Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

Analysis of physical activity and plasma levels of soluble CD40 and CD40L in older people with gastrointestinal tract cancer.

Regular physical activity prevents and treats cancer patients by assisting and improving the immune system. Co-stimulatory molecules that activate the immune system have been studied in cancer, such as immune checkpoint molecules of the CD40/CD40L pathway. This study aimed to characterize plasma levels of soluble CD40 (sCD40) and CD40 ligand (sCD40L) in older people with gastrointestinal tract (GIT) cancer and associate results with physical activity. This prospective and exploratory cohort study was performed with 24 older people with GIT cancer and 23 healthy elderly individuals as controls. Physical activity level was classified as active or sedentary according to the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Plasma levels of sCD40 and sCD40L were determined using Enzyme-Linked Immunosorbent Assay. Plasma levels of sCD40 were higher, while sCD40L were lower (p = 0.0171) in older people with GIT cancer than controls (p = 0.0038). Regarding physical activity, active older people with GIT cancer presented lower plasma levels of sCD40 and sCD40L than those sedentary with GIT cancer (p = 0.0228 and p = 0.0236), respectively. Our findings suggest that GIT cancer stimulates the immune system in older people, elevates levels of sCD40, and reduces levels of sCD40L. Physical activity may be a protective factor for the immune system of these patients since it acts on sCD40/sCD40L pathway.

Soluble levels of sCD40L and s4-1BB are associated with a poor prognosis in elderly patients with colorectal cancer.

BACKGROUND AND OBJECTIVES: The prognosis of colorectal cancer (CRC) has improved in the last decades, however, a lower overall survival persists in the elderly. The understanding of immunity changes in the elderly with CRC will allow the emergence of new treatments with higher response rates. 4-1BB and CD40L, an immune checkpoint stimulator, play an important role in T-cell responses and platelets. Our aim was to characterize the soluble levels of CD40L and 4-1BB in CRC elderly patients. METHODS: A cross-sectional study was performed in 41 patients with CRC and 35 healthy elderly controls. Patients with CRC were divided into three groups according to staging: 13 patients with advanced tumor restricted to the organ (stages II); 16 patients with lymph node metastasis (stage III); and 12 patients with distant metastasis (stage IV). RESULTS: There were higher levels of soluble s4-1BB and sCD40L in CRC elderly stage II patients when compared with healthy controls (P = .0009 and P < .0001, respectively), stage III patients (P = .008 and P < .0001, respectively) and stage IV patients (P = .007 and P < .0001, respectively). CONCLUSIONS: We concluded that sCD40L and s4-1BB molecules may be prognostic biomarkers, since the reduction in plasma levels of these molecules was associated with disease progression.

Chemokines in pregnant women with sickle cell disease.

Pregnancy in sickle cell disease is a problem due to the adverse outcomes related to the disease. Research into the role of chemokines in sickle cell disease is available, but studies investigating the disease in pregnancy are scarce. Our data show the chemokine profiles of pregnant women with sickle cell disease compared with control groups. There were no differences in MCP-1 level among the groups, but IL-8 and MIG were likely related with disease activity. In addition, levels of IP-10 were higher in pregnant women with sickle cell disease and, interestingly, RANTES levels were higher in normal pregnancy when compared to pregnancy in sickle cell disease. More studies should be encouraged to fully elucidate chemokine activity during pregnancy in sickle cell disease.

Is oxidized low-density lipoprotein the connection between atherosclerosis, cardiovascular risk and nephrolithiasis?

Nephrolithiasis is considered a systemic disease. A link has been established between nephrolithiasis, cardiovascular disease (CVD), the metabolic syndrome and atherosclerosis. A significant correlation has been found between the high levels of oxidized low-density lipoprotein (oxLDL) and CVD and atherosclerosis, including coronary and femoral artery disease. To the best of our knowledge, oxLDL has not been evaluated in patients with nephrolithiasis. This study aimed to evaluate serum levels of oxLDL, anti-oxLDL antibodies (oxLDL-ab) and other markers of atherosclerosis in patients with nephrolithiasis, according to the severity of the disease. The population sample consisted of 94 patients of 30-70 years of age with no symptoms of CVD who presented with renal calculi documented by ultrasonography, abdominal X-ray or computed tomography. The patients were divided into two groups: Group 1 (≥ 3 stones) and Group 2 (1-2 stones). A comparison control group was formed with 21 healthy individuals. Enzyme-linked immunosorbent assays were used to assess oxLDL and oxLDL-ab. Lipid peroxidation indexes were also analyzed. Median serum oxLDL values were higher in Groups 1 and 2 compared to the control group (≥ 3 stones, p = 0.02; 1-2 stones, p = 0.03). Median serum anti-oxLDL antibody levels were lower in the patients in Group 1 compared to the controls (p = 0.03). There was no significant difference in the oxLDL/oxLDL-ab ratio between patients and controls. These findings suggest that this may be the link between nephrolithiasis and the greater incidence of atherosclerosis and cardiovascular disease in patients with kidney stones.

High Levels of CXCL8 and Low Levels of CXCL9 and CXCL10 in Women with Maternal RhD Alloimmunization.

Maternal RhD alloimmunization is an inflammatory response against protein antigens in fetal red blood cells (RBC). However, not all women become alloimmunized when exposed to RhD+ fetal RBC. Thus, this study aimed to evaluate levels of inflammatory chemokines in RhD- pregnant women with erythrocyte alloimmunization. CXCL8, CXCL9, CCL5, and CXCL10 levels were determined from cell culture supernatants by flow cytometry in 46 (30 non-alloimmunized RhD- and 16 previously alloimmunized RhD-) pregnant women. CXCL8 levels were significantly higher (P < 0.004), and CXCL9 (P < 0.008) and CXCL10 (P < 0.003) levels were significantly lower in alloimmunized pregnant women. No significant difference in CCL5 levels was detected between the groups. Fetal RHD genotyping was performed in the alloimmunized RhD- group by real-time PCR. Anti-D alloantibody was detected in 10 mothers and anti-D and -C in six mothers. Twelve fetuses were RHD positive and four were RHD negative. Further studies of serum chemokines and placenta tissue could provide a better understanding of the cells involved in the pathogenesis of maternal erythrocyte alloimmunization.