Adverse pulmonary effects after oral exposure to copper, manganese and mercury, alone and in mixtures, in a Spraque-Dawley rat model.

The rise in respiratory disease has been attributed to an increase in environmental pollution. Heavy metals contribute to environmental contamination via air, water, soil and food. The effects of atmospheric exposure to heavy metals on pulmonary structure and function have been researched, but the effects through drinking water have been neglected. The aim of this study was to investigate the potential in vivo alterations in the pulmonary tissue of male Sprague-Dawley rats after a 28-day oral exposure to copper (Cu), manganese (Mn) and mercury (Hg), alone and in mixtures, at 100 times the World Health Organization's (WHO) safety limit for each heavy metal in drinking water. Forty-eight male Sprague-Dawley rats were randomly divided into eight groups (n = 6): control, Cu, Mn, Hg, Cu + Mn, Cu + Hg, Mn + Hg and Cu, Mn + Hg. The morphology of lung tissue and the bronchioles were evaluated using light- and transmission electron microscopy. For all exposed groups, morphological changes included thickened inter- and intra-alveolar spaces, stratified epithelium, disrupted smooth muscle and early fibrosis and desquamation of the epithelia of the bronchioles to varying degrees. In all exposed groups, ultrastructurally, an increase in disarranged collagen and elastin fibers, nuclear membrane detachment, chromatin condensation, indistinct nucleoli and an increase in collagen fiber disarrangement was observed. This study has identified that oral exposure to Cu, Mn and Hg and as part of mixtures caused pathogenesis due to inflammation, cellular damage and fibrosis with Mn + Hg being the most potent heavy metal group.

The midline interlaminar ligament of the spine: An anatomical study.

INTRODUCTION: During routine cadaveric dissection, Simonds et al. in 2019 found a previously undocumented ligament, which they termed the midline interlaminar ligament (MIL), in 24 out of 36 (76.5%) lumbar spinal levels. The MIL is an unpaired ligament located between and distinctly separate from the right and left ligamenta flava (LF). The purpose of this study was to identify the presence or absence of the MIL in the cervical, thoracic, and lumbar spinal regions and obtain detailed measurements of the ligaments' toughness (R) and elastic modulus (E). MATERIALS AND METHODS: Intact preserved cadaveric vertebrae from C2 to the upper sacral region were dissected. Presence or absence of the MIL was documented, and length and width of each MIL were measured in situ. The R and E of the LFs from corresponding spinal segments were found for comparison. RESULTS: At least one MIL was observed in 90.3% (28) of specimens. Eighty-eight MIL's were observed out of 186 cervical intervertebral levels (0.5%), 371 thoracic intervertebral levels (5.9%), and 101 lumbar intervertebral levels (63.4%). The mean width and length of the MIL were 1.21 ± 0.36 and 16.37 ± 2.17 mm, respectively. The mean R of the MIL and the LF were 1390.27 and 2068.04 J m-2 , respectively. The mean E of the MILs and LFs was 46.78 ± 16.65 and 51.15 ± 21.68 MPa, respectively. CONCLUSIONS: Based on our findings, the MIL was present in the majority of vertebrae in our cadaveric population with a predominance for the lumbar region.

Hot topic: Management of cull dairy cows-Consensus of an expert consultation in Canada.

Many cull dairy cows enter the marketing system and travel to widely dispersed and specialized slaughter plants, and they may experience multiple handling events (e.g., loading, unloading, mixing), change of ownership among dealers, and feed and water deprivation during transport and at livestock markets. The objectives of this study were to describe the diverse management of cull dairy cows in Canada and establish consensus on ways to achieve improvements. A 2-day expert consultation meeting was convened, involving farmers, veterinarians, regulators, and experts in animal transport, livestock auction, and slaughter. The 15 participants, recruited from across Canada, discussed regional management practices for cull cattle, related risk factors, animal welfare problems, and recommendations. An audio recording of the meeting was used to extract descriptive data on cull cattle management and identify points of agreement. Eight consensus points were reached: (1) to assemble information on travel times and delays from farm to slaughter; (2) to increase awareness among producers and herd veterinarians of potential travel distances and delays; (3) to promote pro-active culling; (4) to improve the ability of personnel to assess animal condition before loading; (5) to identify local options for slaughter of cull dairy cows; (6) to investigate different management options such as emergency slaughter and mobile slaughter; (7) to ensure that all farms and auctions have, or can access, personnel trained and equipped for euthanasia; and (8) to promote cooperation among enforcement agencies and wider adoption of beneficial regulatory options.

Population Structure Among and Within Iowa, Missouri, Ohio, and South Dakota Populations of Phytophthora sojae.

Phytophthora root and stem rot, caused by Phytophthora sojae, is an economically important disease of soybean throughout the Midwestern United States. This disease has been successfully managed with resistance (Rps) genes; however, pathogen populations throughout the Midwest have developed virulence to many Rps genes, including those that have not been deployed. To gain a better understanding of the processes that influence P. sojae evolution, the population genetic structure was compared among populations using one isolate collected from 17, 33, and 20 fields in Iowa, Ohio, and South Dakota, respectively, as well as multiple isolates from individual fields in Iowa, Ohio, and Missouri. Genotypic diversity was measured using 21 polymorphic microsatellite (simple-sequence repeat) markers. and pathotype diversity using 15 soybean differentials. For all but three of the populations with low sample size, there was a high level of pathotype diversity and a low to moderate level of genotypic diversity among the populations for both comparisons between states and within-field variation. None of the Rps-gene differentials were resistant to all of the isolates. There were 103 unique multilocus genotypes identified in this study and only 2 were identified from the same field. Although no clones were identified in more than one field, pairwise FST indicated that some gene flow within neighboring fields does occur but not across the region, including fields from neighboring states. These results suggest that there is a strong probability that each state may have their own or several regional populations, as well as provide further evidence of high diversity within this homothallic pathogen which may be due, in part, to limited gene flow, mutation, or outcrossing, and this likely affects the success of deployment of resistance.

In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline.

Omadacycline is the first intravenous and oral 9-aminomethylcycline in clinical development for use against multiple infectious diseases including acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). The comparative in vitro activity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae (H. influenzae). The omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci were 1.0 µg/ml, 0.25 µg/ml, and 0.5 µg/ml, respectively, and the omadacycline MIC90s for PRSP and H. influenzae were 0.25 µg/ml and 2.0 µg/ml, respectively. Omadacycline was active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. In vivo efficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited efficacy against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including tet(M) and tet(K) efflux-containing strains and MRSA strains. The 50% effective doses (ED50s) for Streptococcus pneumoniae obtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED50s for Staphylococcus aureus obtained ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED50 for Escherichia coli was 2.02 mg/kg. These results demonstrate potent in vivo efficacy including activity against strains containing common resistance determinants. Omadacycline demonstrated in vitro activity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacy in vivo.

The relationship between pressure and volume when using Rapid Rhino(r) packs in the management of epistaxis.

Despite the popularity of Rapid Rhino packs, there are no clear guidelines regarding the volume of air to be inflated when used in the management of epistaxis. The manufacturers suggest that subjective assessment by pilot cuff palpation is used to guide inflation. However, studies have clearly demonstrated that clinicians are poor at judging balloon pressure by pilot cuff palpation when used in other settings. Our objective was to investigate the relationship between the volume of air inflated and the resultant intra-nasal pressure generated by nasal balloon packing. Twelve healthy subjects were packed with 5.5 cm Rapid Rhino packs, which were connected to a manometer and 20 ml syringe via a 3-way tap in a closed circuit. Increments of 2.5 mls of air were inflated and the resultant intra-nasal pack pressure was measured. There appeared to be a linear relationship between increasing volume and pack pressure. However, between individuals, there was a large variation in the intra-nasal pack pressure produced for a given fixed volume of air inflated. This is presumably due to variations in nasal anatomy. It may be that a manometer-measured, pressure guided nasal pack inflation technique would represent best practice, especially for less experienced staff.

Integrated Management Strategies for Phytophthora sojae Combining Host Resistance and Seed Treatments.

Phytophthora sojae has re-emerged as a serious soybean pathogen in the past decade. This may be due in part to changes in resistance levels in current cultivars, adoption of P. sojae populations to deployed Rps genes, and highly favorable environments in the past decade. This multilocation study evaluated the effect of seed treatments on the incidence and severity of Phytophthora root and stem rot on soybeans with different combinations of Rps genes and levels of partial resistance. The efficacy of the seed treatments was highly variable across locations. Seed treatments (metalaxyl and mefenoxam) provided protection and increased yields across cultivars in locations where rain or irrigation occurred shortly after planting (Ohio, South Dakota, and Ontario). However, there were no significant differences in stand or yield consistently across cultivars in Iowa, Nebraska, Wisconsin, or Ohio, where heavy precipitation did not occur until later growth stages. The environment, levels of inoculum, and pathogen complex may have played a role in the different responses to the seed treatments and to the different combinations of Rps genes and levels of partial resistance to P. sojae in the cultivars. Fields that are poorly drained and have P. sojae populations with complex pathotypes may benefit the most from seed treatments. Individual fields where producers may see the greatest benefit to utilizing these integrated management strategies will need to be identified.

Efficacy of triazole-based fungicides for fusarium head blight and deoxynivalenol control in wheat: a multivariate meta-analysis.

The effects of propiconazole, prothioconazole, tebuconazole, metconazole, and prothioconazole+tebuconazole (as a tank mix or a formulated premix) on the control of Fusarium head blight index (IND; field or plot-level disease severity) and deoxynivalenol (DON) in wheat were determined. A multivariate random-effects meta-analytical model was fitted to the log-transformed treatment means from over 100 uniform fungicide studies across 11 years and 14 states, and the mean log ratio (relative to the untreated check or tebuconazole mean) was determined as the overall effect size for quantifying fungicide efficacy. Mean log ratios were then transformed to estimate mean percent reduction in IND and DON relative to the untreated check (percent control: C(IND) and C(DON)) and relative to tebuconazole. All fungicides led to a significant reduction in IND and DON (P < 0.001), although there was substantial between-study variability. Prothioconazole+tebuconazole was the most effective fungicide for IND, with a C(IND) of 52%, followed by metconazole (50%), prothioconazole (48%), tebuconazole (40%), and propiconazole (32%). For DON, metconazole was the most effective treatment, with a [Formula: see text](DON) of 45%; prothioconazole+tebuconazole and prothioconazole showed similar efficacy, with C(DON) values of 42 and 43%, respectively; tebuconazole and propiconazole were the least effective, with C(DON) values of 23 and 12%, respectively. All fungicides, with the exception of propiconazole, were significantly more effective than tebuconazole for control of both IND and DON (P < 0.001). Relative to tebuconazole, prothioconazole, metconazole, and tebuconzole+prothioconzole reduced disease index a further 14 to 20% and DON a further 25 to 29%. In general, fungicide efficacy was significantly higher for spring wheat than for soft winter wheat studies; depending on the fungicide, the difference in percent control between spring and soft winter wheat was 5 to 20% for C(IND) and 7 to 16% for C(DON). Based on the mean log ratios and between-study variances, the probability that IND or DON in a treated plot from a randomly selected study was lower than that in the check by a fixed margin was determined, which confirmed the superior efficacy of prothioconazole, metconazole, and tebuconzole+prothioconzole for Fusarium head blight disease and toxin control.

Identification of a mouse protein whose homolog in Saccharomyces cerevisiae is a component of the CCR4 transcriptional regulatory complex.

The CCR4 protein from Saccharomyces cerevisiae is a component of a multisubunit complex that is required for the regulation of a number of genes in yeast cells. We report here the identification of a mouse protein (mCAF1 [mouse CCR4-associated factor 1]) which is capable of interacting with and binding to the yeast CCR4 protein. The mCAF1 protein was shown to have significant similarity to proteins from humans, Caenorhabditis elegans, Arabidopsis thaliana, and S. cerevisiae. The yeast gene (yCAF1) had been previously cloned as the POP2 gene, which is required for expression of several genes. Both yCAF1 (POP2) and the C. elegans homolog of CAF1 were shown to genetically interact with CCR4 in vivo, and yCAF1 (POP2) physically associated with CCR4. Disruption of the CAF1 (POP2) gene in yeast cells gave phenotypes and defects in transcription similar to those observed with disruptions of CCR4, including the ability to suppress spt10-enhanced ADH2 expression. In addition, yCAF1 (POP2) when fused to LexA was capable of activating transcription. mCAF1 could also activate transcription when fused to LexA and could functionally substitute for yCAF1 in allowing ADH2 expression in an spt10 mutant background. These data imply that CAF1 is a component of the CCR4 protein complex and that this complex has retained evolutionarily conserved functions important to eukaryotic transcription.

CCR4 is a glucose-regulated transcription factor whose leucine-rich repeat binds several proteins important for placing CCR4 in its proper promoter context.

The yeast CCR4 protein is required for the expression of a number of genes involved in nonfermentative growth, including glucose-repressible ADH2, and is the only known suppressor of mutations in the SPT6 and SPT10 genes, two genes which are believed to be involved in chromatin maintenance. We show here that although CCR4 did not bind DNA under the conditions tested, it was able to activate transcription when fused to a heterologous DNA-binding domain. The transcriptional activation ability of CCR4, in contrast to that of many other activators, was glucose regulated. Two activation domains one of which was glucose responsive and encompassed a glutamine-proline-rich region similar to that found in other eukaryotic transcriptional factors were identified. The two transactivation regions, when separated from the leucine-rich repeat and the C terminus of CCR4, were unable to complement a defective ccr4 allele, suggesting that the leucine-rich repeat and the C terminus make contacts that link the activation regions to the proper gene context. Native immunoprecipitation of CCR4 revealed that CCR4 was complexed with at least four other proteins. The leucine-rich repeat of CCR4 was both necessary and sufficient for interaction with at least two of these factors. We propose that the leucine-rich repeat links CCR4 through its associated factors to its promoter context at ADH2 and other loci where it is required for proper transcriptional regulation.

A quantitative review of tebuconazole effect on fusarium head blight and deoxynivalenol content in wheat.

ABSTRACT A meta-analysis of the effect of tebuconazole (e.g., Folicur 3.6F) on Fusarium head blight and deoxynivalenol (DON) content of wheat grain was performed using data collected from uniform fungicide trials (UFTs) conducted at multiple locations across U.S. wheat-growing regions. Response ratios (mean disease and DON levels from tebuconazole-treated plots, divided by mean disease and DON levels from untreated check plots) were calculated for each of 139 studies for tebuconazole effect on Fusarium head blight index (IND; field or plot-level disease severity, i.e., mean proportion of diseased spikelets per spike) and 101 studies for tebuconazole effect on DON contamination of harvested grain. A random-effects meta-analysis was performed on the log-transformed ratios, and the estimated mean log ratios were transformed to estimate the mean (expected) percent control for IND ( C(IND) ) and DON ( C(DON)). A mixed effects meta-analysis was then done to determine the effects of wheat type (spring versus winter wheat) and disease and DON levels in the controls on the log ratios. Tebuconazole was more effective at limiting IND than DON, with C(IND) and C(DON) values of 40.3 and 21.6%, respectively. The efficacy of tebuconazole as determined by the impact on both IND and DON was greater in spring wheat than in winter wheat (P < 0.01), with a 13.2% higher C(IND) and a 12.4% higher C(DON) in spring wheat than in winter wheat. In general, C(IND) and C(DON) were both at their lowest values (and not significantly different from 0) when mean IND and DON in the controls, respectively, were low (

The yeast CCR4 protein is neither regulated by nor associated with the SPT6 and SPT10 proteins and forms a functionally distinct complex from that of the SNF/SWI transcription factors.

The CCR4 protein is specifically required for the increased transcription at the ADH2 locus resulting from mutations in the SPT10 (CRE1) and SPT6 (CRE2) genes and is also required for the expression of ADH2 and other genes under non-fermentative growth conditions. The mechanism by which mutations in CCR4 suppress defects in SPT10 and SPT6 was examined. The SPT10 and SPT6 genes were shown not to control CCR4 mRNA or protein expression nor did SPT10 and SPT6 proteins co-immuneprecipitate with CCR4. CCR4 association with two other proteins, 195 and 185 kDa in size, was unaffected by either spt10 or spt6 mutations. Also, the ability of CCR4 to activate transcription when fused to the LexA DNA binding domain was not specifically enhanced by defects in either SPT10 or SPT6. These results suggest that SPT10 and SPT6, in negatively regulating transcription at ADH2, act through a factor that requires CCR4 function, but do not regulate CCR4 expression, control its activity, physically interact with it, or affect its binding to other factors. The relationship of CCR4 to the group of general transcription factors, SNF2, SNF5, SNF6 and SWI1 and SWI3, which comprise a multisubunit complex required for ADH2 and other genes' expression, was also examined. CCR4 protein expression was not controlled by these factors nor did they co-immuneprecipitate or associate with CCR4. In addition, a ccr4 mutation had little effect on an ADH2 promoter alteration in contrast to the large effects displayed by mutations in SNF2 and SNF5. These data suggest that CCR4 acts by a separate mechanism from that used by the SNF/SWI general transcription factors in affecting gene expression.

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.

A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women.

This randomized, double-blind, placebo-controlled, multicenter, 8-week study evaluated short-term effects of raloxifene on bone turnover, serum lipids, and endometrium in healthy, postmenopausal women. A total of 251 women received either placebo, raloxifene HCl 200 or 600 mg/day, or conjugated estrogens (Premarin, 0.625 mg/day). Bone turnover (serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline cross-links, urinary calcium excretion, urinary hydroxyproline) and serum lipids (total serum cholesterol, high- and low-density lipoprotein cholesterol [HDL-C and LDL-C]) were evaluated at weeks 0, 2, 4, and 8. Endometrial biopsies were performed at weeks 0 and 8. Treatment groups were compared for each parameter for baseline-to-endpoint changes. The estrogen and raloxifene groups experienced similar decreases in serum alkaline phosphatase (range 10-11%), serum osteocalcin (range 21-26%), urinary pyridinoline cross-links (range 20-26%), and urinary calcium excretion (range 45-72%). These decreases differed significantly compared with placebo-treated subjects for all markers except serum osteocalcin, the raloxifene HCl 200 mg group. LDL-C decreased significantly in the estrogen and both raloxifene groups (range 5-9%) compared with placebo-treated subjects. HDL-C increased significantly in the estrogen group (16%) but was unchanged in the raloxifene groups. HDL-C:LDL-C ratios increased significantly in the estrogen and raloxifene groups (range 9-29%). Serum cholesterol decreased significantly in both raloxifene groups (range 4-8%) but was unchanged in the estrogen group. Uterine biopsies of raloxifene-treated subjects showed no change in the endometrium during this short-term treatment. Biopsies of the estrogen group showed significant endometrial stimulation. The only adverse event possibly related to raloxifene was vasodilatation (hot flashes) which was most common in the raloxifene HCl 600 mg group. Study results indicate that raloxifene may provide beneficial effects to bone and serum lipids in humans without uterine stimulatory effects.

Raloxifene and estrogen: comparative bone-remodeling kinetics.

The pattern of changes in human bone remodeling produced by raloxifene (60 mg/day) was compared to that of estrogen (given as hormone replacement therapy) in 33 early postmenopausal women randomly assigned to raloxifene, estrogen, or no treatment. Remodeling was measured using calcium tracer kinetic methods employed under a constant diet and full metabolic balance conditions. Studies were performed at baseline and, to detect both early and late remodeling changes, at 4 and 31 weeks of treatment. Both raloxifene and estrogen produced a significant positive calcium balance shift at each treatment measurement point: +74 and +60 mg/day at 4 weeks, and +60 and +91 mg/day at 31 weeks for raloxifene and estrogen, respectively. Externally, this balance change was due to a highly significant fall in the urinary calcium level and marginal improvement in calcium absorption efficiency. Internally, bone resorption was significantly reduced at both measurement points: -64 and -60 mg/day at 4 weeks, and -82 and -162 mg/day at 31 weeks for raloxifene and estrogen, respectively. Bone formation was not significantly affected by either agent at 4 weeks; at 31 weeks, formation was reduced by estrogen, but not by raloxifene. Thus, at 4 weeks, the general pattern of remodeling change was identical for the two agents. At 31 weeks, remodeling suppression was greater for estrogen than for raloxifene; however, remodeling balance was the same for the two agents. We conclude that raloxifene and estrogen affect the bone remodeling apparatus similarly, and that raloxifene, therefore, is acting on bone as an estrogen agonist.

Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles.

Previous studies of raloxifene conducted in animal models and postmenopausal women have demonstrated antiestrogenic action on the endometrium. The purpose of this first study of raloxifene in women with normal menstrual cycles was to determine its reproductive endocrine and endometrial effects. In part I, raloxifene (400 mg) was administered for 5 days in the follicular, periovulatory, or luteal phase of the menstrual cycle (n = 12). In part II, women were randomized to receive raloxifene (100 or 200 mg) for 28 days beginning on day 3 of the cycle (n = 19). All women ovulated in both parts of the study. Raloxifene did not alter the length of the menstrual cycle or the day of the LH surge. A 5-day course of raloxifene administered in any phase of the cycle elevated FSH area under the curve (AUC) for the entire cycle and estradiol AUC for the second half of the cycle compared with those in control cycles. In part II, raloxifene also appeared to increase the FSH AUC and estradiol AUC. Raloxifene decreased the number of gland mitoses in follicular phase endometrial biopsies. Subtle effects suggestive of gland-stromal dysynchrony were noted in a limited number of the secretory phase endometrial biopsies. This study has demonstrated that 1) raloxifene does not prevent ovulation in women with normal menstrual cycles; 2) ovarian estrogen production will continue, and in some cases increase, in response to raloxifene; and 3) antiestrogenic effects of raloxifene on the endometrium are subtle in the endocrine milieu of normal to high circulating estradiol concentrations.

Functional mediastinal parathyroid cyst. Dynamics of parathyroid hormone secretion during cyst aspirations and surgery.

A patient presented with a large neck mass, hypercalcemia, and elevated serum parathyroid hormone levels. Aspiration of the cystic mass yielded 100 ml of fluid that contained a low concentration of thyroxine, but large amounts of parathyroid hormone, as measured by bioassay or with three different radioimmunoassays. After each of four aspirations, the serum calcium level declined significantly. Serial measurements showed that serum amino-terminal and mid-region parathyroid hormone levels and urinary cyclic adenosine monophosphate values declined after aspiration. Surgical resection of the cervical-mediastinal cyst restored normal serum calcium and parathyroid hormone levels, and these have been maintained for nine months. Calculations suggest that parathyroid hormone traversing the cyst lumen might contribute significantly to the excess circulating parathyroid hormone.

Evidence for separate peptide sequences related to the lipolytic and magnesium-accumulating activities of ACTH. Analogy with adrenergic receptors.

Native adrenocorticotropin [ACTH-(1-39)] and ACTH-(1-24) stimulate both lipolysis and magnesium accumulation in rat adipocyte plasma membrane vesicles. ACTH-(1-20) retains full lipolytic activity but has a minimal effect on magnesium accumulation. In contrast ACTH-(11-24) stimulates magnesium accumulation but not lipolysis. These findings indicate that within the ACTH molecule the peptide sequence responsible for stimulation of magnesium accumulation is distinctly separate from the core sequence (residues 4-10) essential for stimulation of adenylyl cyclase activity and cAMP mediated lipolysis. Phentolamine, an alpha-adrenergic antagonist, blocks the bulk of magnesium accumulation stimulated by native ACTH and norepinephrine; propranolol, a beta-adrenergic antagonist, blocks the earliest phase of Mg2+ uptake by these hormones but has little effect on net uptake. Isoproterenol, a beta-adrenergic agonist, stimulates magnesium uptake only minimally. The pattern of uptake stimulated by methoxamine, an alpha-adrenergic agonist, or ACTH-(11-24) is quite similar to that produced by native ACTH in the presence of propranolol. The receptor through which ACTH mediates stimulation of the bulk of magnesium appears to be analogous to the alpha-adrenergic receptor through which norepinephrine stimulates this same process.