Interrelationship between diseases and calving season and their impact on reproductive parameters and milk production of tropical dairy cows.

The interactions between calving season, the occurrence of retained placenta, intrauterine infections (IUI), and early mastitis, and their effects on the reproductive performance and milk yield of Holstein-Friesian cows in a tropical environment were studied using data from 3320 calvings (1948 cows) from two farms in El Salvador. Based on environmental conditions, season of calving was categorized into: quadrimester 1 (November-February), quadrimester 2 (March-June), and quadrimester 3 (July-October) where quadrimester 2 and 3 had the highest ambient temperature and relative humidity, respectively. Cows were classified into 1, 2, and 3 + parities. The effects of quadrimester and of diseases on days to first service, services per conception, days open, interval between services and 305-day milk yield were studied in separated multivariate regressions. The likelihood of experiencing a disease contingent on the calving season and the likelihood of a cow being culled due to poor fertility associated with experiencing a disease were evaluated using logistic regression. Cows calving in quadrimester 2 and 3 were more likely to suffer from IUI and showed poorer reproduction than cows calving in quadrimester 1. Reproduction was more strongly affected by IUI. Mastitis increased the days to first service, days open, and interval between services. Mastitis and IUI also caused a lower 305-day milk yield. Overall, hotter and more humid conditions lead to higher incidence of disease and poorer reproductive performance. The physiological responses that lead to these phenomena should be further studied to understand the interactions between diseases, environmental conditions and reproduction.

No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer.

BACKGROUND: Glucagon-like peptide-1 receptor agonists, such as dulaglutide, exenatide and liraglutide, are approved to treat Type 2 diabetes mellitus. Although these drugs provide substantial glycaemic control, studies in rodents have prompted concerns about the development of medullary thyroid carcinoma. These data are reflected in the US package insert, with boxed warnings and product labelling noting the occurrence of these tumours after clinically relevant exposures in rodents, and contraindicating glucagon-like peptide-1 receptor agonist use in people with a personal or family history of medullary thyroid carcinoma, or in people with multiple endocrine neoplasia type 2. However, there are substantial differences between rodent and human responses to glucagon-like peptide-1 receptor agonists. This report presents the case of a woman with pre-existing medullary thyroid carcinoma who exhibited no significant changes in serum calcitonin levels despite treatment with dulaglutide 2.0 mg for 6 months in the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes-5 clinical study (NCT00734474). CASE REPORT: Elevated serum calcitonin was noted in a 56-year-old woman with Type 2 diabetes mellitus at the 6-month discontinuation visit in a study of long-term dulaglutide therapy. Retroactive assessment of serum collected before study treatment yielded an elevated calcitonin level. At 3 months post-study, calcitonin level remained elevated; ultrasonography revealed multiple bilateral thyroid nodules. Eventually, medullary thyroid carcinoma was diagnosed; the woman was heterozygous positive for a germline RET proto-oncogene mutation. CONCLUSION: The tumour was not considered stimulated by dulaglutide therapy because calcitonin remained stable throughout.

Contemporary factors influencing genetic diversity in the Alaska humpback whitefish Coregonus clupeaformis complex.

Thirteen microsatellite loci were used to address three hypotheses regarding genetic diversity in the humpback whitefish Coregonus clupeaformis complex in Alaska. The test results provided further insight into the factors influencing C. clupeaformis complex population structure and level of genetic variation. First, the microsatellite data did not provide evidence of two spatially distinct Beringian and Eurasian refugial groups as revealed in previous phylogeographic analyses of mitochondrial DNA variation. Rather, the population structure inferred from the microsatellite variation appears to reveal the influence of factors on a more recent time scale, including gene flow among the refugial groups and isolation of some anadromous and freshwater resident populations. Second, anadromous C. clupeaformis complex collections exhibited higher intra-population genetic diversity than freshwater resident collections. This outcome is consistent with previous meta analyses suggesting that freshwater resident populations probably have smaller historical effective population sizes and less conspecific gene flow because the habitat tends to be smaller and supports fewer and smaller populations. Finally, the analysis of contemporary immigration rates was consistent with, but did not provide statistical support for, the hypothesis that gene flow among anadromous C. clupeaformis complex populations along coastal Alaska is influenced by the Alaska Coastal Current. Further studies are needed to evaluate gene flow among coastal Alaska C. clupeaformis complex populations.

Aerosol climate change effects on land ecosystem services.

A coupled global aerosol-carbon-climate model is applied to assess the impacts of aerosol physical climate change on the land ecosystem services gross primary productivity (GPP) and net primary productivity (NPP) in the 1996-2005 period. Aerosol impacts are quantified on an annual mean basis relative to the hypothetical aerosol-free world in 1996-2005, the global climate state in the absence of the historical rise in aerosol pollution. We examine the separate and combined roles of fast feedbacks associated with the land and slow feedbacks associated with the ocean. We consider all fossil fuel, biofuel and biomass burning aerosol emission sources as anthropogenic. The effective radiative forcing for aerosol-radiation interactions is -0.44 W m-2 and aerosol-cloud interactions is -1.64 W m-2. Aerosols cool and dry the global climate system by -0.8 °C and -0.08 mm per day relative to the aerosol-free world. Without aerosol pollution, human-induced global warming since the preindustrial would have already exceeded the 1.5 °C aspirational limit set in the Paris Agreement by the 1996-2005 decade. Aerosol climate impacts on the global average land ecosystem services are small due to large opposite sign effects in the tropical and boreal biomes. Aerosol slow feedbacks associated with the ocean strongly dominate impacts in the Amazon and North American Boreal. Aerosol cooling of the Amazon by -1.2 °C drives NPP increases of 8% or +0.76 ± 0.61 PgC per year, a 5-10 times larger impact than estimates of diffuse radiation fertilization by biomass burning aerosol in this region. The North American Boreal suffers GPP and NPP decreases of 35% due to aerosol-induced cooling and drying (-1.6 °C, -0.14 mm per day). Aerosol-land feedbacks play a larger role in the eastern US and Central Africa. Our study identifies an eco-climate teleconnection in the polluted earth system: the rise of the northern hemisphere mid-latitude reflective aerosol pollution layer causes long range cooling that protects Amazon NPP by 8% and suppresses boreal NPP by 35%.

Complementary sex determination, inbreeding depression and inbreeding avoidance in a gregarious sawfly.

Although most Hymenoptera reproduce via arrhenotokous haplodiploidy, the underlying genetic mechanisms vary. Of these, the most widespread mechanism appears to be single-locus complementary sex determination (sl-CSD), in which individuals that are diploid and heterozygous at a sex-determining locus are female, and individuals that are homozygous or hemizygous are male. Because inbreeding increases the probability of producing diploid males, which are often sterile or inviable, sl-CSD can generate substantial inbreeding depression. To counteract this, Hymenoptera with traits that promote inbreeding, such as gregariousness, may evolve one or more of the following: inbreeding avoidance, functional diploid males or alternative sex determination mechanisms. Here, we investigate sex determination, inbreeding depression and inbreeding avoidance in Neodiprion lecontei, a gregarious, pine-feeding sawfly in the family Diprionidae. First, via inbreeding experiments and flow cytometry, we demonstrate that this species has CSD. By modeling expected sex ratios under different conditions, we also show that our data are consistent with sl-CSD. Second, via tracking survival in inbred and outbred families, we demonstrate that inbred families have reduced larval survival and that this mortality is partly attributable to the death of diploid males. Third, using a no-choice mating assay, we demonstrate that females are less willing to mate with siblings than nonsiblings. Together, these results suggest that inbreeding depression stemming from CSD has shaped mating behavior in N. lecontei. These results also set the stage for future comparative work that will investigate the interplay between sex determination, ecology and behavior in additional diprionid species that vary in larval gregariousness.

Low incidence of anti-drug antibodies in patients with type 2 diabetes treated with once-weekly glucagon-like peptide-1 receptor agonist dulaglutide.

Therapeutic administration of peptides may result in anti-drug antibody (ADA) formation, hypersensitivity adverse events (AEs) and reduced efficacy. As a large peptide, the immunogenicity of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide is of considerable interest. The present study assessed the incidence of treatment-emergent dulaglutide ADAs, hypersensitivity AEs, injection site reactions (ISRs), and glycaemic control in ADA-positive patients in nine phase II and phase III trials (dulaglutide, N = 4006; exenatide, N = 276; non-GLP-1 comparators, N = 1141). Treatment-emergent dulaglutide ADAs were detected using a solid-phase extraction acid dissociation binding assay. Neutralizing ADAs were detected using a cell-based assay derived from human endothelial kidney cells (HEK293). A total of 64 dulaglutide-treated patients (1.6% of the population) tested ADA-positive versus eight (0.7%) from the non-GLP-1 comparator group. Of these 64 patients, 34 (0.9%) had dulaglutide-neutralizing ADAs, 36 (0.9%) had native-sequence GLP-1 (nsGLP-1) cross-reactive ADAs and four (0.1%) had nsGLP-1 neutralization ADAs. The incidence of hypersensitivity AEs and ISRs was similar in the dulaglutide versus placebo groups. No dulaglutide ADA-positive patient reported hypersensitivity AEs. Because of the low incidence of ADAs, it was not possible to establish their effect on glycaemic control.

Treponema infection associated with genital ulceration in wild baboons.

The authors describe genital alterations and detailed histologic findings in baboons naturally infected with Treponema pallidum. The disease causes moderate to severe genital ulcerations in a population of olive baboons (Papio hamadryas anubis) at Lake Manyara National Park in Tanzania. In a field survey in 2007, 63 individuals of all age classes, both sexes, and different grades of infection were chemically immobilized and sampled. Histology and molecular biological tests were used to detect and identify the organism responsible: a strain similar to T pallidum ssp pertenue, the cause of yaws in humans. Although treponemal infections are not a new phenomenon in nonhuman primates, the infection described here appears to be strictly associated with the anogenital region and results in tissue alterations matching those found in human syphilis infections (caused by T pallidum ssp pallidum), despite the causative pathogen's greater genetic similarity to human yaws-causing strains.

Improving live weight gain of crossbred Limousin bulls with cassava peel silage.

There is a growing demand for beef products across developing countries. Formulating rations to include locally available waste products has the potential to increase the live weight gain (LWG) of cattle and improve the livelihoods of smallholder farmers; however, upper limit inclusion levels of cassava peel products require investigation. An experiment evaluated the effect of using cassava peel silage (CPS) at the DM inclusion levels of 30, 40, 50, 60 and 70% (with the remainder protein meals and maize stover in the diet) on the LWG of crossbred Limousin × Ongole bulls (269 ±â€¯48.8 kg). Thirty bulls, approximately two years of age, were allocated in a completely randomised block design with six blocks based on initial live weight (LW) and five treatments based on level of CPS. The combination of CPS (with 2% urea of the CPS) and protein meals significantly affected LWG with the highest values obtained at levels of 30 and 50% inclusion of CPS (1.16-1.35 kg/day) (P < 0.05). Polynomial analysis of LWG data revealed the optimal LWG is theoretically achieved at 37% CPS with a LWG of 1.31 kg/day; however, LWG was similar from 30 to 50% inclusion levels and then declined. There was little significant difference at CPS inclusion levels of 30-60%, for DM intake (DMI) which ranged from 2.3 to 2.6% LW, organic matter (OM) digestibility (77.8-81.6%), feed conversion ratio (FCR) (6.56-7.56 kg DM/kg LWG) and feed cost of gain (Indonesia rupiah (IDR)/kg LW 18 612 - 21 398). At a high (70%) level of CPS inclusion, these values were markedly changed when compared to the 30% inclusion level of CPS. Feed treatments did not affect rumen pH, NH3-N, concentration or molar percentage of volatile fatty acids or protozoal population (P < 0.05). Rumen pH measured three hours after morning feed ranged from 6.7 to 6.8 and NH3-N ranged from 14.1 to 19.3 mg NH3-N/dl. It was concluded that inclusion of CPS up to 60% mixed with protein meals and urea and 20% maize stover maximised LWG and profitability of the production system.

Formulating rations with cassava meal to promote high live weight gain in crossbred Limousin bulls.

Formulating rations with high energy and protein feeds such as cassava and locally sourced protein meals is an important strategy to increase live weight gain (LWG) of crossbred bulls in Indonesia. Current systems of production for Indonesian smallholders fatten bulls using cut and carry. Formulating a diet for an optimal combination of available feeds will increase production and potential profitability for smallholders. An experiment was conducted to evaluate the effect of using cassava meal in the diet at levels of 70C, 60C, 50C, 40C and 30C% (with most of the remainder being the protein meals) on the LWG of Limousin × Ongole bulls so as to determine the optimum combination of cassava meal and protein meals for LWG. Thirty bulls were allocated in a completely randomized block design with 6 blocks based on initial live weight (LW) and 5 treatments based on level of cassava meal. The combination of cassava meal (with 2% urea) and protein meals significantly affected LWG with the highest (1.35 kg/day) recorded at 40C (40% cassava meal, 40% protein meals and 20% maize stover). The LWG and nutrient intake increased curvilinearly with decreasing cassava meal and increasing protein meals (P < 0.05). Measured cassava meal inclusion in the final ration as a consequence of the changes in intake was 60, 56, 47, 37 and 28% for the designated 70C, 60C, 50C, 40C and 30C treatments, respectively. Dry matter intake reached 96 g/kg0.75 per day or equal to 2.24% LW at this 40% level of inclusion. At the 70C treatment with 60% cassava meal and 9% protein meals, DM digestibility (69.1%) was lowest and that value increased as the proportion of cassava meal decreased and was highest at the 40C treatment (75.8%). Feed treatments significantly affected rumen pH, ammonia N (NH3N) and volatile fatty acid concentrations (P < 0.05). There was no significant effect on protozoal population (P > 0.05). Rumen pH ranged from 6.3 to 6.9. It was concluded that a combination of 40% dried cassava meal and 40% protein meals with roughage (20%) maximized intake and LWG and beyond that level of cassava meal inclusion, LWG and intake decreased markedly.

Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

Effects of arzoxifene on bone, lipid markers, and safety parameters in postmenopausal women with low bone mass.

UNLABELLED: In this Phase 2 study of postmenopausal women with low bone, arzoxifene (a selective estrogen receptor modulator (SERM)) significantly reduced bone turnover marker levels and increased bone mineral density (BMD) versus placebo. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene, a SERM in current clinical use. Arzoxifene's safety profile appeared similar to raloxifene. INTRODUCTION: This 6-month, Phase 2, double-blind, placebo- and raloxifene-controlled study was designed to assess the effects of arzoxifene on bone turnover and overall safety in postmenopausal women with low bone mass. METHODS: Postmenopausal women (N = 219; mean age, 59 years) with a T-score between -1 and -2.5 were randomly assigned to daily arzoxifene 5, 10, 20, or 40 mg, raloxifene 60 mg, or placebo. All received daily calcium. RESULTS: All arzoxifene doses significantly reduced osteocalcin (primary endpoint), type 1 collagen C-telopeptide, bone specific alkaline phosphatase, and procollagen type I amino-terminal propeptide versus placebo, and increased lumbar spine BMD. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene. Arzoxifene decreased cholesterol, low-density lipoprotein cholesterol, and fibrinogen versus placebo. Endometrial thickness change with arzoxifene was not significantly different from placebo or raloxifene; no cases of endometrial hyperplasia or adenocarcinoma were observed. Adverse event reporting with arzoxifene was similar to that with raloxifene, as were hot flush and night sweat reporting. CONCLUSIONS: Arzoxifene suppressed bone turnover and increased BMD. Within the limitations of this study, the endometrial safety profile of arzoxifene appeared similar to that of raloxifene. While no clear dose effect was evident, arzoxifene 20 and 40 mg/day appeared the optimal doses for reducing bone turnover.

Differential resource utilization by the sexes of dioecious plants.

The distribution of male and female plants was examined in five dioecious, wind-pollinated species representing five plant families and two classes (gymnosperms and angiosperms). The arid to semiarid habitats occupied by these species in northern Utah were stratified for sampling into two categories: chronically xeric and seasonally moist. The results show that for all species, males are more abundant on xeric microsites, while females are over represented on the moister parts of each local environment. Differential distribution of the sexes along a soil moisture gradient is a strategy that maximizes seed set of females and pollen dispersal of males; it also tends to minimize intraspecific competition between the sexes.

Targeted resequencing identifies genes with recurrent variation in cerebral palsy.

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

Vitamin D binding protein sequesters monomeric actin in the circulation of the rat.

Plasma vitamin D binding protein (DBP) may scavenge actin released during cell lysis. We examined the plasma disappearance and tissue appearance of 125I-DBP, 125I-G-actin, and the DBP-G-actin complex after their intravenous administration to rats. The plasma disappearance of DBP and DBP-actin were indistinguishable, with rapid initial (t1/2 = 2.6 h) and slower second (t1/2 = 7 h) slopes. After 125I-G-actin (nanomole) injection, plasma disappearance paralleled that of DBP and DBP-actin. All injected actin was associated with DBP, without evidence of free actin, actin-gelsolin complexes or actin oligomers. Tissue appearances of 125I-apo-DBP (apo) or holo-DBP were similar, with highest accumulations in perfused liver, kidney, and skeletal muscle. Although more complex phenomena (plasma entry of F-actin and intracellular actin binding proteins) would occur in vivo after cell lysis, our results suggest a role for DBP in the sequestration and disposition of actin monomers in the circulation.

A pain assessment tool for patients with limited communication ability.

This article outlines the development and implementation of a multi-dimensional pain assessment tool for use in acute hospitals. The tool can assist nurses in caring for various patient groups, including patients with limited communication.

Comparison of proximal isovelocity surface area method with pressure half-time and planimetry in evaluation of mitral stenosis.

OBJECTIVES: This study sought to 1) compare the accuracy of the proximal isovelocity surface area (PISA) and Doppler pressure half-time methods and planimetry for echocardiographic estimation of mitral valve area; 2) evaluate the effect of atrial fibrillation on the accuracy of the PISA method; and 3) assess factors used to correct PISA area estimates for leaflet angulation. BACKGROUND: Despite recognized limitations of traditional echocardiographic methods for estimating mitral valve area, there has been no systematic comparison with the PISA method in a single cohort. METHODS: Area estimates were obtained in patients with mitral stenosis by the Gorlin hydraulic formula, PISA and pressure half-time method in 48 patients and by planimetry in 36. Two different factors were used to correct PISA estimates for leaflet angle (theta): 1) plane-angle factor (theta/180 [theta in degrees]); and 2) solid-angle factor [1-cos(theta/2)]. RESULTS: After exclusion of patients with significant mitral regurgitation, the correlation between Gorlin and PISA areas (0.88) was significantly greater (p < 0.04) than that between Gorlin and pressure half-time (0.78) or Gorlin and planimetry (0.72). The correlation between Gorlin and PISA area estimates was lower in atrial fibrillation than sinus rhythm (0.69 vs. 0.93), but the standard error of the estimate was only slightly greater (0.24 vs. 0.19 cm2). The average ratio of the solid- to the plane-angle correction factors was approximately equal to previously reported values of the orifice contraction coefficient for tapering stenosis. CONCLUSIONS: 1) The accuracy of PISA area estimates in mitral stenosis is at least comparable to those of planimetry and pressure half-time. 2) Reasonable accuracy of the PISA method is possible in irregular rhythms. 3) A simple leaflet angle correction factor, theta/180 (theta in degrees), yields the physical orifice area because it overestimates the vena contracta area by a factor approximately equal to the contraction coefficient for a tapering stenosis.

Identification of an autosomal locus affecting steroid sulfatase activity among inbred strains of mice.

We have found an activity variant for testicular and liver steroid sulfatase among inbred strains of mice that is not X-linked. C57BL/6J, SM/J and SWR/J testicular extracts hydrolyze 3H-dehydroepiandrosterone sulfate twice as rapidly as do A/J extracts. The C3H/HeJ and DBA/2J strains were intermediate. The Km values for C57BL/6J and A/J are 2.29 +/- 0.10 and 1.01 +/- 0.02 microM, respectively. The F1 values in both directions were intermediate, which argues against X-linkage of this trait. F2 values show scattered high-intermediate-low values compatible with assay variation superimposed on the segregation of codominant alleles. When assayed for both testicular and liver steroid sulfatase, nine recombinant inbred lines between A/J and C57BL/6J segregate to near the parental strain values. Thus, this activity variation for steroid sulfatase appears to be determined by a single gene, which is not X-linked. Sex and steroidal hormone differences in liver steroid sulfatase activity were not present in the A/J strain, but females of the C57BL/6J and some recombinant inbred lines had higher levels. Electrophoretic studies only disclosed a variant in the SM/J strain, which seems to be secondary to the well-known neuraminidase variation in SM/J.

Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials.

BACKGROUND: In postmenopausal women, raloxifene hydrochloride has favorable effects on bone and lipid metabolism and does not stimulate reproductive tissues. The studies reported herein evaluated the long-term (3-year) effects of raloxifene treatment on bone mineral density (BMD), serum lipid levels, and drug tolerability in healthy postmenopausal women. METHODS: A total of 1145 healthy European and North American postmenopausal women aged 45 through 60 years were enrolled in 2 parallel, double-blind, randomized, placebo-controlled trials of identical design and randomly assigned to receive raloxifene hydrochloride, 30, 60, or 150 mg, or placebo daily; all groups received 400 to 600 mg of elemental calcium. Assessments included measurements for BMD by dual-energy x-ray absorptiometry, markers of bone turnover, and serum lipid levels. RESULTS: Lumbar spine BMD changed from baseline to 36 months as follows: placebo (mean percentage change + SE), -1. 32% +0.22%; raloxifene, 30 mg, 0.71% +0.23%; raloxifene, 60 mg, 1. 28% +0.23%; and raloxifene, 150 mg, 1.20% +0.24%. Comparable BMD changes were observed in the hip and total body. Biochemical markers of bone turnover were suppressed by raloxifene to normal premenopausal ranges through 3 years. Serum low-density lipoprotein cholesterol was reduced 7% to 12% below baseline through 3 years. Study withdrawals due to any reason (37%) and withdrawals due to adverse events (14%) were not different among groups. The only significant adverse effect of therapy was hot flashes (25% in the 60-mg raloxifene group vs 18% in the placebo group); hot flashes were typically reported as mild and were not associated with study withdrawal (1.7% for 60-mg raloxifene vs 2.4% for placebo). CONCLUSIONS: Raloxifene preserves BMD at important skeletal sites, lowers serum low-density lipoprotein cholesterol levels, and has a tolerability profile comparable to placebo. These results indicate a favorable benefit-risk profile of raloxifene for long-term use in healthy postmenopausal women. Arch Intern Med. 2000;160:3444-3450.

Delayed appearance of radiation-induced mutations at the Hprt locus in murine hemopoietic cells.

Earlier work in this laboratory identified high levels of non-clonal chromatid aberrations in the clonal descendants of murine hemopoietic stem cells after many cell divisions postirradiation with densely-ionizing, high linear energy transfer (LET) alpha-particles, but not with sparsely ionizing low LET X-rays. Using the Hprt locus as a marker, we have now demonstrated genomic instability in murine hemopoietic stem cells for greater than 20 cell divisions following both high and low LET irradiation. The increase in Hprt-deficient variants demonstrated following X- as well as alpha-particle and neutron irradiation indicates that there is a difference in the LET-dependence of delayed gene mutations and higher-order cytogenetic effects. Over 90% of the mutations identified arose in the expanding colonies after more than 12 cell divisions postirradiation and therefore cannot be attributed to the initial DNA damage. Such a high frequency of delayed mutations has important implications for mechanistic studies of radiation mutagenesis and for risk estimation.

Improved assessment of lumbar vertebral body strength using supine lateral dual-energy x-ray absorptiometry.

Clinical and biomechanical investigations indicate that assessment of vertebral body bone mineral density (BMD) by anteroposterior dual-energy x-ray absorptiometry (DXA) is a useful index of vertebral body strength and fracture risk in osteoporosis. However, inclusion of non-force-bearing and small-force-bearing mineralized structures, such as the posterior elements and aortic calcifications, in the measurement of anterior BMD obscures the assessment of vertebral body mass by this technique. Indeed, such interference is particularly severe in the presence of posterior element degeneration or previous spinal surgery. Recent anatomic studies illustrate that the lateral view provides unobstructed visualization of the L3, L4, and possibly L2 vertebral bodies, suggesting that supine lateral BMD may more accurately assess vertebral body fracture risk. We evaluated this hypothesis in a blinded using human cadaver spines to compare the value of supine lateral and anteroposterior BMD in assessing vertebral body fracture force, average compressive stress, maximum stored strain energy, and strain at failure. Both measures of BMD significantly correlate with these biomechanical measures. However, statistical comparison of the methods using multiple and stepwise regression reveals that supine lateral BMD provides a better assessment of the vertebral body fracture properties than anteroposterior BMD. The enhanced predictive value of supine lateral BMD occurs because of the variable contribution of posterior element mineral to the anteroposterior BMD measurement. Evaluation to test the utility of supine lateral BMD for the assessment of fracture risk and a fracture threshold in patients with osteoporosis is therefore recommended.