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Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes.

Background: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4that associated with BMI. A novel variant that predicts a p.Ser76Thr in IGFBP4 (Thr-allele frequency = 0.02) was identified which associated with the maximum BMI measured during adulthood (BMI 39.8 kg/m2for Thr-allele homozygotes combined with heterozygotes vs. 36.2 kg/m2for Ser-allele homozygotes, β= 6.7% per Thr-allele, p= 8.0 × 10−5, adjusted for age, sex, birth-year and the first five genetic principal components) and the maximum age- and sex-adjusted BMI z-score measured during childhood/adolescence (z-score 0.70 SD for Thr-allele heterozygotes vs. 0.32 SD for Ser-allele homozygotes, β= 0.37 SD per Thr-allele, p= 8.8 × 10−6). In vitro functional studies showed that IGFBP4 with the Thr-allele (BMI-increasing) had a 55% decrease (p= 0.0007) in FOXO-induced transcriptional activity, reflecting increased activation of the PI3K/AKT pathway mediated through increased IGF signaling. Over-expression and knock-down of IGFBP4 in OP9 cells during differentiation showed that IGFBP4 upregulates adipogenesis through PPARγ, CEBPα, AGPAT2 and SREBP1 expression. We propose that this American Indian specific variant in IGFBP4affects obesity via an increase of IGF signaling.

Diabetic nephropathy accounts for most of the excess mortality in individuals with diabetes, but the molecular mechanisms by which nephropathy develops are largely unknown. Here we tested cytosine methylation levels at 397,063 genomic CpG sites for association with decline in the estimated glomerular filtration rate (eGFR) over a six year period in 181 diabetic Pima Indians. Methylation levels at 77 sites showed significant association with eGFR decline after correction for multiple comparisons. A model including methylation level at two probes (cg25799291 and cg22253401) improved prediction of eGFR decline in addition to baseline eGFR and the albumin to creatinine ratio with the percent of variance explained significantly improving from 23.1% to 42.2%. Cg22253401 was also significantly associated with eGFR decline in a case-control study derived from the Chronic Renal Insufficiency Cohort. Probes at which methylation significantly associated with eGFR decline were localized to gene regulatory regions and enriched for genes with metabolic functions and apoptosis. Three of the 77 probes that were associated with eGFR decline in blood samples showed directionally consistent and significant association with fibrosis in microdissected human kidney tissue, after correction for multiple comparisons. Thus, cytosine methylation levels may provide biomarkers of disease progression in diabetic nephropathy and epigenetic variations contribute to the development of diabetic kidney disease.

ObjectiveRelationships were examined between persistent organic pollutants (POPs) and incident type 2 diabetes, end-stage renal disease (ESRD) and mortality.MethodsIn a nested case–control study, 300 persons without diabetes had baseline examinations between 1969 and 1974; 149 developed diabetes (cases) and 151 remained non-diabetic (controls) during 8.0 and 23.1 years of follow-up, respectively. POPs were measured at baseline. ORs for diabetes were computed by logistic regression analysis. The cases were followed from diabetes onset to ESRD, death or 2013. HRs for ESRD and mortality were computed by cause-specific hazard models. Patterns of association were explored using principal components analysis.ResultsPCB151 increased the odds for incident diabetes, whereas hexachlorobenzene (HCB) was protective after adjusting for age, sex, body mass index, sample storage characteristics, glucose and lipid levels. Associations between incident diabetes and polychlorinatedbiphenyl (PCB) or persistent pesticide (PST) components were mostly positive but non-significant. Among the cases, 29 developed ESRD and 48 died without ESRD. PCB28, PCB49 and PCB44 increased the risk of ESRD after adjusting for baseline demographic and clinical characteristics. Several PCBs and PSTs increased the risk of death without ESRD. The principal components analysis identified PCBs with low-chlorine load positively associated with ESRD and death without ESRD, and several PSTs associated with death without ESRD.ConclusionsMost POPs were positively but not significantly associated with incident diabetes. PCB151 was significantly predictive and HCB was significantly protective for diabetes. Among participants with diabetes, low-chlorine PCBs increase the risk of ESRD and death without ESRD, whereas several PSTs predict death without ESRD.

The Phoenix Epidemiology and Clinical Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases has conducted prospective studies of diabetes and its complications in the Pima Indians living in Arizona, USA for over 50 years. In this review we highlight areas in which these studies provided vital insights into the criteria used to diagnose type 2 diabetes, the pathophysiologic changes that accompany the development of type 2 diabetes, and the course and determinants of diabetes complications—focusing specifically on diabetic kidney disease. We include data from our longitudinal population-based study of diabetes and its complications, studies on the role of insulin resistance and insulin secretion in the pathophysiology of type 2 diabetes, and in-depth studies of diabetic kidney disease that include measures of glomerular function and research kidney biopsies. We also focus on the emerging health threat posed by youth-onset type 2 diabetes, which was first seen in the Pima Indians in the 1960s and is becoming an increasing issue worldwide.

Context:Data are lacking on how metabolic risk factors during childhood affect the long-term risk of type 2 diabetes.Objectives:Assess four metabolic risk factors as predictors of type 2 diabetes and determine whether the risk differs between younger and older children.Design:In a prospective cohort study conducted between 1965 and 2007, participants were followed for development of diabetes. Baseline measurements included body mass index (BMI), blood pressure, serum cholesterol, and 2-hour plasma glucose after an oral glucose tolerance test. Additional analyses divided subjects into two groups according to baseline age, 5–11 and 12–19 years.Setting:Gila River Indian Community in Arizona.Participants:A total of 5532 nondiabetic Pima Indian children 5–19 years old.Results:A total of 1281 children developed diabetes (median follow-up, 12.4 years). Diabetes incidence was higher in overweight children (BMI ≥ 85th percentile) than in nonoverweight children. Nonoverweight children had the lowest risk of diabetes (20-year cumulative incidence, 9.5%), whereas overweight children with impaired glucose tolerance (2-hour glucose ≥ 140 mg/dL) had the highest (79.0%). The relative risk for children with metabolic abnormalities compared with their healthy counterparts was higher in younger children than in older children early in follow-up. BMI and 2-hour glucose were related to incident diabetes in multivariable models (predicted 15-year cumulative incidence for the highest vs lowest quartile was 3.9 and 1.8 times as high for BMI and 2-hour glucose, respectively; P< .001), whereas blood pressure and cholesterol were not.Conclusions:BMI and impaired glucose tolerance in children are strong predictors of type 2 diabetes. Other components of the “metabolic syndrome” are not.

We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria.

Braxton Mitchell is professor of medicine and of epidemiology & public health at the University of Maryland School of Medicine in Baltimore, MD, USA. He obtained his PhD degree at the University of Michigan, MI, USA. He is a genetic epidemiologist whose research program focuses on assessing the genetic contributions to common age-related diseases, gene mapping and evaluating the impact of discovered variants at the population level. In addition to diabetes, his current research focuses mainly in the areas of cardiovascular disease, stroke, osteoporosis and osteoarthritis.Robert Hanson is staff clinician at the Phoenix Epidemiology and Clinical Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, AZ, USA. He obtained his MD degree at the University of Kansas (KS, USA) and his MPH degree at Columbia University (NY, USA). He is an internist and epidemiologist and his research program focuses on the genetic epidemiology of Type 2 diabetes, obesity and complications of diabetes.

African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.

CONTEXT: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE: and Intervention: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). Design, Setting, Participants, and Outcome: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. RESULTS: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08–1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99–1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92–1.45), P = 0.20, respectively] but did not reach statistical significance. CONCLUSIONS: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

Objective: The contribution of visceral adipose tissue (VAT) to insulin resistance is well‐established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. Research Methods and Procedures: This was a cross‐sectional study of 78 nondiabetic African‐American volunteers (44 men, 35 women; age 33.8 ± 7.3 years; BMI 30.9 ± 7.4 kg/m2). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (SI) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. Results: In men, both VAT and SAT were negatively correlated with SI(r for both correlations = −0.57; p< 0.01). In women, the correlation coefficient between VAT and SIwas −0.50 (p< 0.01) and between SAT and SIwas −0.67 (p< 0.01). In women, the correlation coefficient for SIwith SAT was significantly greater than the correlation coefficient with VAT (p= 0.02). Discussion: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For African‐American women, SAT may have a greater effect than VAT on insulin resistance.

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The present analyses were conducted to examine the extent to which insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic factors, and to assess whether these genetic factors overlap with those influencing susceptibility to type 2 diabetes in Pima Indians. Indices calculated from fasting and 2-h post-load insulin (I0, I120) and glucose (G0, G120) concentrations included insulin sensitivity index [ISI0=10⁴/(I0·G0)] and corrected insulin response {CIR120=I120/[G120·(G120–70 mg/dl)]}. Heritability (h²) was determined using variance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait linkage analyses of ISI0 and CIR120 were conducted and affected-sibling analyses of diabetic siblings stratified by prediabetic measurements of ISI0 and CIR120 were also performed. Both ISI0 (h²=0.37±0.06) and CIR120 (h²=0.25±0.07) were moderately heritable. Modest evidence for linkage with CIR120 (logarithm of odds (LOD)=1.6) was observed on chromosome 1q in a region previously shown to have linkage with young-onset diabetes in Pimas. When diabetic siblings were stratified by CIR120, evidence for linkage in this region was strongest (LOD=1.5) among those with a low CIR120. Additional regions with modest evidence for linkage with ISI0 were observed on chromosomes 9p (LOD=2.0) and 14p (LOD=1.7). The present analyses suggest that insulin sensitivity and insulin secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromosome 1q affects insulin secretion. Published in 2001 by John Wiley & Sons, Ltd.

The KCNJ9gene encodes a G-protein-coupled inwardly rectifying potassium channel and is located within a region on human chromosome 1 that has been linked with type 2 diabetes mellitus in Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within KCNJ9to diabetes susceptibility in the Pimas, we have genotyped 11 single nucleotide polymorphisms (SNPs) in 50 Pimas with diabetes and 50 Pimas over the age of 45 without diabetes and in 51 sib pairs, discordant for the disease, who were characterized by decreased allele sharing at the chromosomal location of the maximum LOD score. We detected three SNP clusters exhibiting distinct linkage disequilibria. Polymorphisms in intron 2, exon 3, and the 3′-UTR were in statistically significant linkage disequilibrium with diabetes in the case-control group (P= 0.006), but not the sibling pairs (P= 0.097). A weak association with diabetes was also found in the original linkage set comprising 1150 Pimas (odds ratio = 0.64/P= 0.079 for a dominant model and OR = 0.67/P= 0.005 for a recessive model). However, no effect on linkage was detected following adjustment for one of the most strongly associated SNPs in the entire original linkage set. Our results indicate that variants in KCNJ9are associated with diabetes in Pimas but do not account for the linkage of 1q with diabetes in this population.

Large subcutaneous abdominal adipocyte size (s.c. abd. AS) is associated with insulin resistance and predicts type 2 diabetes in Pima Indians. Because type 2 diabetes is familial, we aimed to determine whether mean s.c. abd. AS is also familial and if so, to identify chromosomal regions linked to this measure. Body composition (hydrodensitometry) and mean s.c. abd. AS (fat biopsy) were measured in 295 Pima Indians (179 with normal, 80 with impaired, and 36 with diabetic glucose tolerance) representing 164 nuclear families. Mean s.c. abd. AS, adjusted for age, sex, and percentage body fat was a familial trait (heritability h2= 0.48, P< 0.0001). A genome-wide autosomal scan revealed suggestive evidence for linkage (LOD 1.73) of adjusted mean s.c. abd. AS to chromosome 1q21–q23, a region containing LMNA,the gene encoding for the nuclear envelope proteins lamin A/C. Rare mutations in LMNAwere recently shown to underlie familial partial lipodystrophy (FPLD), a syndrome characterized by regional loss of adipose tissue, insulin resistance, and glucose intolerance. A common (allelic frequency 0.43) single nucleotide polymorphism (silent 1908C → T substitution) in exon 10 of LMNA(GenBank X03444) was associated with reduced age-, sex- and percentage body fat-adjusted mean s.c. abd. AS [0.80 ± 0.17 (CC), 0.76 ± 0.15 (CT), 0.73 ± 0.16 (TT) μg lipid/cell, P< 0.05 for CC vs TT]. These findings indicate that approximately half of the variance in mean s.c. abd. AS can be attributed to familial factors and that genetic variation in LMNAmight not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population.

•Multilabel probes increase fluorescence signal from labeled bacterial plasmids by 3-fold.•Bacterial plasmid from a dilute sample is concentrated on a porous acrylate monolith in a sequence-specific manner.•Fluorescence signal is linear with loaded plasmid concentration between 1 pM and 1 nM.•This system can serve to increase signal for single-molecule counting and DNA hybridization technologies.

Having focused in last month's JONA on the concepts and principles for an effective management information system, Hanson here takes a closer look at a management informa-tion system (MIIS) for staffing. Using a specific staffing situation, he discusses elements of data and examines their value as information. As the exploration of an MIS for staffing progresses, three primary data elements-producti-vity, budget utilization, and budget adequacy-evolve in relation to management objectives. Nursing acbninistrators willfind the specific process of the MIS model valuable in interpreting and using information and data most effec-tive& for management decisions and actions. This and the previous article by Hanson are based on material in a forthcoming book, Management Systems for Nursing Ser-vice Staffing, to be published by Aspen Systems Corpora-tion, Rockville, Maryland.

A management information system (MIS) is a tool for managing resources effectively. After reviewing some concepts and principles for effective data management, Hanson clearly applies the concepts to nurse staffing systems, which manage human resources. He defines a seven-step process for establishing an MIS, from defining the management objective to implementing the system. Pointing out that an MIS need not be computerized to be effective, Hanson presents a positive perspective and clarifies some often-misconceived notions about management information systems and the paper printouts they generate. In the next issue of JONA, a second article by Hanson will take a more detailed look at the variety, use, and usefulness of staffing statistics available from an MIS for staffing.

BACKGROUND: Screening for non-insulin-dependent diabetes mellitus (NIDDM) can be useful in clinical practice and in epidemiologic and genetic studies, but the available information for choosing between screening methods is limited. In this study, characteristics of several screening tests for NIDDM were compared. METHODS: Among Pima Indians participating in an epidemiologic study, the sensitivity and specificity for detecting NIDDM of fasting plasma glucose (FPG) levels and two measures of glycated hemoglobin (HbA1 or HbA1c) were compared in 2092 fasting subjects. Glycated hemoglobin, quantitative glycosuria, and dipstick glycosuria were compared in 237 nonfasting subjects. Diabetes was diagnosed using an oral glucose tolerance test if the 2-hour postload venous plasma glucose concentration was 11.1 mmol/L (200 mg/dL) or greater. The area under the relative operating characteristic curve was used to compare tests. RESULTS: In fasting subjects, the sensitivity for detecting diabetes with 98% specificity was 78.8% for HbA1 level of 7.5% or greater, 80.3% for HbA1c level of 6.3% or greater, and 88.0% for FPG level of 6.83 mmol/L (123 mg/dL) or greater. By relative operating characteristic analysis, there were no significant differences between FPG and HbA1c, but FPG was significantly more sensitive than HbA1. In nonfasting subjects the sensitivity at 98% specificity was 92.9% for HbA1 level of 7.3% or greater, 80.6% for quantitative urine glucose level of 1.94 mmol/L (35 mg/dL) or greater, and 64.3% for trace or greater of dipstick glycosuria. The area under the relative operating characteristic curve was significantly greater for glycated hemoglobin than for either measure of glycosuria. CONCLUSIONS: Although FPG has the best screening properties, HbA1c, HbA1, and quantitative urine glucose also provide high specificity and approximately 80% sensitivity in detecting NIDDM. The choice of a particular method could depend on cost, convenience, and availability.(Arch Intern Med. 1993;153:2133-2140)

Objective:To assess the relationship between dietary calcium and blood pressure.Methods:Cross-sectional study of 404 adult Pima Indians of Arizona. Dietary variables were assessed by the 24-hour recall. Hypertension (HTN) was defined as systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg or drug treatment.Results:Controlled for age and sex, dietary calcium intake was higher in subjects with HTN than in those without (p<0.01), and higher dietary calcium was associated with a higher prevalence of HTN (odds ratio comparing highest with lowest tertile group of calcium=2.6, 95% CI 1.4–4.8). Age-sex-adjusted mean DBP in low, middle and high tertiles of calcium was 74, 76, and 79 mmHg, respectively (p<0.001). SBP was not significantly different in the three tertiles (p=0.07). Multiple regression analyses that controlled for age, sex, body mass index, sodium, potassium and alcohol also suggested a positive association between DBP and dietary calcium (p<0.01), an association which was stronger at higher glucose concentrations (p<0.01 for the calcium-glucose interaction).Conclusion:In Pima Indians, a population with a high incidence of diabetes, the inverse association between dietary calcium and blood pressure reported in other populations was not found.

The role of plasma lipoproteins in the development of non-insulin-dependent diabetes mellitus (NIDDM) was studied in 787 non-diabetic (2-h glucose<11.1 mmol/l) Pima Indians (265 men and 522 women). Subjects were followed for a mean of 9.8 (range: 1.8–16.4) years, during which 261 (76 men and 185 women) developed NIDDM. In men and women, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglyceride, low-density lipoprotein triglyceride and total triglyceride, controlled for age, predicted NIDDM (P<0.01 for each). These effects diminished when controlled for age, sex, body mass index, systolic blood pressure and 2-h glucose. However, high-density lipoprotein (HDL) cholesterol, controlled for age, body mass index, systolic blood pressure and 2-h glucose, was a significant protective factor for NIDDM in women (hazard rate ratio (HRR)=0.35, 95% CI (0.23–0.54), P<0.001, 90th compared with 10th percentile) but not in men (HRR=1.04, 95% CI (0.53–2.05), P=0.915). This association remained significant in women when controlled for fasting or 2-h plasma insulin concentrations, other estimates of insulin resistance or alcohol consumption. The protective effect of HDL cholesterol was similar among women with normal (2-h glucose<7.8 mmol/l) or impaired (7.8 mmol/l≤2-h glucose<11.1 mmol/l) glucose tolerance at baseline. These results indicate that lipoprotein disorders are an early accompaniment of the abnormalities that lead to NIDDM.

In a survey of 160 hospital employees, those employed in an area where the air supply was potentially contaminated with the exhaust air from other hospital areas had a higher prevalence of certain work-related symptoms than em ployees from other areas. There was little difference between the two groups in overall health. These findings have implications for building intolerance, and larger studies are needed to investigate the role of ventilation system design, especially as it relates to the potential for contamination, in the cause of this syndrome.

The contemporary nursing adntinistrator faces an era of financial andpersonnel resource constraints that wilIforce criticalreviews of the management of human resources and productivity in nursing service. In this article, Hanson chal-lenges traditional views of productivity and offers exciting alternative concepts and models for evaluating resources and their relationships to productivity. Workable formulas and practial examples help translate the concepts into results that can be applied in real-world decision making.

To identify specific genes affecting vulnerability or resistance, we performed a whole-autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. Genotypes at 517 autosomal microsatellite loci and clinical evaluations were available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs. Highly suggestive evidence for linkage emerged for two genomic regions using two- and multipoint sib-pair regression methods; both regions harbored neurogenetic candidate genes. The best evidence is seen with D11S1984 (nominal P = 0.00007, lod ≊ 3.1) on chromosome 11p, in close proximity to the DRD4 dopamine receptor and tyrosine hydroxylase (TH) genes. Good evidence is seen with D4S3242 (nominal P = 0.0002, lod ≊ 2.8) on chromosome 4p, near the β1 GABA receptor gene. Interestingly, three loci in the alcohol dehydrogenase gene cluster on chromosome 4q showed evidence for linkage with two-point analyses, but not multipoint analysis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:216–221, 1998. Published 1998 Wiley-Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.

The equations in the following commentary and reply may make this discussion look formidably technical. But nurse administrators who take the time to read through the exchange, as well as the April1 982 JONA article on which it is based, will gain a useful and much needed method for relating staffing requirements to patients nursing care needs. A t a time when administrators decisions are gov-erned more than ever by total expenditures, a mechanism for relating qualitative and quantitative factors in staffing can be a boon. The contribution Virginia Cleland made in her article on this crucial topic was to factor quality into the equation: assessing not just how many hours of care are needed for patients with various leveh of need, but what kind of staff, what level of competence. Robert Hanson,whose comment suggests revivions to improve the formulas, will address the same issue in his own article Managing Human Resources in the December 1982 JONA.

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The relationship between oestrogen replacement therapy and breast cancer risk was examined based on data obtained from a population-based case-control study of breast cancer on Long Island, New York, USA. Cases were defined as female residents of two Long Island counties, aged 20–79, who were diagnosed with breast cancer between 1 January 1984 and 31 December 1986. Age- and county-matched controls were selected from driver's licence files. Among all postmenopausal women, there was no significant association between ever-use of hormones to treat menopausal symptoms and breast cancer risk. There was also no significant positive association in any subgroup defined by type of menopause (natural, hysterectomy with at least one ovary intact, bilateral oophorectomy) or age at menopause. Additionally, there was no increasing trend in risk with duration of use either overall or in any subgroup, nor was there an effect at any interval since last use. A significant elevation in risk was observed in women with 10–19 years since first exposure, which was concentrated in women with a natural menopause or hysterectomy with at least one ovary remaining, and women aged >45 at menopause. Results of logistic regression analysis revealed no important confounding by any of several established breast cancer risk factors. However, a significant interaction was observed between body mass index (BMI) and oestrogen use, with an effect of oestrogen use being seen only in the thinnest tercile. Although biologically plausible explanations for this finding exist, the effect of chance cannot be ruled out.