Sequence-Based analysis of the HLA-DRB1 polymorphism in Metalsa Berber and Chaouya Arabic-speaking groups from Morocco

To examine the genetic diversity in Morocco, the polymorphism at the HLA-DRB1 locus was investigated in two populations: the Metalsa group consisting of Berbers from north Morocco (who speak the Tarifit language and live in the Nador area), and the Chaouya group who are Arabic-speaking people from west Morocco (Atlantic coast) living in the Settat area. The DRB1 alleles of 197 healthy unrelated individuals were identified by direct DNA sequencing of exon 2 using fluorescently-labeled primers. A total of 28 and 29 alleles at DRB1 locus were identified in the Metalsa and Chaouya groups, respectively. The most frequent alleles in the Metalsa group are DRB1*03011 (20.2%), DRB1*0701 (12.12%), and DRB1*1302 (11.11%). In the Chaouya group, DRB1*0701 (16.33%), DRB1*15011 (12.76%), and DRB1*03011 (11.73%) are most common. Each population exhibits some specific variants and some uncommon alleles. The frequency of the DRB1*03011 allele differs significantly between the two populations (p = 0.0311). The DRB1 frequency distributions in the two groups suggest the effects of balancing selection. The interpopulation analysis highlighted a strong relatedness, based on genetic distances, between the two Moroccan groups and the other north Africans (the Moroccans from El Jadida area, Moroccan Souss Berbers, Algerians, and Tunisians), and to a lesser extent with the Iberians, French, and Ethiopians.     

<Superscript>18</Superscript>F-FDG-PET/CT Imaging to Diagnose Septic Emboli and Mycotic Aneurysms in Patients with Endocarditis and Cardiac Device Infections

Purpose of review

This review analyzes recent studies evaluating the diagnostic value of ¹⁸F-FDG-PET/CT for the detection of peripheral emboli and secondary infectious foci in patients with infective endocarditis and cardiac device infections.

Recent findings

Detection of extracardiac septic localizations in patients with infective endocarditis and cardiac device infections is crucial, as it may impact the diagnosis, prognosis, and therapeutic management. Recent literature substantiated the clinical usefulness of ¹⁸F-FDG-PET/CT in this setting.

Summary

¹⁸F-FDG-PET/CT has proven its high diagnostic value for the detection of peripheral emboli in patients with infective endocarditis and cardiac device infections, substantially affecting patients’ outcome and treatment. A multimodal approach, combining the high sensitivity of ¹⁸F-FDG-PET/CT with morphological imaging seems promising.

     

Leptin and Ob-Rb receptor isoform in the human digestive tract during fetal development

CONTEXT: Leptin, partially produced by the stomach, is a hormone involved in energy balance and regulation of food intake. It also regulates some digestive functions through its functional receptor Ob-Rb expressed by gastrointestinal epithelial cells. OBJECTIVE: The objective of the study was to investigate the temporal and spatial appearance of Ob-Rb in the human digestive tract and leptin in the stomach. DESIGN: The esophagus, stomach, and intestine samples of 7- to 24-wk-old human fetuses and adult mucosae were studied by RT-PCR, immunohistochemistry, and Western blot. Leptin was measured by RIA in amniotic fluids at 16-33 wk gestation. RESULTS: All mucosae expressed Ob-Rb (mRNA and/or protein) between 7 and 9 wk gestation. Leptin protein appeared by 8 wk in the gastric mucosa, whereas leptin mRNA was detected around 11 wk. Leptin levels in amniotic fluids were significantly higher during the second than during the third trimester. Overall, Ob-Rb immunoreactivity was higher in young fetuses, during the period corresponding to the formation of gastric buds and primitive intestinal crypts and the beginning of differentiation of epithelial cell types, than in the oldest. Leptin added to culture medium of gastrointestinal explants from 10- to 12-wk-old fetuses appeared to affect DNA synthesis as compared with controls, indicating that leptin receptor functionality was developing. CONCLUSIONS: The strong expression of leptin, in amniotic fluid when fetuses begin swallowing then in the gastric mucosa, and the early presence of Ob-Rb in mucosae suggest a possible role for leptin, exerted endoluminally and in a paracrine pathway, in the developmental process (growth and/or maturation) of the human digestive tract.     

Novel mode for neutrophil protease cathepsin G-mediated signaling: membrane shedding of epidermal growth factor is required for cardiomyocyte anoikis

Neutrophils are thought to orchestrate myocardial remodeling during the early progression to cardiac failure through the release of reactive oxygen species, antimicrobial peptides, and proteases. Although neutrophil activation may be beneficial at early stages of disease, excessive neutrophil infiltration can induce cardiomyocyte death and tissue damage. The neutrophil-derived serine protease cathepsin G (Cat.G) has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis. However, the involved signaling mechanisms for Cat.G are not well understood. This study identifies epidermal growth factor receptor (EGFR) transactivation as a mechanism whereby Cat.G induces signaling in cardiomyocytes. Cat.G induced a rapid and transient increase in EGFR tyrosine phosphorylation, and inhibition of EGFR kinase activity, either with AG1478 or by expression of kinase inactive EGFR mutants (EGFR-CD533), markedly attenuated EGFR downstream signaling and myocyte anoikis induced by Cat.G. Consistent with this effect of EGFR, high level expression of wild-type EGFR was sufficient to promote myocyte apoptosis. We also found that matrix metalloproteinase-dependent membrane shedding of heparin-binding EGF was involved in Cat.G signaling and that membrane type 1 matrix metalloproteinase activation may constitute a potential target that entails matrix metalloproteinase activation induced by Cat.G. The paradoxical proapoptotic effect of EGFR appeared to be dependent on protein tyrosine phosphatase SHP2 (Src homology domain 2-containing tyrosine phosphatase 2) activation and focal adhesion kinase downregulation. These results show that Cat.G-induced cardiomyocyte apoptosis involves an increase in EGFR-dependent activation of SHP2 that promotes focal adhesion kinase dephosphorylation and subsequent cardiomyocyte anoikis.     

Chronic Pain and Psychological Distress Among Undocumented Latinx Immigrants in the USA

BackgroundUndocumented immigration is often accompanied by multiple and complex stressors, which over time may increase the risk for chronic pain.ObjectiveThis study aimed to identify the prevalence of chronic pain and its association with psychological distress among undocumented Latinx immigrants in the USA.Design/ParticipantsWe used respondent-driven sampling to collect and analyze data from clinical interviews with 254 undocumented Latinx immigrants, enabling inference to a population of 22,000.Main MeasuresChronic pain was assessed using the World Health Organization Composite International Diagnostic Interview (CIDI) Chronic Conditions Module. For all analyses, inferential statistics accounted for design effects and sample weights to produce weighted estimates. We conducted logistic regression analyses to assess the association between chronic pain and psychological distress after controlling for age, years in the USA, and history of trauma.ResultsA total of 28% of undocumented Latinx immigrants reported having chronic pain, and 20% of those had clinically significant psychological distress. Significant differences in the prevalence of chronic pain were reported across age groups, years in the USA, and trauma history. After controlling for relevant covariates, chronic pain was significantly associated with psychological distress (OR = 1.06, 95% CI [1.02, 1.09]), age (OR = 1.05, 95% CI [1.02; 1.09]), and history of trauma (OR = 1.10 per additional traumatic event, 95% CI [1.02; 1.19]; C-statistic = 0.79).ConclusionAmong undocumented Latinx immigrants, chronic pain is significantly associated with psychological distress, older age, and trauma history. Given that undocumented immigrants have restricted access to healthcare and are at high risk for chronic pain, developing alternatives to facilitate access to chronic pain interventions and risk-reduction prevention are needed.KEY WORDS: chronic pain, distress, mental health, undocumented immigrants, Latinx

Chronic pain is a global health concern associated with detrimental pathophysiological, functional, economic, and social consequences.¹ Chronic pain is generally defined as continuous or intermittent pain or discomfort that persists for at least 3 months.² Approximately 1.5 billion people live with chronic pain worldwide, with US national estimates exceeding 100 million.³ Furthermore, in the USA, racial/ethnic disparities exist with regards to experiencing chronic pain.¹ For instance, Latinxs tend to report a lower prevalence of chronic pain and less pain interference with daily functioning when compared with non-Latinx whites, but greater pain severity.⁴ Likewise, disparities between these groups exist in accessing, seeking, and responding to treatment for pain.⁴ Nonetheless, less is known about the prevalence of pain and the pain experience among Latinxs who are hidden or hard-to-reach, such as undocumented immigrants.The undocumented immigration path is often accompanied by multiple and complex stressors, which over time may increase the risk for chronic pain. Hazardous working conditions, limited healthcare access, exploitation, and stigmatization are factors that could make undocumented immigrants vulnerable to chronic pain. For instance, undocumented immigrants are more likely than their documented counterparts to undertake physically demanding jobs in industries with high rates of injuries and exposure to hazardous conditions.^5–7 Non-job-related trauma is another cause of pain in immigrants^8,9—approximately 83% of undocumented immigrants report a lifetime history of trauma.¹⁰ Compounding these problems, limited healthcare access and lack of insurance force immigrants to pay out of pocket for healthcare; turn to unsafe or non-evidence-based healing practices (e.g., herbal remedies, hueseros, or bone/muscle therapy); or neglect healthcare altogether.¹¹ All of the aforementioned risk factors suggest that undocumented immigrants may be vulnerable population to chronic pain.Information about the prevalence of chronic pain among undocumented immigrants is needed to inform prevention, intervention, advocacy, and policy efforts. To our knowledge, no prior studies have addressed chronic pain among undocumented immigrants. Therefore, this study aimed to (1) assess the prevalence of chronic pain and associated vulnerabilities, including history of trauma, among undocumented Latinx immigrants residing near the US–Mexico border and (2) determine whether there is an association between chronic pain and psychological distress in this immigrant population.     

CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications

Fas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versus-host disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-alpha, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-alpha. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an inhibitor of caspase-8, the upstream caspase coupled to CD95 death signaling. Vascular lesions are likely to play an important role in the pathogenesis of allogeneic immune responses and of other diseases involving circulating CD95L-expressing cells or smCD95L, and the prevention of CD95-mediated death signaling in endothelial cells may have therapeutic implications in these diseases.