Prospective associations of C-reactive protein (CRP) levels and CRP genetic risk scores with risk of total knee and hip replacement for osteoarthritis in a diverse cohort.

OBJECTIVE: To examine associations of high-sensitivity C-reactive protein (CRP) levels and polygenic CRP genetic risk scores (GRS) with risk of end-stage hip or knee osteoarthritis (OA), defined as incident total hip (THR) or knee replacement (TKR) for OA. DESIGN: This study included a cohort of postmenopausal white, African American, and Hispanic women from the Women's Health Initiative. Women were followed from baseline to date of THR or TKR, death, or December 31, 2014. Medicare claims data identified THR and TKR. Hs-CRP and genotyping data were collected at baseline. Three CRP GRS were constructed: 1) a 4-SNP GRS comprised of genetic variants representing variation in the CRP gene among European populations; 2) a multilocus 18-SNP GRS of genetic variants significantly associated with CRP levels in a meta-analysis of genome-wide association studies; and 3) a 5-SNP GRS of genetic variants significantly associated with CRP levels among African American women. RESULTS: In analyses conducted separately among each race and ethnic group, there were no significant associations of ln hs-CRP with risk of THR or TKR, after adjusting for age, body mass index, lifestyle characteristics, chronic diseases, hormone therapy use, and non-steroidal anti-inflammatory drug use. CRP GRS were not associated with risk of THR or TKR in any ethnic group. CONCLUSIONS: Serum levels of ln hs-CRP and genetically-predicted CRP levels were not associated with risk of THR or TKR for OA among a diverse cohort of women.

Reallocating time spent in sleep, sedentary behavior and physical activity and its association with pain: a pilot sleep study from the Osteoarthritis Initiative.

OBJECTIVE: Being physically active has broad health benefits for people with osteoarthritis (OA), including pain relief. Increasing physical activity (PA) requires reducing time in other behaviors within a fixed 24-h day. We examined the potential benefits in relation to pain from trading time in one type of wake or sleep behavior for another. METHOD: In this cross-sectional study, we used isotemporal logistic regression models to examine the estimated effect on pain from replacing time in one behavior with equal time in another, controlling for sociodemographic and health factors. Stratified analysis was conducted by the report of restless sleep. Sleep and wake behaviors [sedentary behavior (SB), light PA, moderate PA] were monitored by accelerometer in a pilot study of 185 Osteoarthritis Initiative (OAI) participants. Outcomes were bodily pain interference and knee pain. RESULTS: Moderate PA substituted for an equivalent time in sleep or other types of wake behaviors was most strongly associated with lower odds of pain (bodily pain interference odds reduced 21-25%, knee pain odds reduced 17-20% per 10-min exchange). These beneficial associations were particularly pronounced in individuals without restless sleep, but not in those with restless sleep, especially for bodily pain interference. CONCLUSION: Interventions promoting moderate physical activities may be most beneficial to address pain among people with or at high risk for knee OA. In addition to encouraging moderate-intensity PA, pain management strategies may also include the identification and treatment of sleep problems.

Lay public's use of a support group for general dental problems.

OBJECTIVE: To categorize and tabulate layperson inquiries made to an Internet dental health support site to identify oral conditions and associated behaviors of concern. METHODS: A retrospective tabulation of wall postings was made from an established dental health support website hosted by WebMD over a 2-year period (April 2013-April 2015). A mixed method approach of content and thematic analysis was used. Content analysis identified content of oral health concerns, while thematic analysis using grounded theory identified themes and beliefs concerning associated behaviors. RESULTS: The presence of non-descript growths on the tongue and swelling and/or discoloration of the lips elicited the most inquires. These were often self-diagnosed as oral candidiasis, a STD or a carcinoma, provoking high levels of self-concern. Unprotected sexual activity, excessive ingestion of soft and hard beverages, smoking and overexposure to the sun were the most frequently self-reported behaviors associated with their concerns. Many questions focused upon "normal" healing, including the amount of edema and discomfort that could occur following oral surgery or other dental procedures. Information concerning alternative treatments was often solicited, and many alluded that they had not been provided sufficient information to make informed decisions prior to dental treatment. CONCLUSIONS: Laypersons have many oral health concerns particularly in relationship to the development of undiagnosed pathologies in conjunction with a history of volitional behaviors. The dental community should monitor these sites to provide advice and links to information about common oral health concerns and their possible association with detrimental behaviors.

Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.

SUMMARY: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

Renal function and nonvertebral fracture risk in multiethnic women: the Women's Health Initiative (WHI).

UNLABELLED: To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women's Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups. INTRODUCTION: The purpose of this study was to determine whether renal function is associated with fracture risk within racial/ethnic groups. METHODS: A nested case-control study was conducted among 93,673 postmenopausal women; incident nonvertebral fractures were identified in 362 Black, 183 Hispanic, 110 Asian, and 45 American-Indian women. A random sample of 395 White women with incident nonvertebral fracture was chosen. One nonfracture control for each case was selected (matched on age, race/ethnicity, and blood draw date). Cystatin C levels were measured using baseline serum, and estimated glomerular filtration rate calculated (eGFR(cys-c)). RESULTS: Each 1 SD increase in cystatin C was associated with a 1.2-fold increased risk of fracture among White women (adjusted odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.04-1.46). The OR of fracture was 1.16 (95% CI, 0.85-1.58) among women with eGFR(cys-c) 60-90 mL/min/1.73 m(2) and 2.46 (95% CI, 1.16-5.21) among those with eGFR(cys-c) <60 mL/min/1.73 m(2) compared to the reference group (eGFR(cys-c) >90 mL/min/1.73 m(2)) (p trend = 0.05). The association was reduced after adjustment for cytokine TNFα soluble receptors (OR, 1.62; 95% CI, 0.59-4.46 for eGFR(cys-c) <60 mL/min/1.73 m(2)). Among Blacks, there was an association between cystatin C and fracture risk (OR per 1 SD increase, 1.15; 95% CI, 1.00-1.32); after adjustment, this association was only modestly attenuated, but no longer statistically significant. There was no evidence of significant associations among Hispanic, Asian, or American-Indian women. CONCLUSION: Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture. Effects of renal function on chronic inflammation may mediate this association. Reduced renal function may increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.

Semi-automated segmentation to assess the lateral meniscus in normal and osteoarthritic knees.

OBJECTIVE: The goal of this study was to develop an algorithm to semi-automatically segment the meniscus in a series of magnetic resonance (MR) images to use for normal knees and those with moderate osteoarthritis (OA). METHOD: The segmentation method was developed then evaluated on 10 baseline MR images obtained from subjects with no evidence, symptoms, or risk factors of knee (OA), and 14 from subjects with established knee OA enrolled in the Osteoarthritis Initiative (OAI). After manually choosing a seed point within the meniscus, a threshold level was calculated through a Gaussian fit model. Under anatomical, intensity, and range constraints, a threshold operation was completed followed by conditional dilation and post-processing. The post-processing operation reevaluates the pixels included and excluded in the area surrounding the meniscus to improve accuracy. The developed method was evaluated for both normal and degenerative menisci by comparing the segmentation algorithm results with manual segmentations from five human readers. RESULTS: The semi-automated segmentation method produces results similar to those of trained observers, with an average similarity index over 0.80 for normal participants and 0.75, 0.67, and 0.64 for participants with established knee OA with Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) scores of 0, one, and two respectively. CONCLUSION: The semi-automatic segmentation method produced accurate and consistent segmentations of the meniscus when compared to manual segmentations in the assessment of normal menisci in mild to moderate OA. Future studies will examine the change in volume, thickness, and intensity characteristics at different stages of OA.

Estimating evaporation: a technique adaptable to remote sensing.

A procedure is presented for calculating 24-hour totals of evaporation from wet and drying soils. Its application requires a knowledge of the daily solar radiation and the maximum and minimum air temperatures (standard Weather Service measurements), moist surface albedo (readily estimated or obtainable from a one-time measurement), and maximum and minimum surface temperatures (obtainable from surface or airborne sensors). Tests of the technique on a bare field of Avondale loam at Phoenix, Arizona, have shown it to be independent of season.

Remote-sensing of crop yields.

Our research efforts with durum wheat have led to the development of the SDD concept. Its application makes possible crop yield estimates from remotely acquired canopy temperatures and auxiliary air temperature measurements obtained during the period from head emergence to the cessation of head growth. Canopy albedo measurements appear adequate to delineate this critical period, making the technique potentially adaptable to predictions of crop yields by remote-sensing. The trifactor nomograms produced from combinations of the linear regression equations also suggest that the SDD concept may be used for scheduling irrigations by remote-sensing.

Remote detection of biological stresses in plants with infrared thermometry.

Green leaves of mature sugar beets infected with Pythium aphanidermatum and cotton infected with Phymatotrichum omnivorum had midday radiant leaf temperatures 3 degrees to 5 degrees warmer than adjacent plants with no sign of disease. The temperature difference persisted under varying conditions of soil moisture and could be used to detect biological stress imposed by these soilborne root-rotting fungi.

Incidence of fractures compared to cardiovascular disease and breast cancer: the Women's Health Initiative Observational Study.

UNLABELLED: To compare the absolute risk of fracture to the risk of other conditions by race/ethnicity, we studied 83,724 women, aged 70-79. The projected number of fractures was similar to or exceeded the combined number of cardiovascular events and breast cancers. Osteoporosis prevention efforts should target women of all ethnicities. INTRODUCTION: The relative risk of fracture is lower in non-white compared to white women but the absolute risk of fracture in comparison to other common chronic conditions is uncertain. METHODS: We performed a prospective cohort study of 83,724 women, age 50-79 years. Cardiovascular disease (CVD), invasive breast cancer and all fractures were identified over an average of 7.7 +/- 2.6 years. RESULTS: The incidence of fracture, breast cancer, stroke and CVD varied across ethnicity. The annualized (%) incidence of fracture was greatest in whites (2.4%) and American Indians (2.8%) and lowest among blacks (1.3%). The majority of hip fractures occurred in white women. The projected number of women who will experience a fracture in one year exceeded the combined number of women who would experience invasive breast cancer or a broad category of CVD events in all ethnic groups except blacks. In 10,000 black women, an estimated 153 women would experience CVD, and 35 women, breast cancer compared to 126 women expected to fracture in one year. CONCLUSION: The annual risk of suffering a fracture is substantial in women of all ethnicities. Osteoporosis prevention efforts should target all women irrespective of their race/ethnic backgrounds.

Class II composite resin restorations: faster, easier, predictable.

Composite resin continues to displace amalgam as the preferred direct restorative material in developed countries. Even though composite materials have evolved to include nanoparticles with high physical properties and low shrinkage stress, dentists have been challenged to efficiently create quality, long lasting, predictable restorations. Unlike amalgam, composite resin cannot be condensed making the establishment of a predictable, proper contact more difficult. In addition, composite requires an understanding of adhesives and an appreciation for their exacting application. These facts combined with the precise adaptation and light-curing of multiple layers makes placement of quality Class II composite restorations tedious and time-consuming. For private practicing dentists, it can also have an effect on economic productivity. Clinicians have always wanted an easier, efficient placement technique for posterior composite restorations that rivals that for amalgam. It appears that advances in instrumentation, materials and technology have finally delivered it.

Weight-training effects on bone mineral density in early postmenopausal women.

We tested the hypothesis that weight training would be an effective modality in maintaining or increasing bone mineral density (BMD) at the lumbar spine, femoral neck, and bone mineral content (BMC) at the distal wrist in early postmenopausal women. A total of 17 women completed a 9 month weight-training program, and 9 women served as a control group. Resistance training occurred three times per week using exercises designed to increase muscular strength. Mean change in lumbar BMD in the weight-trained group (1.6 +/- 1.2%, mean +/- SEM) was significantly different from the change in the control group (-3.6 +/- 1.5%, p less than 0.01) over the 9 month period. No significant weight-training effect was detected at the femoral neck or distal wrist site. We conclude that weight training may be a useful exercise modality for maintaining lumbar BMD in early postmenopausal women.

Characterization of a large molecular weight prolactin in women with idiopathic hyperprolactinemia and normal menses.

This study reports the presence of a large molecular sized PRL as the major form of circulating immunoactive PRL in five women with idiopathic hyperprolactinemia and normal menses. Gel filtration patterns of serum from these patients revealed 98-100% predominance of a 150,000- to 160,000-dalton PRL in contrast to the predominance of the 22,000-dalton species in other hyperprolactinemic patients. This 150,000- to 160,000-dalton PRL was immunologically similar to the 22,000-dalton PRL, and its size on gel filtration was not altered using denaturing conditions. With reduction of disulfide bonds, there was a shift of the peak I PRL to smaller mol wt peptides. In addition, studies of one woman with idiopathic hyperprolactinemia and normal menses revealed preservation of 98% peak I predominance during physiological and pharmacological perturbations of PRL secretion. Finally, assay of the bioactivity of the large molecular sized PRL in the Nb2 rat lymphoma line revealed diminished activity compared to the 22,000-dalton species. This latter finding may help explain the maintenance of normal menses and relative lack of clinical signs in patients with this form of hyperprolactinemia.

Persistence of large molecular weight prolactin secretion during pregnancy in women with macroprolactinemia and its presence in fetal cord blood.

Two hyperprolactinemic women with marked increases in circulating 150K PRL were studied from conception throughout pregnancy and delivery. The serum PRL increase during pregnancy in these women was considerably less than that in normal pregnant women (2- and 3.5-fold vs. 10- to 20-fold increases, respectively). The 150K PRL species persisted as the predominant circulating form of PRL throughout each trimester of pregnancy in these women. In contrast, the predominant form of PRL in serum from normal pregnant women was the 22K PRL form. Gel filtration analysis of the umbilical venous cord serum of infants of the macroprolactinemic women demonstrated excessive concentrations of 150K and 50K PRL compared to the molecular species of PRL in the cord serum of normal infants. Repeat analysis of the PRL species in one infant at age 3 yr continued to reveal excessive secretion of 150K PRL (11% vs. less than 6% in normals). These data suggest that genetic influences may be operative in determining PRL heterogeneity.

Chronic use of the calcium channel blocker nifedipine has no significant effect on bone metabolism in men.

Calcium channel blockers have been reported to have such diverse effects on reduction in protein synthesis, diminished incorporation of proline into new collagen, and decreased hormone release in vitro. The chronic affect of the calcium channel blocker nifedipine was examined in vivo to determine the possible impact of pharmacologic calcium channel blockade on bone metabolism. Eleven Caucasian males treated with an average of 40 mg/d nifedipine for an average of three years were compared to 11 control males matched for age, height, weight, activity level, cardiovascular status, and calcium intake. No significant differences between groups were noted in bone mineral density at the lumbar spine (L2-4), proximal femur (femoral neck, Ward's triangle and trochanter), and proximal and distal radius. There were also no significant differences in parameters of bone turnover (alkaline phosphatase, osteocalcin, urine calcium/creatinine, and hydroxyproline/creatinine ratio), or hormones that might affect calcium metabolism and bone (testosterone, PTH, 25(OH) vitamin D, and calcitonin). In summary, chronic nifedipine use in males is not associated with either a beneficial or adverse effect on bone metabolism.

Bone mass and endocrine adaptations to training in spinal cord injured individuals.

To investigate whether exercise training can produce increases in bone mass in spinal cord-injured (SCI) individuals with established disuse osteopenia, nine subjects (age 28.2 years, time since injury 6.0 years, level of injury C5-T7) were recruited for a 9-month training program using functional electrical stimulation cycle ergometry (FES-CE), which produces active muscle contractions in the paralyzed limb. After training, bone mineral density (BMD, by X-ray absorptiometry) increased by 0.047 +/- 0.010 g/cm2 at the lumbar spine; changes in BMD at the femoral neck, distal femur, and proximal tibia were not significant for the group as a whole. In a subset of subjects training at > or = 18 W for at least 3 months (n = 4), BMD increased by 0.095 +/- 0.026 g/cm2 (+18%) at the distal femur. By 6 months of training, a 78% increase in serum osteocalcin was observed, indicating an increase in bone turnover. Urinary calcium and hydroxyproline, indicators of resorptive activity, did not change over the same period. Serum PTH increased 75% over baseline values (from 2.98 +/- 0.15 to 5.22 +/- 0.62 pmol/L) after 6 months' training, with several individual values in hyperparathyroid range; PTH declined toward baseline values by 9 months. These data establish the feasibility of stimulating site-specific increases in bone mass in severely osteopenic bone with muscle contractions independent of weight-bearing for those subjects able to achieve a threshold power output of 18 W with FES-CE. Calcium supplementation from the outset of training in osteopenic individuals may be advisable to prevent training-induced increases in PTH.

Sequential prolactin evaluation of a "cured" patient with recurrence of prolactinoma.

Several investigators have suggested that prolactin secretion in some subjects with hyperprolactinemia associated with pituitary macroadenomas may have a resistance to the prolactin inhibitory hormone, dopamine. This report describes a male subject with a prolactinoma whose preoperative evaluation demonstrated a resistance of prolactin release to inhibition by dopamine. Evaluation of prolactin secretion from monolayer culture of his tumor also revealed a resistance to inhibition by dopamine. Four months postoperatively, normal serum prolactin levels and a normal maximal inhibition of prolactin to a dopamine infusion of 0.04 microgram/kg/minute suggested surgical cure. However, a 24-hour prolactin sampling revealed blunted nocturnal augmentation of prolactin release, an early escape of inhibition of prolactin release at 150 minutes from a 0.04 microgram/kg/minute dopamine infusion, and abnormal prolactin response to a low-dose (0.004 microgram/kg/minute) dopamine infusion. Hence, persistent abnormalities in prolactin secretory dynamics were noted with more extensive testing in this patient when he was thought to have been cured. One year postoperatively, the hyperprolactinemia recurred, prolactin release was markedly resistant to dopamine, and an abnormal 24-hour prolactin profile of release was present. Thus, resistance of prolactin secretion to inhibition by dopamine was present in this patient with a prolactinoma. Additionally, an abnormal prolactin response to dopamine was noted to precede the development of hyperprolactinemia with tumor recurrence.