Association Between CA 15-3 and 18F-FDG PET/CT Findings in Recurrent Breast Cancer Patients at a Tertiary Referral Hospital in Kenya.

The tumor marker cancer antigen 15-3 (CA 15-3) is that most commonly used to monitor metastatic breast cancer during active therapy and surveillance for disease recurrence after treatment. The association of CA 15-3 and 18F-FDG PET/CT findings can be considered complementary, since any significant rise may indicate the presence of disease and imaging is able to map the tumor sites. Although current guidelines do not recommend the routine performance of CA 15-3 in asymptomatic patients being followed up after definitive breast cancer treatment, most oncologists perform serial assessment of the tumor markers as part of routine follow-up of patients. The aim of this study was to evaluate the correlation between CA 15-3 levels and 18F-FDG PET/CT scan findings in patients with recurrent breast cancer. Methods: This was a cross-sectional study with data collected retrospectively. Patients being evaluated for breast cancer recurrence with 18F-FDG PET/CT imaging and CA 15-3 level were included. Evaluation of the association between CA 15-3 levels and 18F-FDG PET/CT scan findings was then done. Results: In total, 154 cases were included in this study; 62 patients had recurrence (positive) on the 18F-FDG PET/CT scans, whereas 92 patients had normal (negative) findings on follow-up 18F-FDG PET/CT scans. There was an association between CA 15-3 levels and the presence or absence of recurrence on 18F-FDG PET/CT scans, with 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on 18F-FDG PET/CT and 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on 18F-FDG PET/CT as well as a correlation with the burden of metastases. Most patients with disease recurrence on 18F-FDG PET/CT, however, had normal CA 15-3 levels. Conclusion: Higher CA 15-3 levels correlate with breast cancer recurrence on 18F-FDG PET/CT as well as with burden of metastasis. Notably, CA 15-3 levels within the reference range do not exclude breast cancer disease recurrence since more than half of patients with recurrence had normal CA 15-3 levels. 18F-FDG PET/CT should therefore be considered in patients with suspected breast cancer recurrence but normal CA 15-3 levels.

Metastatic breast cancer in Kenya: survival, prognosis and management at a tertiary referral centre.

There has been an increase in breast cancer in Africa with up to 77% of patients diagnosed with advanced disease. However, there is little data on survival outcomes and prognostic factors affecting survival in patients with metastatic breast cancer (MBC) in Africa. The study objective was to establish the survival of patients with MBC at a single tertiary health facility, the clinical and pathological characteristics affecting survival and describe the treatment modalities used. This was a retrospective descriptive study conducted at Aga Khan University Hospital, Nairobi of patients diagnosed with MBC between 2009 and 2017. Survival data was collected on metastatic free survival, survival time between diagnosis of first metastasis and death and overall survival. Data on patient's age, menopausal status and stage at diagnosis, tumour grade, receptor status, site of metastasis and treatment given was also collected. The Kaplan-Meier Estimator was used to estimate survival. Prognostic factors for survival outcomes were analysed using univariate analysis. Standard descriptive statistics were used to describe patient characteristics. A total of 131 patients were included in the study. The median survival was 22 months. The 3 and 5-year survivals were 31.3% and 10.7%, respectively. On univariate analysis, the Luminal A molecular subtype was a significant positive prognostic factor hazard ratios (HR 0.652 95% confidence interval (CI) 0.473-0.899) while metastasis to the liver or brain were significant negative prognostic factors (HR 0.615 95% CI 0.413-0.915 and HR 0.566 95% CI 0.330-0.973, respectively). A large proportion (87.0%) received some treatment for metastatic disease. Our study concluded that survival rates for patients diagnosed with MBC were lower compared to studies from Western countries but higher than in studies from Sub-Saharan Africa. Luminal A molecular subtype was found to be a positive prognostic factor and metastasis to the liver or brain were found to be negative prognostic factors. Improved access to adequate treatment for MBC is required in the region.

Factors associated with depressive symptoms in patients with benign prostatic enlargement.

BACKGROUND: Depression is a common condition that may lead to suicide at its worst. It is considered one of the primary causes of morbidity globally. Among the urological causes of depression is benign prostatic enlargement (BPE). AIM: To determine the prevalence and factors associated with depressive symptoms among BPE patients. SETTING: This study was conducted in the Urology and Family Medicine Clinic at the Aga Khan University Hospital, Nairobi and Urology clinic at the Aga Khan Hospital Mombasa. METHODS: The study was a cross-sectional design recruiting 308 males above the age of 40. Patient Health Questionnaire-9 and International Prostate Symptom Score (IPSS) were used to assess depressive symptoms and lower urinary tract symptoms (LUTS), respectively. Association between depressive symptoms and LUTS was determined. Factors associated with depressive symptoms were analysed by logistic regression. RESULTS: Prevalence of depressive symptoms among patients with symptomatic benign prostatic enlargement (sBPE) was 42.90%. Factors associated with depressive symptoms included comorbid conditions, medication side effects, reduced libido, alcohol use, disturbed sleep at night and anxiety in regard to the prostate condition. CONCLUSION: There is a high prevalence of depressive symptoms among men with BPE. Assessment and early intervention for depressive symptoms among men with BPE should be initiated before clinical depression sets in.Contribution: The study has created a knowledge base on factors associated with depressive symptoms among men with sBPE in the African context.

HIV Prevalence and Characteristics Among Patients With AIDS-Defining and Non-AIDS-Defining Cancers in a Tertiary Hospital in Kenya.

PURPOSE: Antiretroviral therapy (ART) has resulted in a higher life expectancy of persons living with HIV. This has led to an aging population at risk for both non-AIDS-defining cancers (NADCs) and AIDS-defining cancers (ADCs). HIV testing among patients with cancer in Kenya is not routinely performed, making its prevalence undefined. The aim of our study was to determine the prevalence of HIV and the spectrum of malignancies among HIV-positive and HIV-negative patients with cancer attending a tertiary hospital in Nairobi, Kenya. MATERIALS AND METHODS: We conducted a cross-sectional study between February 2021 and September 2021. Patients with a histologic cancer diagnosis were enrolled. Demographic data and HIV- and cancer-related clinical variables were obtained. HIV pretest counseling and consent were done, and testing was performed using a fourth-generation assay. Positive results were confirmed using a third-generation assay. RESULTS: We enrolled 301 patients with cancer; 67.8% (204 of 301) were female; the mean age was 50.7 ± 12.5 years. From our cohort, 10.6% (95% CI, 7.4 to 14.7, n = 32 of 301) of patients were HIV-positive with the prevalence of a new HIV diagnosis of 0.7% (n = 2 of 301). Of the HIV-positive patients, 59.4% (19 of 32) had a NADC. The commonest NADC was breast cancer (18.8%; 6 of 32), whereas non-Hodgkin lymphoma (18.8%; 6 of 32) and cervical cancer (18.8%; 6 of 32) were the most prevalent ADCs among HIV-positive patients. CONCLUSION: The prevalence of HIV infection among patients with cancer was twice the Kenya national HIV prevalence. NADCs comprised a larger percentage of the cancer burden. Universal opt-out HIV testing of patients attending for cancer care regardless of cancer type may facilitate early recognition of HIV-infected patients and aid in appropriate selection of ART and cancer therapies and preventive strategies.

Tumour Infiltrating Lymphocytes (TILs) and immune composition in breast cancer patients from Kenya: Spatial distributions and associations with risk factors and tumour characteristics.

BACKGROUND: The immune landscape of breast cancer (BC) in patients from Sub Saharan Africa is understudied. Our aims were to describe the distribution of Tumour Infiltrating Lymphocytes (TILs) within the intratumoural stroma (sTILs) and the leading/invasive edge stroma (LE-TILs), and to evaluate TILs across BC subtypes with established risk factors and clinical characteristics in Kenyan women. METHODS: Visual quantification of sTILs and LE-TILs were performed on Haematoxylin and eosin -stained pathologically confirmed BC cases based on the International TIL working group guidelines. Tissue Microarrays were constructed and stained with immunohistochemistry (IHC) for CD3, CD4, CD8, CD68, CD20, and FOXP3. Linear and logistic regression models were used to assess associations between risk factors and tumour features with IHC markers and total TILs, after adjusting for other covariates. RESULTS: A total of 226 invasive BC cases were included. Overall, LE-TIL (mean = 27.9, SD = 24.5) proportions were significantly higher than sTIL (mean = 13.5, SD = 15.8). Both sTILs and LE- TILs were predominantly composed of CD3, CD8, and CD68. We found higher TILs to be associated with high KI67/high grade and aggressive tumour subtypes, although these associations varied by TIL locations. Older age at menarche (≥ 15 vs. < 15 years) was associated with higher CD3 (OR: 2.06, 95%CI:1.26-3.37), but only for the intra-tumour stroma. CONCLUSION: The TIL enrichment in more aggressive BCs is similar to previously published data in other populations. The distinct associations of sTIL/LE-TIL measures with most examined factors highlight the importance of spatial TIL evaluations in future studies.

A pilot phase Ib/II study of whole-lung low dose radiation therapy (LDRT) for the treatment of severe COVID-19 pneumonia: First experience from Africa.

BACKGROUND: Low dose radiation therapy (LDRT) has been used for non-malignant conditions since early 1900s based on the ability of single fractions between 50-150 cGy to inhibit cellular proliferation. Given scarcity of resources, poor access to vaccines and medical therapies within low and middle income countries, there is an urgent need to identify other cost-effective alternatives in management of COVID-19 pneumonia. We conducted a pilot phase Ib/II investigator-initiated clinical trial to assess the safety, feasibility, and toxicity of LDRT in patients with severe COVID-19 pneumonia at the Aga Khan University Hospital in Nairobi, Kenya. Additionally, we also assessed clinical benefit in terms of improvement in oxygenation at day 3 following LDRT and the ability to avoid mechanical ventilation at day 7 post LDRT. METHODS: Patients with both polymerase chain reaction (PCR) and high-resolution computer tomogram (HRCT) confirmed severe COVID-19 pneumonia, not improving on conventional therapy including Dexamethasone and with increasing oxygen requirement were enrolled in the study. Patients on mechanical ventilation were excluded. Eligible patients received a single 100cGy fraction to the whole lung. In the absence of any dose limiting toxicity the study proposed to treat a total of 10 patients. The primary endpoints were to assess the safety/feasibility, and toxicity within the first 24 hours post LDRT. The secondary endpoints were to assess efficacy of LDRT at Day 3, 7, 14 and 28 post LDRT. RESULTS: Ten patients were treated with LDRT. All (100%) of patients were able to complete LDRT without treatment related SAE within the first 24 hours post treatment. None of the patients treated with LDRT experienced any acute toxicity as defined by change in clinical and respiratory status at 24hr following LDRT. Majority (90%) of patients avoided mechanical ventilation within 7 days of LDRT. Four patients (40%) demonstrated at least 25% improvement in oxygen requirements within 3 days. Six patients (60%) were discharged and remained off oxygen, whereas four progressed and died (1 due to sepsis and 3 in cytokine storm). Median time to discharge (n = 6) was 16.5 days and median time to death (n = 4) was 11.0 days. Patients who ultimately died showed elevated inflammatory markers including Ferritin, CRP and D-dimers as compared to those who were discharged alive. CONCLUSION: LDRT was feasible, safe and shows promise in the management of severe COVID-19 pneumonia including in patients progressing on conventional systemic treatment. Additional phase II trials are warranted to identify patients most likely to benefit from LDRT.

Epilepsy research in Africa: A scoping review by the ILAE Pediatric Commission Research Advocacy Task Force.

OBJECTIVE: Despite the high prevalence of epilepsy in Africa, evaluation of epilepsy research trends on the continent is lacking. Without establishing effective research, improvement in care for people with epilepsy cannot be effectively strategized or targeted. METHODS: A scoping review of the peer-reviewed literature on epilepsy from Africa (1989-2019) was conducted. The aim was to understand from this what areas are well researched versus underresearched based on published epilepsy topics. RESULTS: A total of 1227 publications were identified and assessed. A significant increase in publications occurred over the 30 years assessed. African author leadership was evident in most reports. Nine countries had >50 publications identified; the remaining 45 countries had <50 or no publications. Research studies were typically of lower quality (case series and observational studies). Research themes were more focused on clinical epilepsy (descriptive observational studies) and social aspects (qualitative surveys). However, there were a number of unique and strong themes, specifically for neurocysticercosis and nodding syndrome, where strong research collaborations were evident, basic science understandings were explored, and interventional models were established. SIGNIFICANCE: Despite Africa being the continent with the most countries, it is lacking in the quantity, quality, and for some areas, relevance of research on epilepsy. Targeted approaches are needed to upskill the strength of research undertaken with more basic science, interventional, and randomized controlled studies. Themes of research need to promote those with unique African content but also to align with current international research areas that have impact on care delivery, such as epilepsy surgery and epilepsy genetics. For this to be possible, it is important to strengthen research hubs with collaborations that empower Africa to own its epilepsy research journey.

Cardiovascular risk factors and markers of myocardial injury and inflammation in people living with HIV in Nairobi, Kenya: a pilot cross-sectional study.

OBJECTIVES: To determine the prevalence of cardiovascular disease (CVD) risk factors and explore associations with high-sensitivity cardiac troponin I (hscTnI) and high-sensitivity C-reactive protein (hsCRP) in people living with HIV (PLHIV) in Kenya. DESIGN: Pilot cross-sectional study. SETTING: Data were collected from community HIV clinics across two sites in Nairobi, Kenya, from July 2019 to May 2020. PARTICIPANTS: Convenience sample of 200 PLHIV (≥30 years with no prior history of CVD). OUTCOME MEASURES: Prevalence of cardiovascular risk factors and its association with hsTnI and hsCRP levels. RESULTS: Across 200 PLHIV (median age 46 years, IQR 38-53; 61% women), the prevalence of hypercholesterolaemia (total cholesterol >6.1 mmol/L) and hypertension were 19% (n=30/199) and 30% (n=60/200), respectively. Smoking and diabetes prevalence was 3% (n=5/200) and 4% (n=7/200). HscTnI was below the limit of quantification (<2.5 ng/L) in 65% (n=109/169). High (>3 mg/L), intermediate (1-3 mg/L) and low (<1 mg/L) hsCRP levels were found in 38% (n=75/198), 33% (n=65/198) and 29% (n=58/198), respectively. Framingham laboratory-based risk scores classified 83% of PLHIV at low risk with 12% and 5% at intermediate and high risk, respectively. Older age (adjusted OR (aOR) per year increase 1.05, 95% CI 1.01 to 1.08) and systolic blood pressure (140-159 mm Hg (aOR 2.96; 95% CI 1.09 to 7.90) and >160 mm Hg (aOR 4.68, 95% CI 1.55 to 14) compared with <140 mm Hg) were associated with hscTnI levels. No associations were observed between hsCRP and CVD risk factors. CONCLUSION: The majority of PLHIV-using traditional risk estimation systems-have a low estimated CVD risk likely reflecting a younger aged population predominantly consisting of women. Hypertension and hypercholesterolaemia were common while smoking and diabetes rates remained low. While hscTnI values were associated with increasing age and raised blood pressure, no associations between hsCRP levels and traditional cardiovascular risk factors were observed.

Supporting Kenyan women with advanced breast cancer through a network and assessing their needs and quality of life.

INTRODUCTION: Metastatic breast cancer (MBC) patients have several unmet needs. The needs and quality of life of MBC women living in sub-Saharan Africa (SSA) are understudied. Facilitating the interaction of various caregivers is beneficial in addressing the needs. Internet-based resources play an important role in reaching out to these patients. We aimed to bring the various stakeholders into a joint network force, create a web-based portal, understand the needs of MBC patients, and assess the utilization of web-based resources for women from Kenya. METHODS: A network of various stakeholders considered crucial in the care of Kenyan women with MBC was created. We conducted educational camps and assessed their needs, quality of life (QoL), and knowledge. We assessed the impact of utilizing web-based resources by MBC patients from here. RESULTS: We formed a network involving partners and launched the first dedicated website for MBC from Kenya. The website has received 13,944 visits and 310,379 hits in 2 years. One hundred fourteen women living with MBC were interviewed, and our findings show that psychological needs (63%), physical support needs (60%), and health care system needs (55%) are leading areas of needs that increase with rural residence (p = 0.001), less education (p = 0.003), and aggressive treatments (p = 0.008). Quality of life (QoL) confirmed better scores with urban residence (p = 0.002), internet access (p = 0.010), and stable disease (p = 0.042). CONCLUSIONS: Creating a network of caregivers provides opportunities for cohesive efforts in understanding the psychosocial and medical needs of patients with MBC. Internet-based resources are an effective way of reaching out to them. Kenyan patients show extremely good uptake of internet-based resources.

Eligibility and patient barriers to peritoneal dialysis in patients with advanced chronic kidney disease.

INTRODUCTION: The burden of chronic kidney disease (CKD) is increasing in Kenya and is a significant cause of morbidity and mortality. While definitive treatment is renal transplantation, many patients require kidney replacement therapy with haemodialysis (HD) or peritoneal dialysis (PD). The predominant modality utilized in Kenya is currently HD. There is a need to explore why PD remains underutilized and whether patient factors may be contributory to barriers that limit the uptake of PD. METHODS: This was a descriptive cross-sectional study where patients with advanced CKD were assessed by a multidisciplinary team for PD eligibility using a standardized tool. Contraindications and barriers to the modality were recorded as was the presence or absence of support for the provision of PD. Demographic and clinical data were recorded using a standardized questionnaire. The impact of support on PD eligibility was determined. RESULTS: We found that 68.9% patients were eligible for PD. Surgery-related abdominal scarring was the most common contraindication. Barriers to PD were identified in 45.9% and physical barriers were more common than cognitive barriers. Presence of support was associated with a significant increase in PD eligibility (p < 0.001). CONCLUSION: The rate of eligibility for PD in this study was similar to that found in other populations. Surgical-related factors were the most commonly identified contraindication. Physical and cognitive barriers were commonly identified and may be overcome by the presence of support for PD.

Assessment of Palliative Care Needs in a Kenyan Intensive Care Unit Using a Trigger-Based Model.

CONTEXT: Palliative care triggers have been used in the intensive care unit (ICU) setting, usually in high-income countries, to identify patients who may benefit from palliative care consults. The utility and benefits of palliative care triggers in the ICU have not been previously studied in sub-Saharan Africa. OBJECTIVES: Our objectives were to determine the prevalence of ICU admissions in those who met at least one palliative care trigger and whether a palliative care consult influenced the length of ICU stay and time to change of goals order. METHODS: We conducted a prospective observational cohort study within our ICU at the Aga Khan University Hospital, Nairobi, between December 2019 and August 2020. Data including initiation of a palliative care consult, length of ICU stay, mortality, and time to change of goals order were collected. RESULTS: During our study period, 72 of 159 (45.9%) patients met at least one palliative care trigger point. Of the patients who met the palliative care triggers, only 29.2% received a palliative care consult. Patients who received palliative care consults had higher rates of change of goals orders signed (52.3%) vs. those who did not (P = 0.009). There was no statistically significant difference between the consult and nonconsult groups in regard to length of ICU stay, time to change of goals order, and mortality. CONCLUSION: A trigger-based model, geared to the needs of the specific ICU, may be one way of improving integration of palliative care into the ICU, especially in sub-Saharan Africa.

Primitive neuroectodermal tumor incidence, treatment patterns, and outcome: An analysis of the National Cancer Database.

BACKGROUND: Primitive neuroectodermal tumors (PNETs) comprise less than 1% of all sarcomas. The rarity of this disease has resulted in a paucity of information about disease process and management. This study sought to evaluate the incidence, treatment patterns, and outcomes among patients with PNET. METHODS: The National Cancer Database was queried for diagnoses of PNET between 2004 and 2014. Patients were dichotomized based on tumor type (central [cPNET] vs peripheral [pPNET]). Demographic, tumor, treatment, and outcome variables were analyzed for the entire patient cohort and by type of PNET. RESULTS: White (86.4%) males (56.6%) represented the majority of patients. The incidence of PNET remained stable over the study period (r2 = 0.0821). A total of 70.7% underwent surgical resection of the primary site, 50.3% received radiation, and 74.7% received systemic chemotherapy. Compared to those with pPNET, patients with cPNET more often received radiation treatment (P < .001), primary tumor resection (P < .001), and experienced increased 90-day mortality (P < .014). CONCLUSION: cPNET and pPNET are rare and aggressive malignancies that tend to arise in White males. Multimodal treatment including surgery, chemotherapy, and radiation is conventional. Patients with cPNET more often receive radiation and primary tumor resection with increased 90-day mortality.

Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury.

BACKGROUND Myocardial ischemia reperfusion (I/R) injury is associated with complex pathophysiological changes characterized by pH imbalance, the accumulation of lipid peroxidation products acrolein and 4-hydroxy trans-2-nonenal, and the depletion of ATP levels. Cardioprotective interventions, designed to address individual mediators of I/R injury, have shown limited efficacy. The recently identified enzyme ATPGD1 (Carnosine Synthase), which synthesizes histidyl dipeptides such as carnosine, has the potential to counteract multiple effectors of I/R injury by buffering intracellular pH and quenching lipid peroxidation products and may protect against I/R injury. METHODS AND RESULTS We report here that ß-alanine and carnosine feeding enhanced myocardial carnosine levels and protected the heart against I/R injury. Cardiospecific overexpression of ATPGD1 increased myocardial histidyl dipeptides levels and protected the heart from I/R injury. Isolated cardiac myocytes from ATPGD1-transgenic hearts were protected against hypoxia reoxygenation injury. The overexpression of ATPGD1 prevented the accumulation of acrolein and 4-hydroxy trans-2-nonenal-protein adducts in ischemic hearts and delayed acrolein or 4-hydroxy trans-2-nonenal-induced hypercontracture in isolated cardiac myocytes. Changes in the levels of ATP, high-energy phosphates, intracellular pH, and glycolysis during low-flow ischemia in the wild-type mice hearts were attenuated in the ATPGD1-transgenic hearts. Two natural dipeptide analogs (anserine and balenine) that can either quench aldehydes or buffer intracellular pH, but not both, failed to protect against I/R injury. CONCLUSIONS Either exogenous administration or enhanced endogenous formation of histidyl dipeptides prevents I/R injury by attenuating changes in intracellular pH and preventing the accumulation of lipid peroxidation derived aldehydes.

Metastatic Breast Cancer in Kenya: Presentation, Pathologic Characteristics, and Patterns-Findings From a Tertiary Cancer Center.

PURPOSE: The purpose of this research was to describe the sociodemographic and clinical characteristics of Kenyan women with metastatic breast cancer diagnosed and treated at Aga Khan University Hospital in Nairobi, Kenya from 2012 to 2018. PATIENTS AND METHODS: We reviewed charts of Kenyan women with metastatic breast cancer and analyzed sociodemographic data, breast cancer risk factors, and tumor characteristics associated with stage at diagnosis, receptor status (ie, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]), and site of metastasis using χ2, analysis of variance, two-sample t tests, and logistic regressions. RESULTS: A total of 125 cases with complete medical records were included in the analysis. Forty women (32%) had metastases at diagnosis. Of the others, those diagnosed in stage III developed metastases sooner than those diagnosed in stage II (P < .001). Fifty-eight percent of patients had metastases to bone, 14% to brain, 57% to lungs, and 50% to liver. Seventy-four percent of patients presented with more than one metastatic site. Metastases to bone were associated with greater age at diagnosis (P = .02) and higher parity (P = .04), and metastases to the brain were associated with early menopause (P = .04), lower parity (P = .04), and lack of breastfeeding (P = .01). Patients whose tumors were triple negative (estrogen receptor-negative, progesterone receptor-negative, and HER2 negative) were more likely to develop brain metastases (P = .01), and those whose tumors were HER2 positive were more likely to develop liver metastases (P = .04). CONCLUSION: Although our data on patterns of metastases and pathologic subtypes are similar to those in published literature, some unique findings concerning hormonal risk factors of women with metastatic breast cancer and specific metastatic sites need additional exploration in larger patient populations.

Systemic Toxicity of Smokeless Tobacco Products in Mice.

Introduction: Smokeless tobacco products such as snuff and snus are used worldwide. However, little is known about the systemic and cardiovascular toxicity of smokeless tobacco exposure. Methods: Biomarkers of endothelial activation and injury, immune functions, platelet activation and insulin resistance were measured in 8-week old male C57BL/6 mice exposed to commercial snuff, CRP-2 reference snuff, commercial snus, CRP-1 reference snus, and nicotine in drinking water (100 µg/mL) for 4, 12, and 24 weeks. Results: Twenty-four weeks of exposure to smokeless tobacco products or nicotine significantly decreased the levels of circulating Flk+/Sca+ endothelial progenitor cells. Twelve and 24 weeks of exposure to all the smokeless tobacco products and nicotine significantly decreased the levels of circulating CD19+ B cells, CD4+ T cells, CD8+ T cells, and CD11b+ monocytes, whereas 4 weeks of exposure to Camel snus and Copenhagen snuff significantly depleted the levels of peripheral blood CD19+ B cells and CD11b+ monocytes. Twenty-four weeks of exposure to smokeless tobacco products or nicotine significantly decreased plasma IFNγ levels. However, plasma TNFα levels were significantly increased in mice exposed to Copenhagen snuff or nicotine for 24 weeks. This was accompanied by a five to sevenfold increase in the hepatic expression of TNFα. Neither smokeless products nor nicotine affected plasma lipoproteins, platelet activation, or systemic insulin sensitivity. Conclusions: Chronic exposure to snuff and snus suppresses circulating levels of EPCs, endothelial microparticles and immune cells, but increases plasma TNF-α levels. These effects of smokeless tobacco products are attributable, at least in part, to nicotine. Implications: Exposure to smokeless tobacco products results in the depletion of endothelial progenitor cells, which may impair the endothelium repair. Suppression of the circulating levels of immune cells upon exposure to smokeless tobacco products may increase the susceptibility to secondary infection. Increased formation of proinflammatory cytokines such as TNFα by nicotine or Copenhagen snuff may lead to vascular inflammation and thereby exacerbate atherogenesis.

Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction.

Circulating angiogenic cells (CACs) of various described phenotypes participate in the regeneration of the damaged endothelium, but the abundance of these cells is highly influenced by external cues including diabetes. It is not entirely clear which CAC populations are most reflective of endothelial function nor which are impacted by diabetes. To answer these questions, we enrolled a human cohort with variable CVD risk and determined relationships between stratified levels of CACs and indices of diabetes and vascular function. We also determined associations between CAC functional markers and diabetes and identified pro-angiogenic molecules which are impacted by diabetes. We found that subjects with low levels of CD34+/AC133+/CD31+/CD45dim cells (CAC-3) had a significantly higher incidence of diabetes (p = 0.004), higher HbA1c levels (p = 0.049) and higher CVD risk scores. Furthermore, there was an association between low CAC-3 levels and impaired vascular function (p = 0.023). These cells from diabetics had reduced levels of CXCR4 and VEGFR2, while diabetics had higher levels of certain cytokines and pro-angiogenic molecules. These results suggest that quantitative and functional defects of CD34+/AC133+/CD31+/CD45dim cells are associated with diabetes and vascular impairment and that this cell type may be a prognostic indicator of CVD and vascular dysfunction.

Biomarkers of Chronic Acrolein Inhalation Exposure in Mice: Implications for Tobacco Product-Induced Toxicity.

Exposure to tobacco smoke, which contains several harmful and potentially harmful constituents such as acrolein increases cardiovascular disease (CVD) risk. Although high acrolein levels induce pervasive cardiovascular injury, the effects of low-level exposure remain unknown and sensitive biomarkers of acrolein toxicity have not been identified. Identification of such biomarkers is essential to assess the toxicity of acrolein present at low levels in the ambient air or in new tobacco products such as e-cigarettes. Hence, we examined the systemic effects of chronic (12 weeks) acrolein exposure at concentrations similar to those found in tobacco smoke (0.5 or 1 ppm). Acrolein exposure in mice led to a 2- to 3-fold increase in its urinary metabolite 3-hydroxypropyl mercapturic acid (3-HPMA) with an attendant increase in pulmonary levels of the acrolein-metabolizing enzymes, glutathione S-transferase P and aldose reductase, as well as several Nrf2-regulated antioxidant proteins. Markers of pulmonary endoplasmic reticulum stress and inflammation were unchanged. Exposure to acrolein suppressed circulating levels of endothelial progenitor cells (EPCs) and specific leukocyte subsets (eg, GR-1+ cells, CD19+ B-cells, CD4+ T-cells; CD11b+ monocytes) whilst other subsets (eg, CD8+ cells, NK1.1+ cells, Ly6C+ monocytes) were unchanged. Chronic acrolein exposure did not affect systemic glucose tolerance, platelet-leukocyte aggregates or microparticles in blood. These findings suggest that circulating levels of EPCs and specific leukocyte populations are sensitive biomarkers of inhaled acrolein injury and that low-level (<0.5 ppm) acrolein exposure (eg, in secondhand smoke, vehicle exhaust, e-cigarettes) could increase CVD risk by diminishing endothelium repair or by suppressing immune cells or both.

Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133+ Circulating Angiogenic Cells.

OBJECTIVES: Previous studies have shown that residential proximity to a roadway is associated with increased cardiovascular disease risk. Yet, the nature of this association remains unclear, and its effect on individual cardiovascular disease risk factors has not been assessed. The objective of this study was to determine whether residential proximity to roadways influences systemic inflammation and the levels of circulating angiogenic cells. APPROACH AND RESULTS: In a cross-sectional study, cardiovascular disease risk factors, blood levels of C-reactive protein, and 15 antigenically defined circulating angiogenic cell populations were measured in participants (n=316) with moderate-to-high cardiovascular disease risk. Attributes of roadways surrounding residential locations were assessed using geographic information systems. Associations between road proximity and cardiovascular indices were analyzed using generalized linear models. Close proximity (<50 m) to a major roadway was associated with lower income and higher rates of smoking but not C-reactive protein levels. After adjustment for potential confounders, the levels of circulating angiogenic cells in peripheral blood were significantly elevated in people living in close proximity to a major roadway (CD31(+)/AC133(+), AC133(+), CD34(+)/AC133(+), and CD34(+)/45(dim)/AC133(+) cells) and positively associated with road segment distance (CD31(+)/AC133(+), AC133(+), and CD34(+)/AC133(+) cells), traffic intensity (CD31(+)/AC133(+) and AC133(+) cells), and distance-weighted traffic intensity (CD31(+)/34(+)/45(+)/AC133(+) cells). CONCLUSIONS: Living close to a major roadway is associated with elevated levels of circulating cells positive for the early stem marker AC133(+). This may reflect an increased need for vascular repair. Levels of these cells in peripheral blood may be a sensitive index of cardiovascular injury because of residential proximity to roadways.