DNA sequencing. We also measured serum ficolin-2 levels in 70 control Syrian Arabs and correlated the serum concentrations to FCN2 genotypes and haplotypes respectively. Results: Nine new FCN2 variants including two with non synonymous substitutions in exon6 and exon8 were observed. The homozygous genotypes +6424T/T were distributed more in controls and none in patients (P = 0.04). The AGACG haplotype were observed more in patients than in controls (OR = 2.0, 95%CI 1.2–3.4, P = 0.006). The serum ficolin-2 levels were significantly distributed among the reconstructed ficolin-2 haplotypes (P,0.008) and the haplotype AGACG was observed with higher ficolin-2 levels in 70 control individuals. Conclusion: Our results demonstrate a significant association of FCN2 AGACG haplotype with cutaneous leishmaniasis in a Syrian Arab population. These first results provide a basis for a future study that could confirm or disprove possibl

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Primer pairs utilized for characterization of the entire <i>FCN2</i> gene in 40 Syrian Arabs.

*<p>used only for sequencing.</p

Haploview plot illustrating the linkage disequilibrium of the <i>FCN2</i> functional variants in controls (2A) and patients (2B).

<p>At the top the SNPs are shown according to their succession from the start of translation of the <i>FCN2</i> gene. <i>Empty squares</i> indicate a high degree of LD (LD coefficient D′ = 1) between pairs of markers. Numbers indicate the D′ value expressed as a percentile. <i>Red squares</i> indicate pairs in strong LD with LOD scores for LD ≥70; purple squares, D′ = 1 with LOD >1; <i>white squares</i>, D′ <1.0 and LOD ≤2.</p

Primers and probes employed for genotyping three promoter SNPs in the <i>FCN2</i> gene.

<p>YAK and FAM are the reporter fluorophores Yakima Yellow and Fluorescein, respectively.</p><p>Each probe carries at the 3′-end the dark BBQ (BlackBerry Quencher).</p

Distribution of serum ficolin levels to five major haplotypes (−986/−602/−4/+6359/+6424) in 70 control individuals.

<p>Distribution of serum ficolin levels to five major haplotypes (−986/−602/−4/+6359/+6424) in 70 control individuals.</p

Haploview plot illustrating the linkage disequilibrium of the <i>FCN2</i> promoter region from 40 healthy Syrian individuals.

<p>At the top the SNPs are shown according to their succession from the start of translation of the <i>FCN2</i> gene. <i>Empty squares</i> indicate a high degree of LD (LD coefficient D′ = 1) between pairs of markers. Numbers indicate the D′ value expressed as a percentile. <i>Red squares</i> indicate pairs in strong LD with LOD scores for LD ≥2; purple squares, D′ = 1 with LOD = 2; <i>white squares</i>, D′ <1.0 and LOD ≤2.</p

<i>FCN2</i> haplotypes in Cutaneous Leishmaniasis patients and healthy controls.

<p><i>FCN2</i> haplotypes in Cutaneous Leishmaniasis patients and healthy controls.</p