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Black women in the United States are disproportionately affected by early-onset, triple-negative breast cancer. DNA methylation has shown differences by race in healthy and tumor breast tissues. We examined associations between genome-wide DNA methylation levels in breast milk and breast cancer risk factors, including race, to explain how this reproductive stage influences a woman's risk for, and potentially contributes to racial disparities in, breast cancer. Breast milk samples and demographic, behavioral, and reproductive data, were obtained from cancer-free, uniparous, and lactating U.S. black (n = 57) and white (n = 82) women, ages 19–44. Genome-wide DNA methylation analysis was performed on extracted breast milk DNA using the Infinium HumanMethylation450 BeadChip. Statistically significant associations between breast cancer risk factors and DNA methylation beta values, adjusting for potential confounders, were determined using linear regression followed by Bonferroni Correction (P < 1.63 × 10−7). Epigenetic analysis in breast milk revealed statistically significant associations with race and lactation duration. Of the 284 CpG sites associated with race, 242 were hypermethylated in black women. All 227 CpG sites associated with lactation duration were hypomethylated in women who lactated longer. Ingenuity Pathway Analysis of differentially methylated promoter region CpGs by race and lactation duration revealed enrichment for networks implicated in carcinogenesis. Associations between DNA methylation and lactation duration may offer insight on its role in lowering breast cancer risk. Epigenetic associations with race may mediate social, behavioral, or other factors related to breast cancer and may provide insight into potential mechanisms underlying racial disparities in breast cancer incidence.

BackgroundPrior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts.MethodsDNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. After quality control, 368,171 autosomal CpG loci were analyzed. Cell type proportion estimates from RefFreeCellMix were calculated and adjusted for in this Epigenome Wide Association Study using linear mixed effects models adjusted for history of breast biopsy, age, time of delivery, cell type proportion estimates, array chip, and subject as random effect.ResultsEpigenome-wide analyses identified 58 differentially methylated CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer (q-value < 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls, and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls.ConclusionBreast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors, and improving primary and secondary prevention of breast cancer.

BACKGROUND: Analysis of cytokines and growth factors in human milk offers a noninvasive approach for studying the microenvironment of the postpartum breast, which may better reflect tissue levels than testing blood samples. Given that Black women have a higher incidence of early onset breast cancers than White women, we hypothesized that milk of the former contains higher levels of pro-inflammatory cytokines, adipokines, and growth factors. METHODS: Participants included 130 Black and 162 White women without a history of a breast biopsy who completed a health assessment questionnaire and donated milk for research. Concentrations of 15 analytes in milk were examined using two multiplex and 4 single-analyte electrochemiluminescent sandwich assays to measure pro-inflammatory cytokines, angiogenesis factors, and adipokines. Mixed-effects ordinal logistic regression was used to identify determinants of analyte levels and to compare results by race, with adjustment for confounders. Factor analysis was used to examine covariation among analytes. RESULTS: Thirteen of 15 analytes were detected in ≥25% of the human milk specimens. In multivariable models, elevated BMI was significantly associated with increased concentrations of 5 cytokines: IL-1β, bFGF, FASL, EGF, and leptin (all p-trend < 0.05). Black women had significantly higher levels of leptin and IL-1β, controlling for BMI. Factor analysis of analyte levels identified two factors related to inflammation and growth factor pathways CONCLUSION: This exploratory study demonstrated the feasibility of measuring pro-inflammatory cytokines, adipokines and angiogenesis factors in human milk, and revealed higher levels of some pro-inflammatory factors, as well as increased leptin levels, among Black as compared with White women.

TGF-β plays a dual role in breast carcinogenesis, acting at early stages as tumor-suppressors and later as tumor-promoters. TGF-β isoforms are expressed in breast tissues and secreted in milk, suggesting that analysis of levels in milk might be informative for breast cancer risk. Accordingly, we assessed TGF-β2 levels in milk from women who had undergone a breast biopsy and related the concentrations to diagnosis. Milk donated by women who had undergone or were scheduled for a breast biopsy was shipped on ice for processing and testing. Breast cancer risk factors were obtained through a self-administered questionnaire, and biopsy diagnoses were extracted from pathology reports. TGF-β2 levels in milk, assessed as absolute levels and in relation to total protein, were analyzed in bilateral samples donated by 182 women. Linear regression was used to estimate relationships of log-transformed TGF-β2 levels and TGF-β2/ total protein ratios to biopsy category. Milk TGF-β2 levels from biopsied and non-biopsied breasts within women were highly correlated (r 2 = 0.77). Higher mean TGF-β2 milk levels (based on average of bilateral samples) were marginally associated with more severe breast pathological diagnosis, after adjusting for duration of nursing current child (adjusted p trend = 0.07). Our exploratory analysis suggests a borderline significant association between higher mean TGF-β2 levels in breast milk and more severe pathologic diagnoses. Further analysis of TGF-β signaling in milk may increase understanding of postpartum remodeling and advance efforts to analyze milk as a means of assessing risk of breast pathology.

Background Diets rich in fruits and vegetables (F/V) can reduce the inflammatory profile of circulating cytokines and potentially decrease the risk of breast cancer. However, the extent to which a diet rich in F/V alters cytokine levels in breast tissue remains largely unknown. Breast milk provides a means of assessing concentrations of secreted cytokines in the breast microenvironment and is a potential tool for studying the effects of diet on inflammation in breast tissue and breast cancer risk. Objective The aim of this pilot randomized trial was to test the feasibility of increasing F/V intake in breastfeeding women and of measuring changes in markers of inflammation in breast milk. Design and intervention Participants randomized to the intervention (n=5) were provided weekly boxes of F/V, along with dietary counseling, to increase consumption of F/V to 8 to 10 daily servings for 12 consecutive weeks. Controls (n=5) were directed to the US Department of Agriculture’s “ChooseMyPlate” diet for pregnancy and breastfeeding. Participants/setting Ten breastfeeding women consuming fewer than five servings of F/V per day, as estimated by the National Institutes of Health “All-Day” Fruit and Vegetable Screener (F/V Screener), were recruited through flyers and a lactation consultant between February and May 2016 in the Western Massachusetts area. Main outcome measures Baseline demographic and F/V intake data were collected during enrollment. At week 1 and week 13 (final) home visits, participants provided milk samples and anthropometric measurements were recorded. Participants completed F/V screeners at baseline and at study end. Adiponectin, leptin, C-reactive protein, and 11 additional cytokines were measured in breast milk collected at weeks 1 and 13. Statistical analyses F/V consumption at baseline and after the final visit, and between controls and intervention groups, was compared with dependent and independent t tests, respectively. Differences between cytokine levels at weeks 1 and 13 were assessed with a mixed-effects repeated-measures model. Results All women in the intervention increased F/V intake and were consuming more servings than controls by week 13; daily serving of F/V at baseline and final visit: controls=1.6 and 2.0, diet=2.6 and 9.9. Most cytokines were detected in the majority of milk samples: 12 were detected in 90% to 100% of samples, one was detected in 75% of samples, and one was detected in 7.5% of samples; coefficients of variation were below 14% for 11 of the cytokines. Conclusions These preliminary findings indicate that it is feasible to significantly increase F/V intake in breastfeeding women and provide support for conducting a larger diet intervention study in breastfeeding women, in which longer-term benefits of the intervention are assessed.

Roughly two-thirds of all breast cancers are ERα-positive and can be treated with the antiestrogen, Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 y. Aberrant DNA methylation, an epigenetic mechanism that alters gene expression in cancer, is thought to play a role in this resistance. To develop an understanding of Tamoxifen-resistance and identify novel pathways and targets of aberrant methylation, DNA from MCF-7 breast cancer cells and Tamoxifen-resistant derivatives, TMX2-11 and TMX2-28, were analyzed using the Illumina HumanMethylation450 BeadChip. Normalizing against MCF-7 values, ERα-positive TMX2-11 had 4000 hypermethylated sites and ERα-negative TMX2-28 had over 33 000. Analysis of CpG sites altered in both TMX2-11 and TMX2-28 revealed that the Tamoxifen-resistant cell lines share 3000 hypermethylated and 200 hypomethylated CpGs. ZNF350 and MAGED1, two genes hypermethylated in both cell lines, were examined in greater detail. Treatment with 5-aza-2ꞌdeoxycitidine caused a significant reduction in promoter methylation of both ZNF350 and MAGED1 and a corresponding increase in expression in TMX2-28. A similar relationship between methylation and expression was not detected in TMX2-11. Our findings are indicative of the variable responses to methylation-targeted breast cancer therapy and highlight the need for biomarkers that accurately predict treatment outcome.

Background: Breast cancer risk increases during pregnancy and remains elevated for a number of years thereafter. Cancer-associated proteins that are secreted into breast milk may provide a means to detect cancer in the lactating breast or to assess future breast cancer risk. Objective: To determine whether proteins linked to breast cancer would be differentially expressed in matched (both breasts from each participant) human milk samples collected from women with unilateral breast cancer. Methods: Five cancer-associated proteins (basic fibroblast growth factor [bFGF], YKL-40, neutrophil gelatinase-associated lipocalin, and transforming growth factor β1 and β2) were analyzed in milk provided by 5 lactating women, 4 of whom were known to have cancer in 1 breast (and the opposite breast clinically disease free) at the time of milk collection and 1 who developed breast cancer 2 years after milk collection. Results: Expression was significantly higher for TGFβ2 ( P = .03) and bFGF ( P =.03) in the breasts with cancer. Conclusion: These proteins may play a role in assessing a woman’s risk of pregnancy-associated breast cancer. Because of variable protein concentration among patients and the limited sample size, the results are considered preliminary.

Accurately identifying women at increased risk of developing breast cancer will provide greater opportunity for early detection and prevention. DNA promoter methylation is a promising biomarker for assessing breast cancer risk. Breast milk contains large numbers of exfoliated epithelial cells that are ideal for methylation analyses. Exfoliated epithelial cells were isolated from the milk obtained from each breast of 134 women with a history of a non-proliferative benign breast biopsy (Biopsy Group). Promoter methylation of three tumor suppressor genes, RASSF1, SFRP1 and GSTP1, was assessed by pyrosequencing of bisulfite-modified DNA. Methylation scores from the milk of the 134 women in the Biopsy Group were compared to scores from 102 women for whom a breast biopsy was not a recruitment requirement (Reference Group). Mean methylation scores for RASSF1 and GSTP1 were significantly higher in the Biopsy than in the Reference Group. For all three genes the percentage of outlier scores was greater in the Biopsy than in the Reference Group but reached statistical significance only for GSTP1. A comparison between the biopsied and non-biopsied breasts of the Biopsy Group revealed higher mean methylation and a greater number of outlier scores in the biopsied breast for both SFRP1 and RASSF1, but not for GSTP1. This is the first evidence of CpG island methylation in tumor suppressor genes of women who may be at increased risk of developing breast cancer based on having had a prior breast biopsy.

Purpose Poor living conditions are posited as an underlying cause of American Indian (AI) infant mortality, which is unusually high in the postneonatal period. We explore whether the effects of neighborhood poverty on AI infant death are identifiable by using observational data. Methods Vital records for infants born between 1990 and 1999 to AI women in a metropolitan area (n = 4751) are linked with tract-level poverty data. A counterfactual framework, an explicit causal contrast study design, and propensity score matching methods were used. For each comparison, we created exchangeable groups by matching infants with the same probability of exposure to poverty when one was exposed and the other was not. Results Our results suggest that neighborhood poverty has little effect on AI infant death outcomes. Importantly, the study design makes transparent the challenge of identifying appropriate analytic comparison groups in studies of neighborhood poverty and health. Conclusions Collecting additional data will likely not overcome the fact that AIs with a high probability of living in poverty rarely reside in low-poverty neighborhoods. Yet, some of them must if a meaningful counterfactual comparison is to be made and the effects of neighborhood poverty on AI infant death are to be identified.

In this study, we investigate the extent to which women and men differ in patterns of medication use, based on quantitative and qualitative data from a household survey in Western Massachusetts. Using a broad definition of medications, 96% of the sample reported taking one or more medications in the month preceding the survey (86% if vitamins, supplements, and alternative medications are excluded). Twenty-one percent of respondents reported taking five or more medications, and women were significantly more likely to report taking five or more medications in the month preceding the survey. For both sexes, analgesics and vitamins were the most commonly used medications, but women were more likely to report having taken hormones, supplements, and antihistamines. The likelihood of medicating reported health conditions did not differ by sex, but the frequency of reporting health conditions was higher among women, and the difference was significant for body aches and psychosomatic conditions. Analyses of qualitative data indicate that female networks of relatives and friends are an important source of advice on medications for both men and women. Responses to open-ended questions suggest that women's discourse about the effect of medications differs from men's in terms of the range and detail of descriptions of symptoms and side effects.

Background: Breast cancer is the most frequently diagnosed cancer among Turkish women and both the incidence and associated mortality appear to be increasing. Of particular concern is the percentage of young women diagnosed with breast cancer; roughly 20% of all breast cancer diagnoses in Turkey are in women younger than 40 years. Increased DNA methylation in the promoter region of tumor suppressor genes is a promising molecular biomarker, and human milk provides exfoliated breast epithelial cells appropriate for DNA methylation analyses. Comparisons between DNA methylation patterns in epithelial (epithelial-enriched) and nonepithelial (epithelial-depleted) cell fractions from breast milk have not been reported previously. Objective: In the present study, we examined promoter methylation of 3 tumor suppressor genes in epithelial-enriched and epithelial-depleted cell fractions isolated from breast milk of 43 Turkish women. Methods: Percentage methylation in the promoter region of Rass association domain family 1 (RASSF1), secreted frizzle related protein 1 (SFRP1), and glutathione- S-transferase class pi 1 was determined by pyrosequencing of the epithelial-enriched and epithelial-depleted cell fractions. Results: Pyrosequencing identified a few subjects with significantly increased methylation in 1 or more genes. There was little correlation between the 2 cell fractions within individuals; only 1 woman had increased methylation for 1 gene (SFRP1) in both her enriched and depleted cell fractions. Methylation was positively associated with age for SFRP1 (epithelial-depleted fraction) and with body mass index for RASSF1 (epithelial-enriched cell fraction), respectively. Conclusion: Overall, results show that the methylation signals vary between different cell types in breast milk and suggest that breast milk can be used to assess DNA methylation patterns associated with increased breast cancer risk.

S-phase kinase-associated protein 2 (SKP2) is an important cell cycle regulator, targeting the cyclin-dependent kinase (CDK) inhibitor p27 for degradation, and is frequently overexpressed in breast cancer. p27 regulates G1 /S transition by abrogating the activity of cyclin/CDK complexes. p27 can undergo phosphorylation at serine 10 (pSer10p27). This phosphorylation event is associated with increased cell proliferation and poor prognosis in patients with glioma. The relationship between SKP2 and pSer10p27 in breast cancer has not been previously investigated. Immunohistochemistry (IHC) of SKP2, p27, pSer10p27, and other genes involved in this pathway, was analyzed in 188 breast tumors and 50 benign reduction mammoplasty samples. IHC showed SKP2 to be more highly expressed in estrogen receptor α (ERα)-negative breast cancers and demonstrated that triple-negative tumors were more likely to have high expression of SKP2 than were non-triple negative, ERα-negative tumors. A significant positive relationship was discovered for SKP2 and pSer10p27. High levels of SKP2 and pSer10p27 were observed significantly more often in ERα-negative and triple-negative than in ERα-positive breast cancers. Use of the triple-negative TMX2-28 breast cancer cell line to address the role of SKP2 in cell cycle progression confirmed that SKP2 contributes to a more rapid cell cycle progression and may regulates pSer10p27 levels. Together, the results indicate that presence of high SKP2 plus high pSer10p27 levels in triple-negative breast cancers is associated with aggressive growth, and highlight the validity of using SKP2 inhibitors as a therapeutic approach for treating this subset of breast cancers.

Bisphenol A (BPA) is a synthetic, endocrine-disrupting compound. Free BPA has been detected in human samples indicating that humans are internally exposed to estrogenically active BPA. The purpose of this study was to develop a sensitive method to detect free BPA in human breast milk. BPA was isolated from the milk of 21 nursing mothers in the U.S. by solid-phase extraction. It was then derivatized to improve sensitivity and subsequently analyzed by ultra high performance liquid chromatography-tandem mass spectrometry. Free BPA was detected in 62% of the milk samples (≤ 0.22-10.8 ng mL(-1), median 0.68 ng mL(-1), mean 3.13 ng mL(-1)). No statistical difference in BPA concentrations was observed between women with a low or high Body Mass Index (BMI) (30 (n=11) and30 (n=10), respectively). However, there was a significant association between BPA concentration and race. Caucasian women had significantly higher levels of free BPA in their breast milk than non-Caucasian women (mean=4.44 (n=14) and 0.52 (n=7), respectively; p0.05). The difference between races could be attributed to variations in exposure, lifestyle or metabolism and suggests that certain populations should take extra precautions to limit BPA exposure, particularly during pregnancy and lactation.

Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. The mechanism of hypertension induced by recombinant human erythropoietin (rHuEPO) is unclear but may include an increase in peripheral vascular resistance. We studied changes of arterial pressure and plasma endothelin in nine consecutive hemodialysis patients before, and 6 and 12 weeks after, starting rHuEPO. In six patients, changes in cardiac index (CI), stroke index (SI) and total peripheral resistance index (TPRI) were measured by bioimpedance, and forearm vascular responsiveness to intra-arterial norepinephrine (30 to 240 pmol/min) and endothelin-1 (5 pmol/min) were assessed. Six healthy age and sex matched subjects also underwent assessment of forearm vascular responsiveness to norepinephrine and endothelin-1. Treatment with rHuEPO significantly increased hemoglobin and mean arterial pressure (MAP). TPRI also increased by 35 ± 11%. Plasma endothelin, although elevated basally, remained unchanged. Intra-arterial infusion of norepinephrine caused a maximal increase in forearm vascular resistance (FVR) of 17 ± 9% before rHuEPO, significantly less than the 32 ± 5% increase in healthy control subjects (P = 0.04). The response increased to 65 ± 15% (P = 0.03) after 12 weeks rHuEPO treatment (P = 0.51 vs. controls). Endothelin-1 caused a maximal increase of FVR at 60 minutes of 45 ± 24% before rHuEPO, which was not significantly different from controls, and tended to decrease with rHuEPO therapy. The response to endothelin-1, but not norepinephrine, correlated inversely with MAP (r = -0.52; P = 0.03) and TPRI (r = -0.51; P = 0.04). In conclusion, these studies show that anemia in chronic renal failure is associated with depressed vascular responsiveness to norepinephrine which is restored by rHuEPO therapy. In contrast, vascular responses to endothelin-1 tend to reduce with rHuEPO therapy. The change in vascular responsiveness to norepinephrine may contribute to the increase in arterial pressure associated with rHuEPO therapy.

To investigate the trunk strength of elite rowers and the impact of low back pain on these measures in order to determine if asymmetries or weakness were present.Twenty two elite rowers were recruited: 13 reported previous low back pain, five current low back pain, and the remainder had no history of low back pain. All subjects were scanned during simulated rowing in an interventional open magnetic resonance imaging scanner. In each simulated rowing position, axial scans were obtained at the level of the L4-5 and L5-S1 disc interspace to determine the cross sectional area of the posterior trunk muscles.Considerable differences were observed between the three groups of rowers. In contrast with expectations and previous literature, the trunk muscles of rowers with low back pain had significantly larger cross sectional areas (p0.001). No left/right asymmetries were observed and no differences between oarside and non-oarside in terms of muscle cross sectional area.These findings suggest that low back pain in rowers does not arise as a result of muscle weakness.

Promoter methylation analysis of genes frequently silenced in breast cancer is a promising indicator of breast cancer risk, as these methylation events are thought to occur long before presentation of disease. The numerous exfoliated epithelial cells present in breast milk may provide the breast epithelial DNA needed for detailed methylation analysis and assessment of breast cancer risk. Fresh breast milk samples and health, lifestyle, and reproductive history questionnaires were collected from 111 women. Pyrosequencing analysis was conducted on DNA isolated from the exfoliated epithelial cells immunomagnetically separated from the total cell population in the breast milk of 102 women. A total of 65 CpG sites were examined in six tumor suppressor genes: PYCARD (also known as ASC or TMS1), CDH1, GSTP1, RBP1 (also known as CRBP1), SFRP1, and RASSF1. A sufficient quantity of DNA was obtained for meaningful analysis of promoter methylation; women donated an average of 86 ml of milk with a mean yield of 32,700 epithelial cells per ml. Methylation scores were in general low as expected of benign tissue, but analysis of outlier methylation scores revealed a significant relationship between breast cancer risk, as indicated by previous biopsy, and methylation score for several CpG sites in CDH1, GSTP1, SFRP1, and RBP1. Methylation of RASSF1 was positively correlated with women's age irrespective of her reproductive history. Promoter methylation patterns in DNA from breast milk epithelial cells can likely be used to assess breast cancer risk. Additional studies of women at high breast cancer risk are warranted.

Emerging industrial communities of nineteenth-century New England experienced both rapid population growth and lagging development of public health infrastructures. In turn, high mortality in these newly urban cities contributed to a delay in the regional mortality transition of the late nineteenth century. Analyzing death records and a file of linked cause-specific death and manuscript census records for the industrializing community of Northampton, Massachusetts, we show that early in the city's development, mortality clustered near industrial activities and open sewers. When industrial areas were sewered, clustering of mortality abated, and differences between industrial and commercial areas of the town were no longer significant. These findings illustrate Szreter's emphasis on considering both the benefits and costs of development. (1) Initial development contributed to high mortality in newly emergent urban-industrial centers like Northampton and was abated only when lagging public health infrastructures caught up with rapid growth and development near the turn of the century.

Using a national survey of facilities governed by the Resource Conservation and Recovery Act (RCRA), we examine the sociospatial distribution of a much larger group of hazardous materials handlers than did previous environmental equity studies. Overall we find that RCRA-governed facilities are more likely to be sited in working-class neighborhoods with lower percentages of minority residents. We do not find evidence of stark environmental inequities. RCRA facilities, however, are close to neighborhoods with a higher percentage of minority residents. And in nonmetropolitan areas, they are slightly more likely to be located in neighborhoods with a higher percentage of black residents.

Data on the prevalence, magnitude and causes of blindness and severe visual impairment in children are needed for planning and evaluating preventive and curative services for children, and for planning special education and low vision services. Prevalence data can be obtained from a variety of different sources, each of which has limitations. The available data suggest that there may be a ten-fold difference in prevalence between the wealthiest countries of the world and the poorest, ranging from as low as 0.1/1000 children aged 0-15 years in the wealthiest countries to 1.1/1000 children in the poorest. In this paper, the available data are reviewed and the epidemiological methods and findings are discussed.

This article presents findtngs of the first national tract-level analysis of the distribution of residential characteristics, including the percentage of selected minorities and socioeconomically disadvan taged groups, in relation to uncontrolled toxic waste sites (i. e., CERCLIS and NPL sites). In contrast to prevailing notions, the authors find that uncontrolled toxic waste sites are not disproportionately located in minority neighborhoods or neighborhoods of soctoeconomtcally disadvantaged residents. However, multivariate analyses of site distribution and a hazard regression analysis of the site prioritization process suggest that communities with a higher percentage of Black residents are less likely to receive NPL (National Priorities List) designation, delaying potential remediation. Biases in the prioritization process are, however, substantively small.

Research addressing "environmental equity" and "environmental racism" claims that facilities for treatment, storage, and disposal of hazardous wastes (TSDFs) are located disproportionately in minority areas. In the first comprehensive study of TSDFs to use census tract-level data, we find no nationally consistent and statistically significant differences between the racial or ethnic composition of tracts which contain commercial TSDFs and those which do not. TSDFs are more likely to be found in tracts with Hispanic groups, primarily in regions with the greatest percentage of Hispanics. Different geographic units of analysis elaborate on, but are consistent with, these results.

Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured in 53 hypertensive patients (26 renally impaired, 27 with normal renal function) before and after treatment with sufficient bunazosin retard or prazosin to control their high blood pressure. After a 3-week placebo run-in period, patients were classified as normal (creatinine clearance80 ml/min) or renally impaired (20-55 ml/min), and randomly assigned to bunazosin retard or prazosin. There followed a dose titration (T) phase of 6-7 weeks, and a maintenance (M) phase of 4 weeks. Blood pressure was satisfactorily controlled (sitting diastolic pressureor = 90 mmHg or decreased byor = 10 mmHg) by both drugs in both groups. Bunazosin Retard was associated with increases in GFR and ERPF in both normal and renally impaired groups; the increases were statistically significant in the renally impaired group (n = 14). Prazosin was associated with small decreases in both measures in both groups. One patient died of myocardial infarction during the placebo run-in. There were no other serious adverse events. Four patients reported dizziness (2 with each drug). We conclude that with appropriate dose titration, bunazosin retard is well tolerated and preserves renal blood flow when used to treat hypertension in patients with renal insufficiency.

Oral infection with Herpes Simplex Virus (HSV) is a frequent and well documented complication in immunosuppressed individuals including patients on immunosuppressive medication. We report the development of severe oral infection with HSV type 1 in a 34 year old woman with type 1 diabetes mellitus and end stage renal disease (ESRD) following cadaveric renal transplantation at the Western General Hospital, Edinburgh. The role of acyclovir in therapy and chemoprophylaxis is discussed.

Fine-needle aspiration (FNA) is a well-recognized technique for sampling solid organs. It is used in renal transplantation to clarify the cause of a poorly functioning graft. Differential scoring techniques with respect to peripheral blood cell populations, and immunocyto-chemistry have been employed in this context. We describe the use of simple morphological criteria alone in renal transplant FNA. We compare these with needle biopsy and clinical parameters and show their value in the detection of active cellular rejection. Their limitations are discussed within the framework of other patterns of transplant pathology.

The efficacy, safety and potential effect on renal function of doxazosin were studied in hypertensive patients with renal impairment. Thirty adult patients with moderate hypertension (DBP between 95-114 mmHg and SBP less than 210 mmHg) and moderately impaired renal function of varying underlying pathology (serum creatinine between 220-640 mumol/l) were given doxazosin, either as monotherapy or part of polytherapy, in an open study. Their average duration of doxazosin therapy was 75 days and the median dose was 2 mg. With doxazosin treatment, the mean supine and standing SBPs were reduced by 15 mmHg and 13 mmHg, respectively. These changes were highly significant (P less than 0.0001). Supine and standing DBPs were also significantly reduced by 16 mmHg and 17 mmHg, respectively (P less than 0.0001). Heart rate was increased by 4 beats/min (mean maximum change); this was statistically, but not clinically, significant. There was a small but significant rise in serum creatinine (mean value, 35 mumol/l) in the group as a whole over a mean period of 75 days. This was considered to be compatible with the natural progression of the underlying renal pathology. Retrospective plotting of the reciprocal of available serum creatinine values against time during the months before doxazosin therapy yielded a linear relationship which supported this hypothesis. One patient withdrew from the study because of a rapid rise in serum creatinine concentration during the placebo run-in phase. Overall, side effects were minimal and did not necessitate reducing the dosage or discontinuing active therapy. The results of this study indicate that doxazosin is effective and well-tolerated in the treatment of hypertension with concomitant renal insufficiency and does not appear to compromise renal function.

We have reviewed the literature relating to the use of monoclonal antibodies in acute renal allograft rejection. More emphasis has been placed on Orthoclone OKT3 which has been more commonly used and summarise our experience with its use as rescue therapy in renal allograft rejection.

Nearly all developed countries have experienced dramatic declines in the seasonality of demographic behavior over the last century. This article examines seasonal behavior in the population of Taiwan between 1906 and 1942, during Japanese colonial rule. First, we analyze seasonal demographic cycles and their ties to the cultural calendar and agriculture. Second, we compare seasonality in two regions (Xinzhu and Tainan) that experienced different agricultural development under the colonial regime. Findings demonstrate that demographic seasonality was less pronounced when urban development and colonial agricultural intensification produced more heterogeneous seasonal patterns of labor. We find that changes in agricultural organization, rather than purely a shift to nonagricultural production, may significantly reduce established seasonal timing of demographic behavior.

Ninety-four renal allograft recipients receiving cyclosporin A (CsA) immunosuppression for up to 4 years were examined for the presence of viral warts, keratoses, and skin cancers. They were compared with a group of 68 recipients on azathioprine who had been matched for duration of immunosuppression and other factors that might influence the occurrence of these lesions. No difference in prevalence of these tumours was found. Viral, bacterial, and fungal infections and other disorders of the skin related to immunosuppression were also noted. Apart from hypertrichosis, which occurred more frequently in the CsA group, no differences were observed. In view of the importance of duration of immunosuppression, the relative effects on the skin of the two drugs will not become apparent until CsA has been in general use for a much longer period of time. In the early stages, however, there appear to be no differences in the dermatological side-effects between CsA- and azathioprine-treated patients.

Summary— A group of 128 consecutive patients was identified on whom renal isotope studies had been performed during the first 2 months after renal transplantation and within 7 days of transplant biopsy. The prospective renogram and biopsy reports were reviewed and graded into 4 categories: severe rejection, predominant rejection, predominant acute tubular necrosis (ATN) and pure ATN. Two extreme patterns of renogram were identified: a sharp rise with a fast decline in the first min, attributed to ATN, and a slowly rising curve with no early peak occurring in severe rejection although not specific to this condition. There was a continuous intermediate spectrum. There was no inter-observer variation in gradings at the 2 ends of the spectrum. In the middle part the difference between 2 independent observers never exceeded more than 1 grade. There was good correlation between the biopsy and renogram gradings, with a discrepancy of more than 1 grade in only 5 patients; 2 of these, with severe rejection on the renogram, showed predominant ATN on biopsy, but the final clinical diagnosis was severe rejection (false positive biopsies). Two patients with biopsies showing severe rejection had a sharp initial up-slope in the renograms but a slower down-slope (over 4 min compared with 1 min in true ATN). With better definition of the criteria these renograms would not have been graded as ATN. There was 1 patient in whom no satisfactory explanation for the discrepancy was found (presumed false positive renogram). When properly defined criteria are used to interpret renograms, this simple test is at least as reliable as renal biopsy in differentiating ATN from rejection in the early post-transplant period, especially in the presence of anuria or severe oligurea.

Two methods of measuring the clearance of 99Tcm DTPA, OIH and iothalamate were compared with standard techniques of measuring the clearance rates of inulin and sodium para-aminohippurate. The best correlation was between the clearance of subcutaneously injected radiolabelled iothalamate or 99Tcm DTPA and that of inulin. 99Tcm DTPA and 131I OIH clearances measured by a two blood sample technique did not give as good a correlation with inulin and PAH clearances respectively. When measurements of GFR and tubular function were repeated on the same patients the changes measured by inulin and PAH clearances did not correlate with those measured by the two blood sample technique using 99Tcm DTPA and OIH. Our results suggest that the clearance of subcutaneously injected iothalamate or DTPA can replace inulin clearance measurements. The two blood sample technique of measuring DTPA and OIH clearance does not directly reflect inulin and PAH clearance and is insufficiently reproducible to be used to follow changes in renal function.

Postural changes in plasma renin activity were studied in three groups of age and duration-matched male diabetics (potent, impotent and with postural hypotension) and in non-diabetic control subjects. Those diabetic subjects with postural hypotension due to automatic neuropathy had no increase in plasma renin activity to the erect posture whereas both the potent and impotent groups had similar plasma renin activity responses to the control subjects. There was a significant inverse correlation between the rise in plasma renin activity on standing and the postural drop in blood pressure (r = 0.476, P less than 0.01) but no correlation with other tests of autonomic reflex function such as the Valsalva manoeuvre and blood pressure response to sustained handgrip. The results suggested that the lesion responsible for the postural hypotension is in the efferent sympathetic pathway. However, neuropathy per se did not wholly explain the decreased postural plasma renin activity response. Diabetic nephropathy, with involvement of cells of juxtaglomerular apparatus, may also be implicated.

The fall in blood base occurring after the administration of secretin and the aspiration of duodenal contents was assessed in normal patients and in patients with chronic pancreatitis. In contrast to normal patients, those with chronic pancreatitis showed only a small fall or no fall in blood base level. There was no correlation between the amount of bicarbonate as determined by aspiration and that calculated from the blood base change. In 3 normal patients the magnitude of the renal compensatory mechanism in the post-secretin hour was found to be insignificant.

In 30 patients with acute myocardial infarction complicated by either advanced atrioventricular or bundle branch block, pulmonary arterial wedge pressures were studied in relation to clinical and radiographic features of left ventricular failure, changes in central venous and pulmonary arterial pressures, and arterial hypoxemia. An increase in mean pulmonary arterial wedge pressure was poorly correlated with the presence of dyspnea, audible third or fourth heart sounds, or persistent basal rales; however, it was significantly related to radiographic evidence of pulmonary venous dilatation or edema, a systolic blood pressure of less than 100 mm Hg, gallop rhythm associated with tachycardia, and heart rate in patients with sinus rhythm and normal atrioventricular conduction. Increased mean right atrial pressure indicated increased mean pulmonary arterial wedge pressure in patients with isolated anterior infarction, but in several patients with isolated inferior infarction the level of right atrial pressure was disproportionately high. The pulmonary arterial diastolic pressure closely reflected the mean pulmonary arterial wedge pressure in the absence of obstructive airways disease or pulmonary embolism. The level of the arterial oxygen tension fell as the mean pulmonary arterial wedge pressure rose, but it was considerably reduced in some patients with only moderately increased pressures. However, the latter usually had radiographic evidence of pulmonary venous dilatation or edema, suggesting that the pressure had been elevated previously to higher levels.

The ventilatory responses to CO2 without hypoxia, to hypoxia at constant PAACOACO2 and to CO2 combined with hypoxia were measured in duplicate with an interval of 20 min. between the two sets of measurements. The PAACOACO2 threshold during the second set differed in only random fashion from that during the first set; so did the CO2 sensitivity in the absence of hypoxia. The CO2 sensitivity during hypoxia, however, was significantly greater during the second set of measurements. The relevance of these results to the investigation of drugs which affect respiration is discussed.

The effect of ethamivan (vanillic acid diethylamide) on the ventilatory response to carbon dioxide has been investigated in healthy young adult males. Intravenous infusion of the drug at a rate of 9 mg/min causes respiratory stimulation depending in degree upon the prevailing alveolar CO(2) tension. When the latter is low stimulation by the drug is most marked and may largely support respiration below the CO(2) threshold. As alveolar Pco(2) increases, the effect of the drug disappears. These findings are discussed.

The antiplatelet drug ticlopidine was assessed as an agent for improving the patency of Brescia-Cimino arteriovenous fistulas as access for hemodialysis. In a double-blind randomized study over 1 month, two of six fistulas in the ticlopidine group and five of nine in the placebo group failed. A further one placebo and two ticlopidine patients still had functioning fistulas at the time of withdrawal for technical reasons from the trial. Ticlopidine appears, therefore, to enhance the efficacy of Brescia-Cimino fistulas, at least in the short term.

Existing methods for estimating population parameters in settings of data deficiency do not provide techniques for analysis of commonly available longitudinal data. In setting where complete population data is unavailable, longitudinal data recorded for only a subset of the total population are often available (e.g., event registers, genealogies). In this article we present and evaluate models which derive population parameters for the population subgroup underlying such longitudinal data. Using the distribution of individual times until first recorded event within a measurement interval, population parameters are estimated which provide basic denominator data for analyzing event occurrence. The models which we derive are especially suited to records which may include migration and population growth trends. The use of the models is demonstrated and evaluated through an application to genealogical records for a nineteenth-century population. Possible extensions of these models and their major limitations are also discussed.

In investigating the role of urinary kallikrein in the pathophysiology of hypertension, we measured 12-hour kallikrein excretion in 1,100 persons in 68 Utah kindreds. The kallikrein excretion was statistically adjusted to account for variations in body size and urine output. Adjusted kallikrein excretion was greater in youths than in adults and correlated with potassium excretion and sodium excretion in persons with normal blood pressure. It was decreased in normotensive subjects with strong family histories of stroke and hypertension, but was not significantly different in adults with hypertension. Adjusted kallikrein excretion was correlated between pairs of siblings, parent-offspring pairs and spouses. Our results indicate that kallikrein excretion is a familial variable, with the familiality due more to shared environmental than genetic factors.

A patient who developed chronic renal failure secondary to the haemolytic uraemic syndrome subsequently developed life threatening microangiopathic haemolytic anaemia following renal transplantation. Transplant nephrectomy was necessary to prevent the progression ofthrombocytopenia and associated pulmonary haemorrhage.

In this randomised, double-blind, crossover trial, the efficacy in hypertension of atenolol and nifedipine as single agents or in combination was compared. 81 patients with mild to moderate essential hypertension (sitting diastolic blood pressure 100–120mm Hg, aged 20–70 years) from 6 outpatient clinics entered the study. By use of a Latin-square design, patients received, in randomised fashion, sustained release nifedipine 20mg twice daily, atenolol 50mg in the morning and then placebo in the evening, or sustained release nifedipine 20mg plus atenolol 50mg in the morning and then placebo in the evening. Each schedule was followed for 4 weeks. All treatments lowered systolic and diastolic blood pressure in the supine and standing positions compared with pretreatment values. The combination regimen significantly reduced supine and standing systolic (p < 0.01 and p < 0.001, respectively) and diastolic (p < 0.001) blood pressure compared with nifedipine alone, and it also significantly reduced supine and standing systolic (p < 0.01 and p < 0.03, respectively) and diastolic (p < 0.01) blood pressure compared with atenolol alone. Heart rate was significantly decreased by atenolol and the combination compared with nifedipine alone. 15 patients withdrew because of side effects: 9 during nifedipine treatment, 2 during atenolol treatment and 4 during combination treatment. Side effects were typical of those associated with nifedipine or atenolol. Flushes and hot sweats, which were frequent with nifedipine, were significantly less (p < 0.001) with atenolol or the combination. For selected patients who do not respond to monotherapy with nifedipine or atenolol, the combination regimen seems an appropriate and useful alternative to β-blocker/diuretic combinations, especially where ischaemic heart disease may co-exist.

We analyze a 140-year series of smallpox deaths in the Aland Islands, Finland. Vaccination, introduced in 1805, dramatically reduced the annual number of smallpox deaths. It also influenced the age distribution of smallpox deaths, changing smallpox from a childhood disease before 1805 to one which affected both adults and children after 1805. This appears to be due to the fact that Alanders were usually vaccinated only once during childhood and often lost their immunity during adulthood. Spectral analysis of the prevaccination time series of smallpox deaths demonstrates a strong seven-year periodicity, reflecting the amount of time necessary to build up a cohort of nonimmune individuals. After the introduction of vaccination, the periodicity changes to eight years. The probability that a parish in Aland was affected by a smallpox epidemic is shown to be highly correlated with migration patterns and parish population sizes.

A study was carried out in 16 patients with moderately severe hypertension to investigate the effects of nifedipine, given alone or combined with a diuretic, on blood pressure and on renal and platelet function. After 4 weeks on placebo, patients were randomized to receive treatment for 6 weeks with either 20 mg, nifedipine twice daily or 25 mg mefruside once daily on a double-blind, double-dummy basis. All patients then received treatment for a further 6 weeks with a combination of the two drugs in the same dosage as before. The results of blood pressure measurements and laboratory investigations during the three phases of the study showed that significantly better blood pressure control was achieved with nifedipine alone than with mefruside alone. Mefruside had an additional hypotensive effect when added to nifedipine. There was no significant change in the renal blood flow or glomerular filtration rate, with a satisfactory control of blood pressure. There was also no detectable change in platelet aggregation with increasing concentrations of ADP and ristocetin. An adaptive mechanism could be responsible for the apparent lack of change compared with single dose studies.

This paper is part of a long-term investigation known as the Mormon Historical Demography Project. It examines the capability of a simulation model, originally proposed by John Bongaarts (1976), to fit the natural fertility pattern which characterized the mid-nineteenth century Mormon population. Application of this model permits estimates to be made of the historical timing and age-incidence of fertility limitation. A sensitivity analysis of the model's parameters demonstrates that simple changes in the model's proximate determinants of fertility, excluding contraceptive practices, would be insufficient to account for later transition effects. Thus the results successfully capture the dynamics underlying the Mormon natural fertility pattern as well as offer a framework for future modeling of the transition away from natural fertility.

Aliquots of plasma samples assayed after storage at -26 degrees C can show a significantly higher level of measured beta-thromboglobulin (beta-TG) than the corresponding unstored aliquots. Blood spun at the recommended speed of 1,800 X g still contains platelets that will release beta-TG on freezing to yield false results--a point that has not been stressed in the literature. Aliquots of blood plasma spun at either 1,800 X g (low speed [LS]) or 20,000 X g (high speed [HS]) were assayed by radioimmunoassay fresh and after storage at 4 degrees C or -26 degrees C. Storage at -26 degrees C increased mean beta-TG values of fresh or 4 degrees C stored LS samples from 0.78 to 1.94 nmol/L (28-70 ng/mL), whereas all HS mean values were +/- 0.51 nmol/L (between 18 and 19 ng/mL). The authors believe that in addition to the accepted precautions regarding blood sampling and handling, it is essential to stress that for accurate measurement of beta-TG in plasma, samples should be centrifuged at HS or, if this is not feasible, that they be assayed as soon as possible without prior freezing.