Discordance between PAM50 intrinsic subtyping and immunohistochemistry in South African women with breast cancer.

PURPOSE: Breast cancer is a heterogeneous disease with different gene expression profiles, treatment options and outcomes. In South Africa, tumors are classified using immunohistochemistry. In high-income countries multiparameter genomic assays are being utilized with implications for tumor classification and treatment. METHODS: In a cohort of 378 breast cancer patients from the SABCHO study, we investigated the concordance between tumor samples classified by IHC and the PAM50 gene assay. RESULTS: IHC classified patients as ER-positive (77.5%), PR-positive (70.6%), and HER2-positive (32.3%). These results, together with Ki67, were used as surrogates for intrinsic subtyping, and showed 6.9% IHC-A-clinical, 72.7% IHC-B-clinical, 5.3% IHC-HER2-clinical and 15.1% triple negative cancer (TNC). Typing using the PAM50 gave 19.3% luminal-A, 32.5% luminal-B, 23.5% HER2-enriched and 24.6% basal-like. The basal-like and TNC had the highest concordance, while the luminal-A and IHC-A group had the lowest concordance. By altering the cutoff for Ki67, and realigning the HER2/ER/PR-positive patients to IHC-HER2, we improved concordance with the intrinsic subtypes. CONCLUSION: We suggest that the Ki67 be changed to a cutoff of 20-25% in our population to better reflect the luminal subtype classifications. This change would inform treatment options for breast cancer patients in settings where genomic assays are unaffordable.

PAM50 intrinsic subtypes, risk of recurrence score and breast cancer survival in HIV-positive and HIV-negative patients-a South African cohort study.

PURPOSE: Treatment decision making for patients with breast cancer increasingly depends on analysis of markers or systems for estimating risk of breast cancer recurrence. Breast cancer intrinsic subtypes and risk of recurrence (ROR) scores have been found to be valuable in predicting survival and determining optimal treatment for individual patients. We studied the association of breast cancer survival with the PAM50 gene expression assay in HIV-positive and HIV-negative patients. METHOD: RNA was extracted from formalin-fixed paraffin-embedded specimens of histologically confirmed invasive carcinoma and was purified using the AllPrep® DNA/RNA FFPE kit, Qiagen (Hilden, Germany). The NanoString RUO PAM50 algorithm was used to determine the molecular subtype and the risk of recurrence score of each sample. The overall and disease-free survival were determined with comparison made among HIV-positive and -negative patients. We then generated Kaplan-Meier survival curves, calculated p-values and estimated hazard ratios and their 95% confidence intervals using Cox regression models. RESULTS: Of the 384 RNA samples analysed, 98.4% met the required RNA quality standard and the specified QC threshold for the test. Luminal B was the most common PAM50 intrinsic subtype and 82.1% of patients were at high risk for disease recurrence based on ROR score. HIV infection, PAM50-based HER2-enriched and basal-like intrinsic subtypes, and high ROR were associated with poor overall and disease-free survival. HIV-positive patients with luminal A & B subtypes had significantly worse survival outcomes than HIV-negative luminal patents. CONCLUSION: Aggressive tumour biology was common in our cohort. HIV infection, PAM50 HER2-enriched,basal-like intrinsic subtypes and high ROR score were associated with poor overall and disease-free survival. HIV infection impacted survival in patients with luminal subtypes only.

The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density.

BACKGROUND: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. METHODS: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. RESULTS: In pooled analyses, later age at menarche was associated with higher per cent density (ß√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (ß√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (ß√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (ß√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. CONCLUSIONS: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Interleukin-6 gene polymorhisms and interleukin-6 levels are associated with atherosclerosis in CKD patients.

Inflammation is a major risk factor for atherosclerosis. Genetic polymorphisms in the inflammatory cytokine genes have been associated with atherosclerosis. Because levels of inflammatory cytokines are markedly elevated in patients with chronic kidney disease (CKD), we hypothesized that genotypic variations in the interleukin-6 (IL-6) gene are a cause of systemic inflammatory states and atherosclerosis in South African CKD patients. 120 CKD patients and 40 healthy controls were included. Serum IL-6 and high-sensitivity C-reactive protein (hs-CRP) levels were measured. Functional polymorphisms in the IL-6 genes were genotyped using polymerase chain reaction-sequence specific primer (PCR-SSP) methods. Carotid intima-media thickness (CIMT) and the presence of plaque were assessed by B-mode ultrasonography. Serum IL-6 and hs-CRP levels were increased in patients with CKD compared with healthy controls (p < 0.001). In CKD patients, serum IL-6 above the median value was associated with carotid plaque (OR: 2.11; 95% CI: 1.74 - 2.57, p = 0.004), with excess risk confined to the group with high IL-6 levels. Significant associations were found between the IL-6 gene and atherosclerosis in the CKD group (for G/G genotype: OR = 1.21, 95% CI = 1.05 - 1.39, p = 0.012; for GG+GC vs. CC: OR = 1.14, 95% CI = 1.02 - 1.28, p = 0.035). Patients with GG+GC genotype of the IL-6 gene polymorphism had higher levels of IL-6 than those with CC genotype (p = 0.029). In South African CKD patients, the IL-6 gene promoter polymorphism is associated with high serum IL-6 levels and atherosclerosis. The relationship between atherosclerosis and -174G/C polymorphism in the IL-6 gene suggests that IL-6 may be a potential pro-inflammatory mediator of atherosclerosis in CKD patients.

Design and methods of the prevalence and pharmacogenomics of tenofovir nephrotoxicity in HIV-positive adults in south-western Nigeria study.

BACKGROUND: Individuals of African descent are at higher risk of developing kidney disease than their European counterparts, and HIV infection is associated with increased risk of nephropathy. Despite a safe renal profile in the clinical trials, long-term use of tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy although the underlying mechanisms remain undetermined. We aim to establish the prevalence of and risk factors for TDF-induced kidney tubular dysfunction (KTD) among HIV-I and II individuals treated with TDF in south-west Nigeria. Association between TDF-induced KTD and genetic polymorphisms in renal drug transporter genes and the APOL1 (Apolipoprotein L1) gene will be examined. METHODS: This study has two phases. An initial cross-sectional study will screen 3000 individuals attending the HIV clinics in south-west Nigeria for KTD to determine the prevalence and risk factors. This will be followed by a case-control study of 400 KTD cases and 400 matched controls to evaluate single nucleotide polymorphism (SNP) associations. Data on socio-demographics, risk factors for kidney dysfunction and HIV history will be collected by questionnaire. Blood and urine samples for measurements of severity of HIV disease (CD4 count, viral load) and renal function (creatinine, eGFR, phosphate, uric acid, glucose) will also be collected. Utility of urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) levels as surrogate markers of KTD will be evaluated. Genomic DNA will be extracted from whole blood and SNP analyses performed using the rhAMP SNP genotyping assays. Statistical analysis including univariate and multivariate logistic regression analyses will be performed to identify factors associated with KTD. DISCUSSION: In spite of TDF being the most commonly used antiretroviral agent and a key component of many HIV treatment regimens, it has potential detrimental effects on the kidneys. This study will establish the burden and risk factors for TDF-induced KTD in Nigerians, and explore associations between KTD and polymorphisms in renal transporter genes as well as APOL1 risk variants. This study may potentially engender an approach for prevention as well as stemming the burden of CKD in sub-Saharan Africa where GDP per capita is low and budgetary allocation for health is inadequate.

Hepcidin and GDF-15 are potential biomarkers of iron deficiency anaemia in chronic kidney disease patients in South Africa.

BACKGROUND: Anaemia is a common presenting feature among patients with chronic kidney disease (CKD) and it is associated with poor clinical outcomes and quality of life. It is not clear if growth differentiation factor-15 (GDF-15) or hepcidin are useful as early markers of iron deficiency anaemia (IDA) among non-dialysis CKD patients. We therefore evaluated the diagnostic validity of GDF-15 and hepcidin as biomarkers of IDA among non-dialysis CKD patients in Johannesburg, South Africa. METHOD: An analytic cross-sectional study was conducted among non-dialysis CKD patients (n = 312) and apparently healthy controls (n = 184) from June to December 2016 at an Academic Hospital, in Johannesburg, South Africa. An interviewer administered proforma was used to obtain the socio-biological and clinical characteristics of the participants. Serum levels of GDF-15 and hepcidin were determined. Predictive logistic regression models were built and post estimation receiver operator characteristics were determined to evaluate diagnostic validity of hepcidin and GDF-15 for absolute and functional iron deficiency anaemia. RESULTS: About half (50.6%) of the participants were female while the participants' mean age was 49.7 ± 15.8 years. The predictive value of diagnosing absolute IDA among CKD patients using GDF-15 was 74.02% (95% CI: 67.62-80.42%) while the predictive value of diagnosing functional IDA among CKD patients using hepcidin was 70.1% (95% CI: 62.79-77.49%).There was a weak negative correlation between hepcidin levels and GFR (r = - 0.19, p = 0.04) in anaemic CKD patients, and between serum GDF-15 and haemoglobin (r = - 0.34, p = 0.001). Serum ferritin (ß = 0.00389, P-value< 0.001), was a predictor of log hepcidin. MCHC (ß = - 0.0220, P-value 0.005) and CKD stage (ß = 0.4761, P-value < 0.001), race (ß = 0.3429, P-value = 0.018) were predictors of log GDF-15. Both GDF-15 (adj OR: 1.0003, 95%CI: 1.0001-1.0005, P = 0.017) and hepcidin (adj OR: 1.003, 95%CI: 1.0004-1.0055, P = 0.023) were associated with iron deficiency anaemia after multiple linear regression modelling. CONCLUSION: Serum GDF-15 is a potential biomarker of absolute IDA, while hepcidin levels can predict functional IDA among CKD patients.

Parenting after Weight Loss Surgery: A Conceptual Model and Two Case Reports.

The ways families approach eating, shape, and weight can result in stress for individual family members and challenge the overall functioning of the family. This is further complicated among families with a parent who has history of obesity or undergone weight loss surgery (WLS). Although WLS can positively impact other family members, it can also exacerbate conflicts regarding feeding and weight. Such conflicts can involve uncertainty regarding the extent to which the entire family should make the dietary changes recommended for the post-WLS parent. Conflict might also center on the appropriate level of concern regarding the children's risk of developing (or maintaining) obesity. This paper uses two case examples to describe the application of a specialized, time-limited intervention: Parent-Based Prevention following Bariatric Surgery (PBP-B). The program was developed to address the unique challenges and concerns that arise after, or are exacerbated by, WLS. Each detailed case example illustrates a common child-feeding challenge and the employment of key PBP-B strategies throughout the course of treatment. In the first case, the parent who had undergone WLS believed the family's current eating behaviors were the same as those that had led to her own overeating, obesity, and co-occurring psychiatric symptoms, while her husband disagreed. In the second case, both parents were concerned about their son's weight, yet due to their prior eating histories, they felt unable to construct boundaries around the feeding experience. Both cases follow families through the entire intervention and illustrate key points and challenges. These cases underscore the need for novel treatment modalities to support families following parental WLS.

Las maneras en las que las familias abordan la alimentación, la figura y el peso pueden causar estrés en los integrantes individuales de la familia y poner a prueba el funcionamiento general de la familia. Esto es aun más complicado entre las familias con un padre que tiene antecedentes de obesidad o que se sometió a una cirugía para adelgazar. Aunque la cirugía para adelgazar puede repercutir de manera positiva en otros miembros de la familia, también puede exacerbar conflictos con respecto a la alimentación y al peso. Dichos conflictos pueden consistir en la incertidumbre con respecto al grado en el cual toda la familia debería hacer los cambios alimentarios recomendados para el padre que se ha operado para adelgazar. El conflicto también podría centrarse en el nivel adecuado de preocupación en relación con el riesgo de los niños de desarrollar (o mantener) la obesidad. Este artículo utiliza dos ejemplos de casos para describir la aplicación de una intervención especializada y limitada temporalmente: "La prevención basada en los padres después de una cirugía bariátrica" (Parent-Based Prevention following Bariatric Surgery, PBP-B). El programa se desarrolló para abordar los desafíos y las preocupaciones particulares que surgen después de la cirugía para adelgazar o que son exacerbados por esta. Cada ejemplo de un caso detallado ilustra un desafío común con respecto a la alimentación de los niños y al empleo de estrategias fundamentales de la PBP-B a lo largo del transcurso del tratamiento. En el primer caso, la madre que se había sometido a la cirugía para adelgazar creía que los comportamientos alimentarios actuales de la familia eran los mismos que los que la habían conducido a su propia sobreingesta, obesidad, y síntomas psiquiátricos concomitantes, mientras que su esposo no estaba de acuerdo. En el segundo caso, ambos padres estaban preocupados acerca del peso de su hijo, sin embargo, debido a sus antecedentes alimentarios previos, se sentían incapaces de establecer límites en torno a la experiencia alimentaria. Ambos casos siguen a las familias durante toda la intervención e ilustran puntos clave y desafíos. Estos casos subrayan la necesidad de incorporar modalidades innovadoras de tratamiento orientadas a apoyar a las familias después de la cirugía para adelgazar de uno de los padres.

Factors associated with carotid intima media thickness in South African children with chronic kidney disease
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BACKGROUND: Increased carotid intima media thickness (cIMT) is one of the early changes seen in chronic kidney disease (CKD) associated cardiovascular disease. This study aimed to determine cIMT measurements and its association with cardiovascular risk factors, including fibroblast growth factor-23 (FGF-23) and fetuin-A, in South African children with CKD. MATERIALS AND METHODS: 72 children (5 - 18 years) with CKD; 20 with CKD I, 23 with CKD II - IV, 29 with CKD V (on dialysis) were recruited. Each patient had a clinical examination and blood samples assessed for creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone, alkaline phosphatase, total cholesterol, hemoglobin, C-reactive protein, vitamin D, fetuin-A, and FGF-23. cIMT was measured with high-resolution ultrasound. RESULTS: The mean age was 10.8 (3.5) years, and there were 49 males and 23 females (2 : 1). The overall median (range) cIMT was 0.505 mm (0.380 - 0.675) and was highest in patients with dialysis-dependent CKD (p = 0.003). Mean arterial pressure (MAP), hemoglobin, and PTH showed a significant correlation with cIMT (p < 0.001, p = 0.034, and p = 0.002, respectively). After adjusting for confounders in a multivariable analysis, disease duration, MAP, hemoglobin, and estimated glomerular filtration rate (eGFR) were independently associated with cIMT, p = 0.039, 0.001, 0.006, and 0.001, respectively. No significant relationship between cIMT and plasma levels of fetuin-A and FGF-23 was found. CONCLUSION: This study reports high cIMT measurements and their independent association with disease duration, MAP, hemoglobin, and eGFR. However, no similar association was found with fetuin-A and FGF-23.

Low prevalence of apolipoprotein L1 gene variants in Black South Africans with hypertension-attributed chronic kidney disease
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Variants in apolipoprotein L1 (APOL1) gene were shown to be associated with higher rates of nondiabetic kidney disease in black patients compared with white patients. Frequencies of these variants differ substantially in African populations, suggesting that their contribution to kidney disease might differ. We determined the frequency and association of (APOL1) risk alleles with markers of kidney disease in black South Africans with hypertension-attributed chronic kidney disease (CKD) and their first-degree relatives. Black patients with hypertension-attributed CKD with an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m2 were included, together with their first-degree relatives. G1 (rs60910145 and rs73885319) and G2: rs71785313 single nucleotide polymorphisms were genotyped by restriction fragment length polymorphism. Similar to previous association studies, we mainly tested recessive genetic models. The allele frequencies of both the G1 and G2 (APOL1) risk alleles were similar amongst all the groups. There was no difference in the two-risk-allele frequency in CKD patients (10%) compared to controls (8.6%), p = 0.790. Carriage of two (APOL1) risk alleles (vs. zero or one risk allele) was not a predictor of hypertension-attributed CKD (OR, 0.85; 95% CI, 0.25 - 2.83; p = 0.790). Patients with CKD and first-degree relatives with and without (APOL1) risk alleles had statistically indistinguishable blood pressures, creatinine and HDL-cholesterol levels. Apolipoprotein L1 risk variants are present in black South Africans with similar frequencies between CKD patients, first-degree relatives, and healthy controls. The lack of association of these variants with hypertension-attributed CKD in this population needs to be explored further in studies with larger sample sizes.
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Influence of vitamin D receptor polymorphisms on biochemical markers of mineral bone disorders in South African patients with chronic kidney disease.

BACKGROUND: It remains unclear whether genetic factors may explain the reported variation in the levels of biochemical markers of chronic kidney disease mineral and bone disorders (CKD- MBD) across ethnic groups. Therefore, the aim of this study was to examine the influence of vitamin D receptor (VDR) polymorphisms on secondary hyperparathyroidism and its association with vitamin D levels in black and white South African study participants. METHODS: This was a cross sectional study involving 272 CKD stage 3- 5D patients and 90 healthy controls. The four major VDR polymorphisms (Bsm 1, Fok 1, Taq 1, and Apa1) were genotyped using the polymerase chain reaction- restriction fragment length polymorphism (PCR -RFLP) method. In addition, biochemical markers of CKD-MBD were measured to determine their associations with the four VDR polymorphisms. RESULTS: With the exception of Taq I polymorphism, the distribution of the VDR polymorphisms differed significantly between blacks and whites. In hemodialysis patients, the Bb genotype was significantly associated with moderate secondary hyperparathyroidism (OR, 3.88; 95 CI 1.13-13.25, p = 0.03) and severe hyperparathyroidism (OR, 2.54; 95 CI 1.08-5.96, p = 0.03). This was consistent with the observed higher levels of median parathyroid hormone, fibroblast growth factor 23 and mean phosphate in patients with Bb genotype. This candidate risk genotype (Bb) was over represented in blacks compared to whites (71.0% versus 55.6%, p < 0.0001). In an unadjusted regression model, FokFf genotype was found to be significantly associated with the risk of developing severe vitamin D deficiency < 15 ng/ml (OR, 1.89; 95 CI 1.17-3.07, p = 0.01). CONCLUSION: The VDR Bb genotype is an independent predictor of developing secondary hyperparathyroidism in patients with end stage kidney disease. In addition, study participants with FokFf genotype are at increased of developing severe 25 -hydroxyvitamin D [25(OH)D] deficiency.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide.

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Cementogenesis and osteogenesis in periodontal tissue regeneration by recombinant human transforming growth factor-ß3 : a pilot study in Papio ursinus.

OBJECTIVES: The aim of this study was to investigate cementogenesis and alveolar bone induction during in vivo periodontal tissue regeneration upon implantation of hTGF-ß3 in furcation defects of Papio ursinus and to evaluate the feasibility of gene expression studies. MATERIALS AND METHODS: Class II furcation defects (day 0) were prepared in mandibular first and second molars of three P. ursinus and on day 30 implanted with and without 75 µg hTGF-ß3 in Matrigel® matrix. On day 0, 30 and 90, cementum and alveolar bone were harvested for gene expression analyses. Coral-derived bioreactors with and without 250 µg hTGF-ß3 were implanted in the rectus abdominis to monitor tissue induction. RESULTS: hTGF-ß3 induced cementogenesis with TGF-ß3 , Cementum Protein-1 (Cemp1) and Osteocalcin (OC) up-regulation, and down-regulation of BMP-2 and OP-1. Matrigel® matrix specimens showed up-regulation of BMP-2, TGF-ß3 , and OC, with down-regulation of OP-1 and Cemp1. hTGF-ß3 induced alveolar bone with down-regulation of OP-1, TGF-ß3 , OC, and Cemp1. hTGF-ß3 bioreactors induced bone at the periphery only. BMP-3, BMP-4, TGF-ß1 and TGF-ß3 were up-regulated in the adjacent muscle with TGF-ß2 down-regulation. CONCLUSIONS: Cementogenesis and osteogenesis by hTGF-ß3 entail the expression and up-regulation of TGF-ß3 and OC with fine tuning and modulation of BMP-2 and OP-1.

Mammographic density assessed on paired raw and processed digital images and on paired screen-film and digital images across three mammography systems.

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p < 0.001). Conversion equations revealed differences converged to zero with increasing dense area. MD differences between screen-film and processed digital on the subsequent screening round were consistent with expected time-related MD declines. CONCLUSIONS: MD was slightly higher when measured on processed than on raw direct digital mammograms. Comparisons of MD on these image formats should ideally control for this non-constant and reader-specific difference.

Investigation of breast cancer sub-populations in black and white women in South Africa.

PURPOSE: Bimodal age distributions at diagnosis have been widely observed among US and European female breast cancer populations. To determine whether bimodal breast cancer distributions are also present in a sub-Saharan African population, we investigated female breast cancer in South Africa. METHODS: Using the South African National Cancer Registry data, we examined age-at-diagnosis frequency distributions (density plots) for breast cancer overall and by their receptor (oestrogen, progesterone and HER2) determinants among black and white women diagnosed during 2009-2011 in the public healthcare sector. For comparison, we also analysed corresponding 2010-2011 US SEER data. We investigated density plots using flexible mixture models, allowing early/late-onset membership to depend on receptor status. RESULTS: We included 8857 women from South Africa, 7176 (81 %) with known oestrogen receptor status, and 95064 US women. Bimodality was present in all races, with an early-onset mode between ages 40-50 years and a late-onset mode among ages 60-70 years. The early-onset mode was younger in South African black women (age 38), compared to other groups (45-54 years). CONCLUSIONS: Consistent patterns of bimodality and of its receptor determinants were present across breast cancer patient populations in South Africa and the US. Although the clinical spectrum of breast cancer is well acknowledged as heterogeneous, universal early- and late-onset age distributions at diagnosis suggest that breast cancer etiology consists of a mixture two main types.

Volume overload and its risk factors in South African chronic kidney disease patients: an appraisal of bioimpedance spectroscopy and inferior vena cava measurements.

BACKGROUND: Fluid retention occurs early in chronic kidney disease (CKD) resulting in increased cardiovascular morbidity and mortality. This study aimed to assess volume and nutritional status among South African CKD participants and determine the relationship between malnutrition, inflammation, atherosclerosis, and volume overload using a body composition monitor (BCM). We also evaluated the usefulness of BCM measurement in assessing volume overload. METHODS: 160 participants comprising hemodialysis, peritoneal dialysis, stage 3 CKD patients, and healthy controls (40 in each group) were studied. A BCM was used to assess fluid and nutritional status. Cardiac dimension measurements, and inferior vena cava diameter (IVCD) and carotid intima media thickness were assessed by echocardiography and ultrasonography, respectively. Serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were measured as markers of inflammation. RESULTS: Fluid overload and malnutrition were present in 68% and 63% of studied patients, respectively. Using physical examination findings as the reference measurements for volume overload, the area under the concentration curves for BCM and IVCD measurements were 0.866 (sensitivity 82%, specificity 74%, p < 0.001) and 0.727 (sensitivity 57%, specificity 70%, p < 0.001), respectively. Lean tissue index, inflammation, and atherosclerosis were associated with volume overload. CONCLUSIONS: Volume overload and malnutrition were common across the spectrum of South African CKD cohorts; volume overload was associated with malnutrition, inflammation, and atherosclerosis. Bioimpedance spectroscopy (BIS) is a useful and sensitive tool for the assessment of fluid status in clinically euvolumic nondialytic CKD patients.

Correlation between volume overload, chronic inflammation, and left ventricular dysfunction in chronic kidney disease patients.

BACKGROUND: Fluid overload is common in chronic kidney disease (CKD) patients, potentially driving chronic inflammation and left ventricular dysfunction. We investigated the association between volume overload, chronic inflammation, and left ventricular dysfunction across subgroups of CKD patients. METHODS: The study included 160 participants, comprising peritoneal dialysis (PD), hemodialysis (HD), stage-3 CKD patients, and age- and sex-matched controls (40 in each group). Fluid status was assessed using a body composition monitor (BCM); serum endotoxin, lipopolysaccharide binding protein (LBP), C-reactive protein (CRP). and interleukin-6 (IL-6) levels were measured as markers of inflammation. Echocardiography was done to assess left ventricular dimension and function. RESULTS: Endotoxemia and volume overload were common across the spectrum of CKD patients and were aggravated by worsening kidney function. Among HD cohorts, postdialysis endotoxemia was increased among patients with dialysis-induced hemodynamic instability and was also closely related to ultrafiltration volume. Endotoxin, IL-6, CRP, and LBP levels were elevated in patients with volume overload compared to euvolemic patients (p < 0.05). Patients with elevated circulating endotoxemia had higher left ventricular mass index (LVMI) compared to patients with lower endotoxin levels. Fluid overload correlated with endotoxin levels, IL-6, and LVMI; while LVMI correlated weakly with LBP and CRP. CONCLUSION: CKD patients typically presented with significant endotoxemia and overt volume overload, which may contribute significantly to chronic low-grade inflammation and left ventricular dysfunction. An additive contribution from hemodialysis treatment may strongly enhance the severity of endotoxemia in HD patients.

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans.

APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

Childhood cancer incidence patterns by race, sex and age for 2000-2006: a report from the South African National Cancer Registry.

Higher childhood cancer incidence rates are generally reported for high income countries although high quality information on descriptive patterns of childhood cancer incidence for low or middle income countries is limited, particularly in Sub-Saharan Africa. There is a need to quantify global differences by cancer types, and to investigate whether they reflect true incidence differences or can be attributed to under-diagnosis or under-reporting. For the first time, we describe childhood cancer data reported to the pathology report-based National Cancer Registry of South Africa in 2000-2006 and compare our results to incidence data from Germany, a high income country. The overall age-standardized incidence rate (ASR) for South Africa in 2000-2006 was 45.7 per million children. We observed substantial differences by cancer types within South Africa by racial group; ASRs tended to be 3-4-fold higher in South African Whites compared to Blacks. ASRs among both Black and White South Africans were generally lower than those from Germany with the greatest differences observed between the Black population in South Africa and Germany, although there was marked variation between cancer types. Age-specific rates were particularly low comparing South African Whites and Blacks with German infants. Overall, patterns across South African population groups and in comparison to Germans were similar for boys and girls. Genetic and environmental reasons may probably explain rather a small proportion of the observed differences. More research is needed to understand the extent to which under-ascertainment and under-diagnosis of childhood cancers drives differences in observed rates.

Stage at breast cancer diagnosis and distance from diagnostic hospital in a periurban setting: a South African public hospital case series of over 1,000 women.

Advanced stage at diagnosis contributes to low breast cancer survival rates in sub-Saharan Africa. Living far from health services is known to delay presentation, but the effect of residential distance to hospital, the radius at which this effect sets in and the women most affected have not been quantified. In a periurban South African setting, we examined the effect of a geographic information system (GIS)-measured straight-line distance, from a patient's residence to diagnostic hospital, on stage at diagnosis in 1,071 public-sector breast cancer patients diagnosed during 2006-2012. Generalized linear models were used to estimate risk ratios for late stage (stage III/IV vs. stage I/II) associated with distance, adjusting for year of diagnosis, age, race and socioeconomic indicators. Mean age of patients was 55 years, 90% were black African and diagnoses were at stages I (5%), II (41%), III (46%) and IV (8%). Sixty-two percent of patients with distances >20 km (n = 338) had a late stage at diagnosis compared to 50% with distances <20 km (n = 713, p = 0.02). Risk of late stage at diagnosis was 1.25-fold higher (95% CI: 1.09, 1.42) per 30 km. Effects were pronounced in an underrepresented group of patients over age 70. This positive stage-distance association held to 40 km, and plateaued or slightly reversed in patients (9%) living beyond this distance. Studies of woman and the societal and healthcare-level influences on these delays and on the late stage at diagnosis distribution are needed to inform interventions to improve diagnostic stage and breast cancer survival in this and similar settings.

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs.

Coral-derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre-loaded with either 500 µg of the calcium channel blocker, verapamil hydrochloride, or 240 µg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT-PCR. On day 15, up-regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate-treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre-loaded with the Ca(++) channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down-regulation of bone morphogenetic protein-2 (BMP-2) together with up-regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre-loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral-derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca(++) activating stem cell differentiation and the induction of bone formation.