Identification of an IGSF1-specific deletion in a five-generation pedigree with X-linked Central Hypothyroidism without macroorchidism.

OBJECTIVES: IGSF1 deficiency syndrome (IDS) is a recently described X-linked congenital central hypothyroidism disorder characterized by loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. The phenotypic spectrum and intrafamilial variability associated with IDS remain unclear due to a paucity of large, well-characterized pedigrees. Here, we present phenotypic analysis and molecular characterization of a five-generation pedigree with IGSF1 deficiency containing 10 affected males. PATIENTS AND METHODS: Pituitary function was assessed in all available family members (n = 8 affected males and n = 5 carrier females). Molecular characterization of the family was performed by Sanger sequencing of PCR products amplified from the IGSF1 locus and by array comparative genomic hybridization. RESULTS: A 42-kb IGSF1 deletion spanning the entire coding sequence was identified in all affected males. TSH deficiency, although subclinical in one case, was identified in all affected males (n = 8). PRL and GH deficiency were also present in 5 of 6 and 4 of 8 affected males, respectively. In contrast to previous reports, macroorchidism was not detected in any of the four affected males who were examined for this feature. Only 1 of 5 carrier females had pituitary dysfunction (TSH and GH deficiency). CONCLUSION: Individuals with identical IGSF1 deletions can exhibit variable pituitary hormone deficiencies, of which overt TSH deficiency is the most consistent feature. We also show that macroorchidism is not obligatory in males with IDS. Mutations of IGSF1 should therefore be considered in males with isolated hypopituitarism that includes TSH deficiency.

A Four-Year Trend in Serum 25-Hydroxyvitamin D Levels in Western Connecticut.

OBJECTIVE: This study describes the trends in blood vitamin D levels in a regional population from 2009-2012 through a cross-sectional study design. METHODS: Over a four-year period (2009-2012), serum levels of 25-hydroxyvitamin D [25(OH)D] have been measured using an automated enzyme immunoassay with a steadily increasing number of tests performed each year. A total of 54700 tests were performed during this period, with a 90% increase in annual tests ordered. RESULTS: Mean and median serum levels of 25(OH) D showed statistically significant increases during this period. Those with 25(OH)D levels below 10 ng/mL represented 1.45% of the subjects in 2009 and 0.3% in 2012. The decrease in the proportion of subjects with 25(OH)D levels below 20 ng/mL and below 30 ng/mL was greatest out of all the proportioned subjects. Mean and median 25(OH)D levels increased with age in males and females. CONCLUSION: These results likely reflect increased health awareness in Western Connecticut compared with national surveys showing a temporal decrease in 25(OH)D levels.

Whole-Body Acute Contact Toxicity of Formulated Insecticide Mixtures to Blue Orchard Bees (Osmia lignaria).

Blue orchard bees, [Osmia lignaria (Say) (Hymenoptera: Megachilidae)], have been developed as an important pollinator for orchard crops in North America over the last 40 years. The toxicity of several pesticides to O. lignaria and other Osmia species has been previously reported. However, the field-realistic toxicity of formulated premix insecticides comprised of multiple active ingredients (each with a different mode of action) to O. lignaria has not been assessed. Here, we use a customized spray tower in a laboratory setting to assess adult male and female whole-body direct contact exposure to four formulated pesticide mixtures: thiamethoxam + lambda-cyhalothrin (TLC), imidacloprid + beta-cyfluthrin (IBC), chlorantraniliprole + lambda-cyhalothrin (CLC) and methoxyfenozide + spinetoram (MS) by directly spraying anesthetized bees in Petri dishes. Separately, adult male and female whole-body direct contact exposure to formulated imidacloprid (I), beta-cyfluthrin (BC) and their 1:1 binary combination (IBC) was assessed using the same experimental method. Resulting mortality in each study was screened up to 96 h post-treatment to determine acute whole-body contact toxicity. In the first study, TLC and IBC resulted in statistically higher mortality at 24 and 48 h than the two other insecticide combinations tested. The CLC and MS combinations were slower acting and the highest mortality for O. lignaria exposed to these mixtures was recorded at 96 h. We did observe significant differences in toxicity between CLC and MS. In the second study, exposure to the 1:1 binary combination of IBC caused overall significantly higher mortality than exposure to I or BC alone. Both active ingredients alone, however, demonstrated equivalent levels of mortality to the 1:1 binary combination treatment at the 96 h observation reading, indicating increased speed of kill, but not necessarily increased toxicity. Significant differences in the onset of mortality following acute contact whole-body exposure to the formulated insecticide mixtures and individual active ingredients tested were consistently observed across all experiments in both studies.

The Importance of Males to Bumble Bee (Bombus Species) Nest Development and Colony Viability.

Bumble bee population declines over the last decade have stimulated strong interest in determining causative factors and necessary conservation measures. Research attention has largely been directed toward bumble bee worker and queen health and their contributions to population stability, while male bees (i.e., drones) have typically been overlooked regarding their role in influencing colony fitness and longevity. In this review we assess existing literature on the diverse role of males within bumble bee nests and their importance to queen health and fitness, as well as to overall nest success. The implications of reproductive measures, including sperm transfer, mating behavior, mating plugs, and male immunity, among other topics, are examined. Overall, bumble bee males are found to drive colony function in a unique manner. Current knowledge gaps pertaining to the role of males are discussed. We highlight the importance of drones to queen success and fitness in many ways, and suggest future research exploring impacts of this often-neglected caste.

Impact of Biotic and Abiotic Stressors on Managed and Feral Bees.

Large-scale declines in bee abundance and species richness over the last decade have sounded an alarm, given the crucial pollination services that bees provide. Population dips have specifically been noted for both managed and feral bee species. The simultaneous increased cultivation of bee-dependent agricultural crops has given rise to additional concern. As a result, there has been a surge in scientific research investigating the potential stressors impacting bees. A group of environmental and anthropogenic stressors negatively impacting bees has been isolated. Habitat destruction has diminished the availability of bee floral resources and nest habitats, while massive monoculture plantings have limited bee access to a variety of pollens and nectars. The rapid spread and increased resistance buildup of various bee parasites, pathogens, and pests to current control methods are implicated in deteriorating bee health. Similarly, many pesticides that are widely applied on agricultural crops and within beehives are toxic to bees. The global distribution of honey bee colonies (including queens with attendant bees) and bumble bee colonies from crop to crop for pollination events has been linked with increased pathogen stress and increased competition with native bee species for limited resources. Climatic alterations have disrupted synchronous bee emergence with flower blooming and reduced the availability of diverse floral resources, leading to bee physiological adaptations. Interactions amongst multiple stressors have created colossal maladies hitting bees at one time, and in some cases delivering additive impacts. Initiatives including the development of wild flower plantings and assessment of pesticide toxicity to bees have been undertaken in efforts to ameliorate current bee declines. In this review, recent findings regarding the impact of these stressors on bees and strategies for mitigating them are discussed.

High bone density due to a mutation in LDL-receptor-related protein 5.

BACKGROUND: Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma. METHODS: We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus. RESULTS: Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5V171). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity. CONCLUSIONS: The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.

Torus palatinus: a new anatomical correlation with bone density in postmenopausal women.

The observation that subjects who have a striking oral exostosis, called torus palatinus, also tended to have normal or high bone densities prompted us to examine an unselected population referred for bone density assessment for a possible correlation with torus palatinus. Subjects referred from community physicians had a visual examination of the open mouth to estimate the size of any torus palatinus (0 for none/trace to 5 for very large) before undergoing a bone density measurement by dual energy x-ray absortiometry. Bone density T- and z-scores were correlated with the size of each subject's torus palatinus. Torus size groups were also correlated with other variables affecting bone density. About 20% of 370 postmenopausal female subjects, >90% Caucasian, had a moderate to large torus palatinus. Regression correlations for torus size were modest, but significantly related to T- and z-scores of lumbar vertebrae and left hip (P < 0.01 for each). Differences due to medication, body mass index, smoking, parity, and several other factors that affect bone density did not diminish the relation to torus size. This study shows a small, but significant, positive relation for postmenopausal, Caucasian women between bone mineral density and torus size after controlling for several variables known to affect bone density were examined. Torus prominence, in association with other factors, can be considered in decisions for testing bone density in otherwise normal postmenopausal women.

Measurement of plasma, serum, and platelet serotonin in individuals with high bone mass and mutations in LRP5.

It has recently been suggested that the low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone mass by suppressing secretion of serotonin from duodenal enterochromaffin cells. In mice with targeted expression of a high bone mass-causing (HBM-causing) LRP5 mutation and in humans with HBM LRP5 mutations, circulating serotonin levels have been reported to be lower than in controls whereas individuals with loss-of-function mutations in LRP5 have high blood serotonin. In contrast, others have reported that conditionally activating a knock-in allele of an HBM-causing LRP5 mutation in several tissues, or genetic deletion of LRP5 in mice has no effect on serum serotonin levels. To further explore the possible association between HBM-causing LRP5 mutations and circulating serotonin, levels of the hormone were measured in the platelet poor plasma (PPP), serum, and platelet pellet (PP) of 16 affected individuals from 2 kindreds with HBM-causing LRP5 mutations (G171V and N198S) and 16 age-matched controls. When analyzed by HPLC, there were no differences in levels of serotonin in PPP and PP between affected individuals and age-matched controls. Similarly, when analyzed by ELISA, there were no differences in PPP or PP between these two groups. By ELISA, serum levels of serotonin were higher in the affected individuals when compared to age-matched controls. A subgroup analysis of only the G171V subjects (n=14) demonstrated that there were no differences in PPP and PP serotonin between affected individuals and controls when analyzed by HPLC. PP serotonin was lower in the affected individuals when measured by ELISA but serum serotonin levels were not different. We conclude that there is no change in PPP serotonin in individuals with HBM-causing mutations in LRP5.

Prevalence and consequences of vitamin D insufficiency in women with takotsubo cardiomyopathy.

OBJECTIVE: The purpose of this study was to identify the prevalence and clinical consequences of vitamin D insufficiency in patients with takotsubo cardiomyopathy. BACKGROUND: Takotsubo cardiomyopathy is a syndrome of acute, transient left ventricular dysfunction seen predominantly in postmenopausal women after acute emotional or physical stress. Postmenopausal women have a high prevalence of bone and musculoskeletal consequences related to hypovitaminosis D. Although rickets is known to cause a reversible dilated cardiomyopathy in children, the importance of vitamin D for adult cardiovascular health is less understood. METHODS: We prospectively identified patients diagnosed with takotsubo cardiomyopathy at Danbury Hospital from April 2009 through January 2011, collected demographic, clinical, laboratory, and angiographic data, and performed serum 25 hydroxyvitamin D levels during the index hospitalization. Vitamin D insufficiency was defined as serum 25-hydroxy-vitamin D less than 30 ng/mL. We compared parameters of myocardial damage and heart failure between patients with and without vitamin D insufficiency. A χ² test and a Student's t test were used for categorical and continuous variables, respectively. Statistical significance was set at P < .05 (2 tailed). RESULTS: Twenty-seven women were diagnosed with takotsubo cardiomyopathy during the study period. The mean age was 67.4 years (SD 10.4). The serum 25-hydroxyvitamin D levels were performed on 25 patients, and 17 of these had hypovitaminosis D (68%). A comparison of laboratory and imaging parameters between the 2 groups revealed that patients with hypovitaminosis D had a slightly higher mean left ventricular end-diastolic pressure and lower mean left ventricular ejection fraction (P < .05), suggestive of slightly worse heart failure. CONCLUSIONS: Women diagnosed with takotsubo cardiomyopathy have a high prevalence of vitamin D insufficiency. In our prospective study of 25 women with takotsubo cardiomyopathy, this was associated with worse hemodynamic parameters.

Chemotherapy-induced hypocalcemia.

OBJECTIVE: To present a unique case of transient, asymptomatic chemotherapy-induced hypocalcemia not attributable to hypomagnesemia or tumor lysis syndrome and review causes of hypocalcemia related to cancer with and without use of chemotherapy. METHODS: We present a case detailing the clinical and laboratory findings of a patient who had severe hypocalcemia during chemotherapy and discuss causes of hypocalcemia with an extensive literature review of chemotherapeutic agents associated with this biochemical abnormality. RESULTS: In a 90-year-old man, hypocalcemia developed during 2 courses of chemotherapy for Hodgkin lymphoma, with partial recovery between courses and normal serum calcium 10 months after completion of treatment. Magnesium, vitamin D, and parathyroid hormone levels were low normal. There was no evidence of tumor lysis syndrome. Of the various agents administered, vinca alkaloids seemed the most likely cause. Serial testing suggested that the underlying mechanism may have been acquired, reversible hypoparathyroidism. No other similar case was found in the published literature. CONCLUSION: The severe hypocalcemia in our patient could not be attributed to hypomagnesemia or tumor lysis syndrome, and it was clearly associated with the timing of his chemotherapeutic regimen. Possibilities include direct parathyroid hormone suppression or alteration of calcium sensing by the chemotherapeutic drugs. Serum calcium surveillance before and during chemotherapeutic management of cancer patients may reveal more instances and provide insight into the exact mechanism of this lesser known yet striking complication.