Endothelial Repair and Regeneration Following Intimal Injury

Coronary artery intervention using device implants significantly reduce the risk of restenosis and the need for revascularization but are associated with endothelial denudation and impaired function. This may be due to incomplete endothelial recovery as a result of intimal injury, presence of polymer and/or high antiproliferative drug accumulation in the intima. The permanent presence of a metal prosthesis or polymer may impair the proliferation of resident endothelial cells to cover empty areas. Attention has focused on the robust replenishment of endothelial monolayer by recruitment of circulating endothelial progenitor cells derived from the bone marrow to areas of endothelial injury. The balance between endothelial damage and repair is critical for the maintenance of intimal integrity, function, and prevention of thrombotic complications. This review will discuss on the aftereffects of intravascular device implants on endothelial injury and the pathways involved in endothelial repair and regeneration with an emphasis on endothelial progenitor cells.     

Calcium,Magnesium, Iron,Zinc and Copper,Compositions of Human Milk from Populations with Cereal and ‘Enset’ Based Diets

Background

As breast milk is normally the only source of food in the early stages of life, the dietary levels of the essential elements in the milk of lactating mothers are significantly important. Ethiopia is a country of many nations and nationalities with distinct dietary habits. This variation in food habit may result in the variation of the nutritional quality of milk of lactating mothers who live in different part of the country, which in turn may affect the intake of nutrients by breast-fed infants. Therefore, a cross-sectional study of the levels of Ca, Mg, Fe, Zn and Cu in milk of mothers from societies with cereal and ‘enset’ based dietary habits was carried out to assess the influence of maternal diet on the levels of the elements in human milk.

Methods

Milk samples were collected from 27 voluntary mothers in Jimma and in 18 rural areas of Welkite. Breast milk samples were collected within four days postpartum and the concentrations of the elements were determined by using FAAS.

Results

Average concentrations (mg/L) of the elements determined in the milk of mothers from Jimma and rural Welkite respectively were: Ca (758 ± 107, 579 ± 168); Mg (22.6 ± 7.87, 30.5 ± 13.4); Fe (0.50 ± 0.08, 0.41 ± 0.17); Zn (2.3 ± 1.2, 2.49 ± 0.88) and Cu (0.28 ± 0.14, 0.16 ± 0.08).

Conclusions

Milk samples from Jimma were found to have significantly higher levels of Ca and Cu than those of rural Welkite (P < 0.05). Breast milk Ca and Cu levels were thus found to be influenced by dietary intake.     

An evaluation of the diagnostic value of clinical and radiological manifestations in patients attending the addis ababa tuberculosis centre.

Our investigation is based on 1,000 consecutive patients attending the routine outpatient services of the Addis Ababa Tuberculosis Demonstration and Training Centre (ATBDTC) in Addis Ababa during the period November 1996-March 1997. By using sputum microscopy for acid-fast bacilli (AFB), chest radiography (CXR) and clinical assessment these patients had been diagnosed as having either AFB-positive pulmonary tuberculosis (PTB) (n = 139), AFB-negative PTB (n = 61) or non-tuberculosis (non-TB) (n = 800). These three diagnostic groups were subsequently re-assessed by us with regard to selected demographic and clinical parameters, including CXR, in order to identify and weight markers significantly linked to proven PTB. The sum of the individual weights provided diagnostic scores (DS); the average DS for AFB-positive patients was 653.5 +/- 174 and that for non-TB patients was 219.1 +/- 138.7. The calculated cut-off value between these two groups was 444. Ten (7.2%) AFB-positive PTB patents had a DS below the calculated cut-off, while 46 (5.8%) of the 800 non-TB cases had diagnostic scores exceeding this value. Our DS system achieved 92.8% sensitivity and 94.3% specificity, with positive and negative predictive values of 73.7% and 98.7%, respectively. When plotting the individual DS values of the 61 AFB-negative TB patients, 24 (39.3%) fell below the cut-off. It is most likely that these patients did not have PTB. We conclude that there is a need for improved and standardized diagnostic approaches for TB-suspected patients who depend upon clinical and CXR criteria for correct diagnosis. Our score system may be helpful in this context.     

Evaluation of functional recovery of recurrent laryngeal nerve using transoral laryngeal bipolar electromyography: a rat model

OBJECTIVES: We developed a standardized method of minimally invasive transoral laryngeal (ToL) bipolar electromyography (EMG) for evaluation of recurrent laryngeal nerve (RLN) recovery after a controlled crush injury in a rat model. METHODS: Ten 200- to 250-g Sprague-Dawley rats underwent a controlled crush injury to the left RLN performed with 60 seconds of use of a calibrated aneurysm clamp with a closing force of 0.61 N. Serial ToL bipolar EMG was performed on adductor muscles and the posterior criocoarytenoid muscle during spontaneous vocal fold motion under anesthesia. Each animal underwent ToL EMG immediately after surgery and 1, 3, and 6 weeks after surgery. RESULTS: The EMG signals showed normal motor unit potentials and recruitment patterns 3 weeks after crush injury. Endoscopic evaluation of vocal fold mobility yielded consistently normal findings 6 weeks after crush injury. CONCLUSIONS: We have developed a standardized method of crush injury to the rat RLN model and a minimally invasive transoral bipolar spontaneous EMG technique to serially evaluate and follow nerve injury and recovery in rats. This model is intended to simulate intraoperative RLN injury, to elucidate the electrophysiological events that occur during nerve recovery, and to form the basis for studying agents to enhance such recovery.     

Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses are enveloped, positive-sense, and single-stranded RNA viruses, many of which are zoonotic pathogens that crossed over into humans. Seven coronavirus species, including SARS-CoV-2, have been discovered that, depending on the virus and host physiological condition, may cause mild or lethal respiratory disease. There is considerable variation in disease prevalence and severity across populations and communities. Importantly, minority populations in the United States appear to have been disproportionally affected by COVID-19 (1, 2). For example, in Chicago, more than 50% of COVID-19 cases and nearly 70% of COVID-19 deaths are in African Americans (who make up 30% of the population of Chicago) (1). While social and economic factors are largely responsible for driving COVID-19 health disparities, investigating genetic diversity at host genes related to SARS-CoV-2 infection could help identify functionally important variation, which may play a role in individual risk for severe COVID-19 infection.In this study, we focused on four key genes playing a role in SARS-CoV-2 infection (3). The ACE2 gene, encoding the angiotensin-converting enzyme-2 protein, was reported to be a main binding site for severe acute respiratory syndrome coronavirus (SARS-CoV) during an outbreak in 2003, and evidence showed stronger binding affinity to SARS-CoV-2, which enters the target cells via ACE2 receptors (3, 4). The ACE2 gene is located on the X chromosome (chrX); its expression level varies among populations (5); and it is ubiquitously expressed in the lung, blood vessels, gut, kidney, testis, and brain, all organs that appear to be affected as part of the COVID-19 clinical spectrum (6). SARS-CoV-2 infects cells through a membrane fusion mechanism, which in the case of SARS-CoV, is known to induce down-regulation of ACE2 (7). Such down-regulation has been shown to cause inefficient counteraction of angiotensin II effects, leading to enhanced pulmonary inflammation and intravascular coagulation (7). Additionally, altered expression of ACE2 has been associated with cardiovascular and cerebrovascular disease, which is highly relevant to COVID-19 as several cardiovascular conditions are associated with severe disease. TMPRSS2, located on the outer membrane of host target cells, binds to and cleaves ACE2, resulting in activation of spike proteins on the viral envelope and facilitating membrane fusion and endocytosis (8). Two additional genes, DPP4 and LY6E, have been shown to play an important role in the entry of SARS-CoV-2 virus into host cells. DPP4 is a known functional receptor for the Middle East respiratory syndrome coronavirus (MERS-CoV), causing a severe respiratory illness with high mortality (9, 10). LY6E encodes a glycosylphosphatidylinositol-anchored cell surface protein, which is a critical antiviral immune effector that controls coronavirus infection and pathogenesis (11). Mice lacking LY6E in hematopoietic cells were susceptible to murine coronavirus infection (11).Previous studies of genetic diversity at ACE2 and TMPRSS2 in global human populations did not include an extensive set of African populations (5, 12–14). No common coding variants (defined here as minor allele frequency [MAF] > 0.05) at ACE2 were identified in any prior population studies. However, few studies included diverse indigenous African populations whose genomes harbor the greatest diversity among humans. This leads to a substantial disparity in the representation of African ancestries in human genetic studies of COVID-19, impeding health equity as the transferability of findings based on non-African ancestries to African populations can be low (15). Including more African populations in studying the genetic diversity of genes involved in SARS-CoV-2 infection is extremely necessary. Additionally, the evolutionary forces underlying global patterns of genetic diversity at host genes related to SARS-CoV-2 infection are not well understood. Using methods to detect natural selection signatures at host genes related to viral infections helps identify putatively functional variants that could play a role in disease risk.We characterized genetic variation and studied natural selection signatures at ACE2, TMPRSS2, DPP4, and LY6E in ethnically diverse human populations by analyzing 2,012 genomes from ethnically diverse Africans (referred to as the “African diversity” dataset), 2,504 genomes from the 1000 Genomes Project (1KG), and whole-exome sequencing of 15,977 individuals of European ancestry (EA) and African ancestry from the Penn Medicine BioBank (PMBB) dataset (SI Appendix, Fig. S1). The African diversity dataset includes populations with diverse subsistence patterns (hunter-gatherers, pastoralists, agriculturalists) and speaking languages belonging to the four major language families in Africa (Khoesan; Niger–Congo, of which Bantu is the largest subfamily; Afroasiatic; and Nilo-Saharan). We identify functionally relevant variation, compare the patterns of variation across global populations, and provide insight into the evolutionary forces underlying these patterns of genetic variation. In addition, we perform an association study using the variants identified from whole-exome sequencing at the four genes and clinical traits derived from electronic health record (EHR) data linked to the subjects enrolled in the PMBB. The EHR data include diseases related to organ dysfunctions associated with severe COVID-19, such as respiratory, cardiovascular, liver, and renal complications. Our study of genetic variation in genes involved in SARS-CoV-2 infection provides data to investigate infection susceptibility within and between populations and indicates that variants in these genes may play a role in comorbidities relevant to COVID-19 severity.     

Aberrant methylation and impaired expression of the p15(INK4b) cell cycle regulatory gene in chronic myelomonocytic leukemia (CMML).

The important cell cycle regulatory gene p15(INK4b) has been shown to be inactivated in acute myeloid leukemia and myelodysplastic syndrome. Little is known about the expression and epigenetic modification of this gene in chronic myelomonocytic leukemia (CMML) that belongs to the myelodysplastic/myeloproliferative disorders (MDS/MPD) with a high proportion of blastic transformation. Analysis of bone marrow trephines in a series of 33 CMML cases showed an aberrant p15(INK4b) gene methylation in up to 58% of cases. Methylation was analyzed employing different methylation-specific PCR and genomic sequencing protocols. It turned out to be spread over a broad area of the 5' region and exhibited substantial heterogeneity between cases and even in individual patients. The degree of aberrant methylation was correlated with a reduced mRNA as well as reduced protein expression, and was associated with a higher expression of DNA methyltransferase DNMT 3A. We conclude that aberrant gene methylation is a frequent event in CMML that might contribute to the pathogenesis of this MDS/MPD.     

Prevalence of anemia and its predictors among patients with chronic kidney disease admitted to a teaching hospital in Ethiopia: A hospital-based cross-sectional study

Anemia is a common complication of chronic kidney disease (CKD) and is associated with adverse patient outcomes. However, data on the prevalence of anemia in CKD patients is sparse, particularly in resource-limited settings. Therefore, this study aimed to assess the prevalence of anemia and its predictors among patients with CKD admitted to the Jimma medical center, southwest Ethiopia. A hospital-based prospective cross-sectional study was conducted from September 1 to November 30, 2020. All adult patients with CKD aged ≥18 years who fulfilled the inclusion criteria were consecutively recruited into the study. Data were entered into the Epi data manager version 4.4.1 and then exported to SPSS version 22 (IBM Corp., Armonk, NY) for analysis. The predictors of anemia were determined using multivariable logistic regression analysis. Statistical significance was set at P < .05. A total of 150 patients were included in this study. Of these, 64.67% were male, 56.67% had stage 5 CKD, 78% had a CKD duration of less than 1 year, and 74% had proteinuria. Hypertension (40.7%) and diabetes (14.7%) were the common causes of CKD. The prevalence of anemia was 85.33%. Of the patients, 28.67%, 40.67%, and 16% had mild, moderate, and severe anemia, respectively. On multivariate logistic regression, stage 4 CKD (adjusted odds ratio [AOR] 3.2, confidence interval [CI]: 1.78–12.91, P = .025), stage 5 CKD (AOR 4.03, CI: 1.17–13.73, P = .016), and CKD duration of less than 1 year (AOR 3, CI: 1.19–9.11, P = .007) were significantly associated with anemia. The prevalence of anemia among stage 3 to 5 CKD patients was very high. Anemia was significantly associated with the severity and duration of CKD. Therefore, serial follow-up of patients with a long duration and advanced stages of CKD may help prevent anemia and its adverse consequences.