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Background: Group A β-hemolytic streptococcus (GAS) and Group B streptococcus (GBS) are two common pathogens that are associated with many diseases in children. Severe infections as a result of these two streptococci are albeit uncommon but associated with high mortality and morbidity, and often necessitate intensive care support. This paper aims to review mortality and morbidity severe infection associated with GAS and GBS isolations at a Pediatric Intensive Care Unit (PICU). Methods: All children admitted to PICU of a teaching hospital between October 2002 and May 2018 with laboratory-proven GAS and GBS isolations were included. Results: There were 19 patients (0.7% PICU admissions) with streptococcal isolations (GAS, n=11 and GBS, n=8). Comparing to GAS, GBS affected infants were younger (median age 0.13 versus 5.47 years, 95% CI, 1.7-8.5, p=0.0003), and cerebrospinal fluids more likely positive (p = 0.0181). All GAS and GBS were sensitive to penicillin (CLSI: MICs 0.06 – 2.0 μg/mL), with majority of GAS sensitive to clindamycin and erythromycin, and half of the GBS resistant to clindamycin and erythromycin. Co-infections were prevalent, but viruses were only isolated with GAS (p=0.024). Isolation of GAS and GBS was associated with nearly 40% mortality and high rates of mechanical ventilation and inotropic supports. All non-survivors had high mortality (PIM2) and sepsis scores. Conclusions: Severe GAS and GBS are rare but associated with high mortality and rates of mechanical ventilation and inotropic supports in PICU. The streptococci are invariably sensitive to penicillin. The high PIM2 and Sepsis scores suggest that prompt recognition of sepsis and timely judicious institution of antibiotics and intensive care support may be life-saving for these devastating infections.

Widespread substance abuse has led to increasing use of urine drug testing in many clinical services. The last two decades have seen a significant rise in prescription drug misuse (especially opioids and benzodiazepines), leading to dramatic increases in drug overdoses and deaths. For some patients, misuse of prescription medications evolves into the abuse of illicit street drugs such as heroin. This chapter discusses the challenges of analytical true positives on urine drug testing that do not represent non-medical drug use by the patient. These include use of a medication containing a target of the urine drug assay, drugs that metabolize to a target of the assay, and food items that contain a target of the assay. Examples from the major drug classes of amphetamines, cocaine, marijuana, and opiates are discussed.

The survival rate of anaplastic thyroid cancer (ATC) is still very poor due to its fast growth and high metastatic potential. Currently, no effective treatment is available. The active form of vitamin D3, 1α,25(OH)2D3, has been shown to have a anti-metastatic effect in pre-clinical studies, however induction of hypercalcemia hampered its clinical application. The new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), is much more potent than 1α,25(OH)2D3 to repress cancer growth and metastasis in a variety of cancers. In this study, we demonstrated that both 1α,25(OH)2D3 and MART-10 could effectively inhibit the migration and invasion of ATC cells, 8305C and 8505C, with MART-10 much more potent than 1α,25(OH)2D3. The anti-metastatic effect of 1α,25(OH)2D3 and MART-10 on ATC cells is mediated by reversal of cadherin switch (upregulation of E-cadherin and downregulation of N-cadherin), which led to the attenuation of EMT process, and decrease of F-actin formation. We further showed that the expressions of Slug, the EMT-related transcriptional factor, and MMP-9 were inhibited by 1α,25(OH)2D3 and MART-10 in 8505C cells, but not in 8303C cells. Since metastasis is the important cause of ATC-related death, our results strongly encourage the further in vivo study of MART-10 application against ATC.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3(1α,25(OH)2D3or calcitriol), is known to inhibit the proliferation and invasiveness of many types of cancer cells, including breast, colon, pancreatic, prostate, and liver cancer cells. These findings support the use of 1α,25(OH)2D3for the treatment of these types of cancer. However, 1α,25(OH)2D3can cause hypercalcemia, so analogs of 1α,25(OH)2D3that are less calcemic but exhibit more potent anti-tumor activity would be good candidates as therapeutic agents. Therefore, a series of 19-norvitamin D analogs, in which the methylidene group on C19 is replaced with 2 hydrogen atoms, have been synthesized by several laboratories. In our laboratory, we have designed and synthesized a series of 2α-functional group substituted 19-norvitamin D3analogs and examined their anti-proliferative activity. Among them, 2α- and 2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3(MART-10 and MART-11) were found to be the most promising. Here, we review the rationale and approaches for the synthesis of different 19-norvitamin D analogs, and the pre-clinical studies using these analogs in breast cancer cells, in particular, we chose MART-10 for its potential application to the prevention and treatment of breast cancer.

Background We evaluated the distribution of 25OH-D2 and 25OH-D3 in a general patient population in Western New York to provide insights into how common detectable vitamin D2 is among samples from a general patient population. Methods Serum 25OH-D2 and 25OH-D3 results measured by LC-MS/MS from June 2009 to December 2012 were retrospectively analyzed. Results A total of 266,269 serum tests were included for analysis. The percentage of tests with 25OH-D2 levels above the assay limit of quantitation (LoQ) decreased from 32% to 17% over the course of the study period. The percentage of tests with 25OH-D2 levels higher than those of 25OH-D3 decreased from 21% to 12%. Sixty-seven percent of the test results with 25OH-D2 levels above the LoQ had serum concentrations of 25OH-D2 higher than those of 25OH-D3. Conclusion Prevalence of tests with quantifiable 25OH-D2 decreased over time and yet 17% of them still had detectable levels of 25OH-D2, 67% of which had 25OH-D2 levels higher than 25OH-D3. To achieve accurate 25-hydroxyvitamin D measurement, clinical laboratories should assess the accuracy of their assays, and if necessary, determine the local prevalence of 25OH-D2 to determine if mass spectrometry is the platform of choice to assess vitamin D deficiency.

In recent years, the abuse of opioid drugs has resulted in greater prevalence of addiction, overdose, and deaths attributable to opioid abuse. The epidemic of opioid abuse has prompted professional and government agencies to issue practice guidelines for prescribing opioids to manage chronic pain. An important tool available to providers is the drug test for use in the initial assessment of patients for possible opioid therapy, subsequent monitoring of compliance, and documentation of suspected aberrant drug behaviors. This review discusses the issues that most affect the clinical utility of drug testing in chronic pain management with opioid therapy. It focuses on the two most commonly used specimen matrices in drug testing: urine and oral fluid. The advantages and disadvantages of urine and oral fluid in the entire testing process, from specimen collection and analytical methodologies to result interpretation are reviewed. The analytical sensitivity and specificity limitations of immunoassays used for testing are examined in detail to draw attention to how these shortcomings can affect result interpretation and influence clinical decision-making in pain management. The need for specific identification and quantitative measurement of the drugs and metabolites present to investigate suspected aberrant drug behavior or unexpected positive results is analyzed. Also presented are recent developments in optimization of test menus and testing strategies, such as the modification of the standard screen and reflexed-confirmation testing model by eliminating some of the initial immunoassay-based tests and proceeding directly to definitive testing by mass spectrometry assays.

Colorectal cancer screening aims to detect colorectal cancer at an early stage, when treatment is more likely to be curative. Lack of participation in such screening is a major issue in primary care practices, where nurse practitioners (NPs) often provide care. This study aimed to determine whether an educational intervention for NPs would increase their awareness of, and increase patients' participation in, colorectal cancer screening. .

Tuberous sclerosis is an autosomal dominant disorder with a wide clinical spectrum of disease. It is characterized by development of benign tumors in multiple organs due to a disturbance in cellular growth and differentiation. It usually affects skin, brain, heart and kidney. Gastrointestinal involvement is rare and mainly restricted to adults and sigmoid colon and rectum. In children there are only two cases; our patient would be the third. We present a patient with tuberous sclerosis who began at the first month of life with repeated intestinal subocclusion. The videocolonoscopy showed a mass protruding into the lumen of the ascending colon. Right hemicolectomy was performed. The anatomopathological report corresponded to a hamartomatous polyp. The clinical and nutritional evolution in the postoperative period was very favorable. Although uncommon, the hamartomatous polyp should be considered in the differential diagnosis of intestinal occlusion in pediatrics.

Background and Purpose— Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. Methods— In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. Results— During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00; P =0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40; P =0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (β±SE=−0.05±0.02; P =0.025), and better visual memory (β±SE=0.18±0.07; P =0.005). Conclusions— Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.

Osteocalcin (OCN), a marker of osteoblast activity, has been implicated in the regulation of energy metabolism by the skeleton and thus may affect body fat measures. We examined the relationships of OCN to body fat measures and whether they vary according to markers of energy and vitamin D metabolism. Data was obtained from 58 obese adolescents aged 13–17.9 years (38 females, 8 black or African-American). We calculated total fat mass (FM) [dual X-ray absorptiometry (DXA)] and visceral adipose tissue (VAT) [computerized axial tomography (CT)]. Blood tests included leptin, OCN, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), thyroid function tests, and triglycerides. Markers of glucose metabolism were obtained from fasting and OGTT samples. Adolescents with 25(OH)D

AIDS-related mortality remains a leading cause of preventable death among African-Americans. We sought to determine if community health workers could improve clinical outcomes among vulnerable African-Americans living with HIV in Miami, Florida. We recruited 91 medically indigent persons with HIV viral loads ≥1,000 and/or a CD4 cell count ≤350. Patients were randomized to a community health worker (CHW) intervention or control group. Viral load and CD4 cell count data were abstracted from electronic medical records. At 12 months, the mean VL in the intervention group was log 0.9 copies/μL lower than the control group. The CD4 counts were not significantly different among the groups. Compared to the control group, patients randomized to CHWs experienced statistically significant improvements in HIV viral load. Larger multi-site studies of longer duration are needed to determine whether CHWs should be incorporated into standard treatment models for vulnerable populations living with HIV.

UNLABELLED Langerhans cell histiocytosis is a heterogeneous disease of unknown etiology characterized by proliferation of Langerhans cells. It is a rare disease. Bone involvement is common but vertebral disease is rare. We present a 4 year old patient with abdominal pain and neurologic symptoms. Magnetic resonance showed vertebra plana in D9 with involvement of paravertebral soft tissues. The child underwent surgery for decompression and biopsy. Biopsy confirmed Langerhans cell histiocytosis. She was treated with vinblastine and prednisone during 6 months following LCH-III with complete recovery of neurologic symptoms. CONCLUSION Langerhans cell histiocytosis is a differential diagnosis in a radiograph with vertebra plana or collapse of vertebral body.

Shih-Wei Yang,1,* Chi-Ying Tsai,2,* Yi-Chun Pan,3 Chun-Nan Yeh,4 Jong-Hwei S Pang,5 Masashi Takano,6 Atsushi Kittaka,6 Horng-Heng Juang,7 Tai C Chen,8 Kun-Chun Chiang4,9 1Department of Otolaryngology– Head and Neck Surgery, Chang Gung Memorial Hospital, Keelung, 2Department of Oral and Maxillofacial Surgery, Chang Gung Memorial Hospital, Taoyuan, 3Department of General Dentistry, Chang Gung Memorial Hospital, Chang Gung University, Keelung, 4General Surgery Department, Chang Gung Memorial Hospital, Keelung, 5Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China; 6Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo, Japan; 7Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China; 8Endocrine Core Laboratory, Boston University School ofMedicine, Boston, MA,USA; 9Zebrafish Center, Chang GungMemorial Hospital, Keelung, Taiwan, Republic of China *These authors contributed equally tothiswork Abstract: Even with multidisciplinary treatment, the prognosis and quality of life of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are still not satisfactory. Previously, 19-Nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3 (MART-10), the new brand 1α,25(OH)2D3 analog, has been demonstrated to be an effective drug to inhibit HNSCC growth in vitro. Since most cancer patients die of metastasis, in this study, the antimetastatic effect of MART-10 on HNSCC was investigated. Our results reveal that both 1α,25(OH)2D3 and MART-10 effectively repressed the migration and invasion of HNSCC cells, with MART-10 being much more potent than 1α,25(OH)2D3. The antimetastatic effect of 1α,25(OH)2D3 and MART-10 was mediated by attenuation of epithelial–mesenchymal transition (EMT), which was supported by the finding that the expression of EMT-inducing transcriptional factors, Sail and Twist, was inhibited by 1α,25(OH)2D3 and MART-10. The upregulation of E-cadherin and downregulation of N-cadherin in FaDu cells induced by both drugs further confirmed the repression of EMT. In addition, 1α,25(OH)2D3 and MART-10 treatment inhibited intracellular MMP-9 expression and extracellular MMP activity in FaDu cells. Collectively, our results suggest that the less-calcemia 1α,25(OH)2D3 analog, MART-10, is a promising drug for HNSCC treatment. Further clinical studies are warranted. Keywords: EMT, head and neck cancer, vitamin D analog, metastasis, MART-10

An epidemic of prescription drug abuse in the United States has increased the burden on clinical toxicology testing laboratories. Urine drug testing provides objective evidence for compliance and aberrant drug behavior in patients on chronic (non-cancer) pain management. This article describes the testing menu, drug testing assays including tandem mass spectrometry and their limitations, interpretation of opiate results and clinical considerations.

Vitamin D deficiency is common in tuberculosis (TB) and this may modulate immune responses. This study investigated vitamin D status in patients with TB and examined the sources of vitamin D in Tbilisi, Georgia.We measured plasma 25-hydroxyvitamin D (25[OH]D) and dietary vitamin D intake in patients with pulmonary TB (n = 85) in Tbilisi, Georgia. To determine the impact of season on vitamin D status, we tested the in vitro conversion of 7-dehydrocholesterol (7-DHC) to previtamin D(3) after sunlight exposure.In subjects with TB, mean plasma 25(OH)D concentrations were 14.4 ± 7.0 ng/mL, and vitamin D insufficiency (25[OH]D30 ng/mL) occurred in 97% of subjects. The dietary sources of vitamin D were mainly fish, eggs, and butter. The daily intake was well below recommended daily intakes in subjects with TB (172 ± 196 IU). The conversion of 7-DHC to previtamin D(3) was undetectable from October to March and highest in June and July from 11:00 to 14:00 h.An insufficient vitamin D dietary intake and a limited production of vitamin D from sunlight for most of the year may explain the high prevalence of vitamin D insufficiency in patients with TB in Tbilisi.

The discovery that the active form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)(2)D] can modulate cellular proliferation and differentiation of cancer cells has led to its potential application as a chemotherapeutic agent to treat a variety of cancers. However, the use of 1α,25(OH)(2)D is limited due to its lethal side effect of hypercalcemia upon systemic administration. To overcome this drawback, numerous analogs have been synthesized. In this report, we examined the anti-proliferative activity of a new analog, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10), in HepG2 liver cancer cells, and studied the potential mechanisms mediating this action. We found that MART-10 exhibited approximately 100-fold greater activity than 1α,25(OH)(2)D(3) in inhibiting HepG2 cell proliferation as determined by cell number counting method. MART-10 was also approximately 100-fold more potent than 1α,25(OH)(2)D(3) in the upregulation of p21 and p27, that in turn arrested HepG2 cells at the G(0)/G(1) phase to a greater extent. Given that no active caspase 3 was detected and treatment with 1α,25(OH)(2)D(3) or MART-10 did not further increase the fractions of apoptotic and necrosis cells over the controls, the growth-inhibitory effect of 1α,25(OH)(2)D(3) and MART-10 on HepG2 cells may not involve apoptosis. Overall, our findings suggest that MART-10 is a good candidate as a novel therapeutic regimen against liver cancer. Further pre-clinical studies using animal models and the subsequent human clinical trials are warranted.

Ursine hibernation uniquely combines prolonged skeletal unloading, anuria, pregnancy, lactation, protein recycling, and lipolysis. This study presents a radiographic and biochemical picture of bone metabolism in free-ranging, female American black bears (Ursus americanus) that were active (spring bears and autumn bears) or hibernating (hibernating bears). Hibernating bears included lactating and non-lactating individuals. We measured serum calcium, albumin, inorganic phosphate, creatinine, bone specific alkaline phosphatase (BSALP), CTX, parathyroid hormone, insulin-like growth factor-I (IGF-l), leptin, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and sclerostin from 35 to 50 tranquilized hibernating bears and 14 to 35 tranquilized spring bears. We compared metacarpal cortical indices (MCI), measured by digital X-ray radiogrammetry, from 60 hunter-killed autumn bears and 79 tranquilized, hibernating bears. MCI was greater in autumn than winter in younger bears, but showed no seasonal difference in older bears. During hibernation eucalcemia was maintained, BSALP was suppressed, and CTX was in the range expected for anuria. During hibernation 1,25(OH)(2)D was produced despite anuria. 1,25(OH)(2)D and IGF-I were less in hibernating than spring bears. In a quarter of hibernating bears, sclerostin was elevated. Leptin was greater in hibernating than spring bears. In hibernating bears, leptin correlated positively with BSALP in non-lactating bears and with CTX in lactating bears. Taken together the biochemical and radiographic findings indicate that during hibernation, bone turnover was persistent, balanced, and suppressed; bone resorption was lower than expected for an unloaded skeleton; and there was no unloading-induced bone loss. The skeleton appears to perceive that it was loaded when it was actually unloaded during hibernation. However, at the level of sclerostin, the skeleton recognized that it was unloaded. During hibernation leptin appeared anabolic in non-lactating bears and catabolic in lactating bears. We hypothesize that ursine hibernation may represent a natural model in which suppression of the sympathetic nervous system prevents unloading-induced bone loss by influencing leptin's skeletal effects and preventing transmission of loading information.

Background: Vitamin D deficiency is a common problem in patients with Crohn's disease (CD). The aim of this study was to determine the ability of normal subjects and patients with quiescent CD to absorb vitamin D2 using a novel vitamin D bioavailability test. In addition, we evaluated whether the location of disease or previous surgery had any influence on the bioavailability of vitamin D2 in CD patients. Methods: Ten normal subjects (50% female) and 37 CD patients with quiescent disease (51% female) were included in this study. Subjects who recently received any vitamin D2 were excluded. The vitamin D bioavailability test was performed in all subjects. After a baseline blood draw, all subjects were then given a single 50,000 IU oral dose of vitamin D2 in a capsule formulation and had their blood drawn 12 hours later to determine serum vitamin D2, which reflected their vitamin D2 absorption capacity. Results: Forty-two percent and 29% of CD patients were found to be either vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL] or insufficient [25(OH)D 21–29 ng/mL], respectively. Twelve hours after ingesting 50,000 IU vitamin D2, vitamin D2 levels rose from a baseline of 0.7 ± 0.7 ng/mL (mean ± SEM) to 49.8 ± 3.0 ng/mL in normal subjects. In CD patients, baseline vitamin D2 levels rose from 0 ng/mL to 34.8 ± 2.8 ng/mL. CD patients had on average a 30% decrease in their ability to absorb vitamin D2 (P = 0.01). Moreover, we found a wide variability of vitamin D2 bioavailability in CD patients. Analysis of variance (ANOVA) revealed no statistical difference of vitamin D2 bioavailability between patients in the CD subgroup stratified by the location of disease, the type of surgery, and receiving or not receiving surgery. Conclusions: More than 70% of the patients with quiescent CD were vitamin D-deficient or insufficient. The ability to absorb vitamin D2 in CD patients is unpredictable and the only way to determine this is to perform a vitamin D bioavailability test. Use of this test may guide clinicians in administering the appropriate therapeutic dose of vitamin D for treating vitamin D deficiency in patients with CD. (Inflamm Bowel Dis 2011;)

Oral fluid is a promising new matrix for drug-testing programs for drug treatment, the workplace, pain management, and driving under the influence of drugs (DUID)7. As with any new technology, there are strengths and limitations. We discuss with international experts the role this new alternative matrix will play in diverse drug-monitoring settings, and the research, development, and legislation needed to permit oral fluid testing to best take its place in the modern laboratory armamentarium.8 Do you believe oral fluid testing will become the most prevalent matrix tested in these programs and why? What are the strengths and limitations of oral fluid testing for each type of program? Alain Verstraete: Oral fluid will probably become the most prevalent matrix for DUID, certainly for roadside screening. Legislators and police officers want to rapidly perform DUID testing at the roadside, eliminating transport to hospitals or police stations. Oral fluid is used for DUID in 5 Australian states, Belgium, and France and is described in Swiss and United Kingdom legislation. The main advantages are ease of collection and a generally shorter window of drug detection than urine, hence a better correlation with duration of impairment. Limitations include difficulty of collection following recent drug use and the potential for passive contamination. For DUID confirmation, presently only Belgium and 4 Australian states utilize oral fluid; in other jurisdictions, positive oral fluid presumptive test results are confirmed with blood tests. Oral fluid also could become the most prevalent matrix for drug treatment due to ease of sampling, despite the shorter drug-detection window. In this setting, cost may play a more important role. If additional visits are required for oral fluid testing, urine testing might remain dominant. A strong advantage of oral fluid testing for drug treatment is the greater detection of 6-acetylmorphine, a marker …

The aim of the study was to examine the relationship between vitamin D status, total and abdominal adiposity, and lipids in black and white children.Plasma 25-hydroxyvitamin D [25(OH)D], adiposity [body mass index (BMI), percentage of total body fat, visceral adipose tissue (VAT), sc adipose tissue (SAT)], and fasting lipids were assessed in healthy obese and nonobese 8- to 18-yr-old black and white children.We studied 237 children (mean ± sd age, 12.7 ± 2.2 yr; 47% black, 47% obese, and 43% male). Mean 25(OH)D concentration for the entire cohort was 19.4 ± 7.4 ng/ml. The majority of the children were vitamin D deficient [25(OH)D20 ng/ml; 73% blacks, 40% whites]. Plasma 25(OH)D was associated inversely with BMI, BMI percentile, percentage of total body fat, VAT, and SAT and positively with HDL cholesterol in the entire cohort. VAT was higher in vitamin D-deficient whites, and SAT was higher in vitamin D-deficient blacks compared with their respective vitamin D-nondeficient counterparts. Race, season, pubertal status, and VAT were independent significant predictors of 25(OH)D status.In black and white youth examined together, lower levels of 25(OH)D are associated with higher adiposity measures and lower HDL. Furthermore, vitamin D deficiency is associated with higher VAT in whites and greater SAT in blacks. Besides therapeutic interventions to correct the high rates of vitamin D deficiency in youth, benefits of vitamin D optimization on adiposity measures and lipid profile need to be explored.

Metabolic syndrome poses additional risk for postmenopausal women who are already at risk for osteoporosis. We hypothesized that a nutritional supplement containing anti-inflammatory phytochemicals and essential bone nutrients would produce a favorable bone biomarker profile in postmenopausal women with metabolic syndrome. In this 14-week, randomized trial, 51 women were instructed to consume a modified Mediterranean-style, low-glycemic-load diet and to engage in aerobic exercise. Those in the intervention arm (n = 25) additionally received 200 mg hop rho iso-alpha acids, 100 mg berberine sulfate trihydrate, 500 IU vitamin D₃, and 500 μg vitamin K₁ twice daily. Forty-five women completed the study. Baseline nutrient intake did not differ between arms. Compared with baseline, the intervention arm exhibited an approximate 25% mean decrease (P < .001) in serum osteocalcin (indicative of bone turnover), whereas the placebo arm exhibited a 21% increase (P = .003). Serum 25-hydroxyvitamin D increased 23% (P = .001) in the intervention arm and decreased 12% (P = .03) in the placebo arm. The between-arm differences for osteocalcin and 25-hydroxyvitamin D were statistically significant. Serum insulin-like growth factor I was statistically increased in both arms, but the between-arm differences were not statistically significant. Subanalysis showed that among those in the highest tertile of baseline insulin-like growth factor I, the intervention arm exhibited a significant increase in amino-terminal propeptide of type I collagen, whereas the placebo arm showed a significant decrease at 14 weeks. Treatment with rho iso-alpha acids, berberine, vitamin D₃, and vitamin K₁ produced a more favorable bone biomarker profile indicative of healthy bone metabolism in postmenopausal women with metabolic syndrome.

Background Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma.

The non-classical actions of vitamin D, namely anti-proliferation, pro-differentiation, immune function modulation, and anti-inflammation, have received great attention during the past decade, in particular, the potential of vitamin D analogs alone or in combination with other anticancer agents for the treatment of a variety of cancers. The association between vitamin D status and the higher incidence of many forms of cancer has suggested that vitamin D may play a role in the etiology of these types of cancer. Although it is still controversial whether this association exists for pancreatic cancer, biochemical evidence clearly indicates pancreatic cancer cells are responsive to the inhibitory effect of vitamin D and its analogs. In this review, we discuss briefly the origin and current therapy of pancreatic cancer, the history, source, metabolism and functions of vitamin D, the recent progress in the epidemiological studies of sunlight, and vitamin D status, and biochemical studies of vitamin D analogs in the prevention and treatment of pancreatic cancer.

OBJECTIVES: The objectives were to characterize the vitamin D status of black and white adolescents residing in the southeastern United States (latitude: ∼33°N) and to investigate relationships with adiposity. METHODS: Plasma 25-hydroxyvitamin D levels were measured with liquid chromatography-tandem mass spectroscopy for 559 adolescents 14 to 18 years of age (45% black and 49% female). Fat tissues, physical activity, and cardiovascular fitness also were measured. RESULTS: The overall prevalences of vitamin D insufficiency ( CONCLUSIONS: Low vitamin D status is prevalent among adolescents living in a year-round sunny climate, particularly among black youths. The relationships between 25-hydroxyvitamin D levels, adiposity, physical activity, and fitness seem to be present in adolescence.

Supplementation of milk with vitamin D virtually eliminated rickets, a disease once ubiquitous in industrialized nations in the early 20th century. In the last decade, however, several reports have indicated that vitamin D deficiency is widespread in industrialized nations, and that rickets is remerging. At present, vitamin D deficiency appears to be prevalent in women of childbearing age and young children. This retrospective cohort study examined vitamin D status in mothers and newborns in Boston and investigated factors associated with vitamin D deficiency. The study was performed between 2005 and 2007 at an urban teaching hospital with a population of primarily low-income Black and Hispanic patients. Blood samples were obtained by venipuncture from the mother and infant within 72 hours of birth. Data on potential variables associated with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] < 20 ng/mL) in mothers and infants were obtained from a questionnaire completed by the mothers and from medical records. The serum level of 25(OH)D level, the primary study outcome, was determined by competitive protein binding. A total of 458 mother/infant pairs were enrolled; after exclusions, the final study population was 376 newborns and 433 women. The median infant 25(OH)D level was 17.2 ng/mL (range, 5.0-60.8 ng/mL), with a 95% confidence interval (CI) of 16.0 to 18.8. The median maternal 25(OH)D level was 24.8 ng/mL (range, 5.0-79.2 ng/mL), with a 95% CI of 23.2 to 25.8. Vitamin D deficiency was found in 58% of the infants and 35.8% of the mothers, and severe deficiency (25[OH]D level

Inflammatory response secondary to hemorrhagic shock (HS) frequently precedes multiple organ failure and death in trauma patients. Researchers have recognized that exercise benefits immune function. However, the effects of exercise on HSinduced death and organ damage are unknown. In this study, the authors aimed to explore the effects of exercise on survival rate and organ injury after HS. Rats were divided into exercise and nonexercise groups. The exercise group received running training 30 min/day five times/week for 4 weeks. After 4 weeks, researchers withdrew 60% of total blood volume in both groups to mimic HS. Levels of blood aspartate transferase (GOT), alanine transferase (GPT), blood urea nitrogen (BUN), creatinine (Cr), lactic acid dehydrogenase (LDH), creatine kinase—myoglobin (CK-MB), blood glucose, and lactate were measured. The survival rate and injury scores for the liver, kidney, and lung were examined 48 hr after HS. Physical activity was measured in surviving rats from the 3rd to the 7th day after HS. Exercise training significantly increased the survival rate (75% for the exercise group vs. 50% for the nonexercise group) after HS and decreased organ injury. In addition, the exercise group was more active than the nonexercise group after HS.

Osteoporosis is a major health issue facing postmenopausal women. Increased production of pro-inflammatory cytokines resulting from declining estrogen leads to increased bone resorption. Nutrition can have a positive impact on osteoporosis prevention and amelioration. The objective of this study was to investigate the impact of targeted phytochemicals and nutrients essential for bone health on bone turnover markers in healthy postmenopausal women. In this 14-week, single-blinded, 2-arm placebo-controlled pilot study, all women were instructed to consume a modified Mediterranean-style low-glycemic-load diet and to engage in limited aerobic exercise; 17 randomized to the placebo and 16 to the treatment arm (receiving 200 mg hop rho iso-alpha acids, 100 mg berberine sulfate trihydrate, 500 IU vitamin D(3) and 500 microg vitamin K(1), twice daily). Thirty-two women completed the study. Baseline nutrient intake did not differ between arms. At 14 weeks, the treatment arm exhibited an estimated 31% mean reduction (P = 0.02) in serum osteocalcin (a marker of bone turnover), whereas the placebo arm exhibited a 19% increase (P = 0.03) compared to baseline. Serum 25-hydroxyvitamin D (25(OH)D) increased by 13% (P = 0.24) in the treatment arm and decreased by 25% (P < 0.01) in the placebo arm. The between-arm differences for OC and 25(OH)D were statistically significant. Serum IGF-I was increased in both arms, but the increase was more significant in the treatment arm at 14 weeks (P < 0.01). Treatment with hop rho iso-alpha acids, berberine sulfate trihydrate, vitamin D(3) and vitamin K(1) produced a more favorable bone biomarker profile that supports a healthy bone metabolism.

Background: Data on the relation between vitamin D status and body fat indexes in adolescence are lacking. Objective: The objective was to identify factors associated with vitamin D status and deficiency in obese adolescents to further evaluate the relation of body fat indexes to vitamin D status and deficiency. Design: Data from 58 obese adolescents were obtained. Visceral adipose tissue (VAT) was measured by computed tomography. Dual-energy X-ray absorptiometry was used to measure total bone mineral content, bone mineral density, body fat mass (FM), and lean mass. Relative measures of body fat were calculated. Blood tests included measurements of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, type I collagen C-telopeptide, hormones, and metabolic factors. Vitamin D deficiency was defined as 25(OH)D 65 ng/mL. Results: The mean (±SD) age of the adolescents was 14.9 ± 1.4 y; 38 (66%) were female, and 8 (14%) were black. The mean (±SD) body mass index (in kg/m2) was 36 ± 5, FM was 40.0 ± 5.5%, and VAT was 12.4 ± 4.3%. Seventeen of the adolescents were vitamin D deficient, but none had elevated PTH concentrations. Bone mineral content and bone mineral density were within 2 SDs of national standards. In a multivariate analysis, 25(OH)D decreased by 0.46 ± 0.22 ng/mL per 1% increment in FM (β ± SE, P = 0.05), whereas PTH decreased by 0.78 ± 0.29 pg/mL per 1% increment in VAT (P = 0.01). Conclusions: To the best of our knowledge, our results show for the first time that obese adolescents with 25(OH)D deficiency, but without elevated PTH concentrations, have a bone mass within the range of national standards (±2 SD). The findings provide initial evidence that the distribution of fat may be associated with vitamin D status, but this relation may be dependent on metabolic factors. This study was registered at www.clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00209482","term_id":"NCT00209482"}}NCT00209482, NCT00120146.

Children suffering severe burns develop progressive vitamin D deficiency because of inability of burned skin to produce normal quantities of vitamin D(3) and lack of vitamin D supplementation on discharge. Our study was designed to determine whether a daily supplement of a standard multivitamin tablet containing vitamin D(2) 400 IU (10 microg) for 6 months would raise serum levels of 25-hydroxyvitamin D [25(OH)D] to normal. We recruited eight burned children, ages 5-18, whose families were deemed reliable by the research staff. These children were given a daily multivitamin tablet in the hospital for 3 months in the presence of a member of the research staff and then given the remainder at home. At 6 months, the subjects returned for measurements of serum levels of 25(OH)D,1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone (iPTH), Ca, P, albumin, and total protein as well as bone mass by dual energy X-ray absorptiometry. Serum 25(OH)D levels were compared to a group of seven age-matched burned children studied at an earlier date without the vitamin supplement but with the same method of determination of 25(OH)D at 6 months post-burn. In addition, the chewable vitamins were analyzed for vitamin D(2) content by high performance liquid chromatography. Serum concentration of 25(OH)D was 21 +/- 11(SD) ng/ml (sufficient range 30-100) with only one of the eight children having a value in the sufficient range. In comparison, the unsupplemented burn patients had mean serum 25(OH)D level of 16 +/- 7, P = 0.33 versus supplemented. Serum levels of 1,25(OH)(2)D, iPTH, Ca, P, albumin, and total protein were all normal in the supplemented group. Vitamin D(2) content of the chewable tablets after being saponified and extracted was 460 +/- 20 IU. Bone mineral content of the total body and lumbar spine, as well as lumbar spine bone density, failed to increase as expected in the supplemented group. No correlations were found between serum 25(OH)D levels and age, length of stay, percent body surface area burn or third-degree burn. Supplementation of burned children with a standard multivitamin tablet stated to contain 400 IU of vitamin D(2) failed to correct the vitamin D insufficiency.

Using all-inclusive data from 126 U.S. Department of Veterans Affairs health care facilities that provide dental services, this study identified the staffing infrastructure under which the Veterans Health Administration can provide graduate dental education without compromising dental clinic productivity. From regression analyses, we found that teaching residents has a negative impact on staff dentists’ productivity; however, when the dental assistant to provider ratio is greater than or equal to 1.0, dental residents’ workload contribution can offset the negative impact on overall clinic productivity. In the presence of dental residents, the dental assistant, front-desk personnel, and dental treatment room to provider ratios have a positive impact on productivity. The optimal ratios were calculated as 1.5 for dental assistants, 2.1 for dental treatment rooms, and 0.57 for front-desk personnel.

We studied the effects of ultraviolet B (UVB) exposure or administration of dietary vitamin D3 on serum vitamin D3, serum 25-hydroxyvitamin D3 (25[OH]D), calcium, and phosphorus in juvenile black-throated monitor lizards (Varanus albigularis) deprived of all sources of vitamin D for 87 days. Deprivation resulted in significant decreases of circulating levels of 25(OH)D (25–35%), vitamin D3 (73–76%), calcium (6%), and phosphorus (16%). The half-life of circulating 25(OH)D during deprivation was estimated to be from 128–139 days. After deprivation, eight monitors were given a single dose of UVB from exposure for 10–20 minutes to a Spectroline UVB lamp. The dose resulted in an average of 14.2% conversion of provitamin D3 to previtamin D3 and photoproducts within in vitro models. When administered once every week for 92 days, the dose failed to significantly modify the decline of serum 25(OH)D; however, the decline of vitamin D3 seemed to level off. The overall effect of the UVB dosing was weak, and ...

Objectives: We report the plasma 25-hydroxyvitamin D [25(OH)D] levels of 16 young children who were undergoing ambulatory surgery for placement of tympanostomy tubes. Methods: We previously obtained blood samples from young children who were undergoing ambulatory surgery and reported that they had lower blood levels than adults of eicosapentaenoic acid (an omega-3 fatty acid), vitamin A, and selenium. Plasma frozen continuously at −80°C was available from 16 subjects who were undergoing placement of tympanostomy tubes. Results: The mean (±SD) age of the patients was 3.7 ± 1.6 years (median, 2.9 years; range, 1.9 to 7.4 years). Sixty-two percent were male; half were white, and half were Hispanic. Sixty-two percent were private patients; the parents reported that half were taking vitamin supplements. None had a history of rickets. None had 25(OH)D levels less than 10 ng/mL; 50% had 25(OH)D levels less than 20 ng/mL (deficient in adults); another 31% had levels from 21 to 29 ng/mL (insufficient in adults). Conclusions: Vitamin D is essential for the production of endogenous antimicrobial peptides, and has been linked to seasonal, epidemic influenza A. However, the level of 25(OH)D needed to prevent infection with various human pathogens has not been defined. In view of increasing bacterial resistance and emerging new pathogens, further research on the relationship of infection to 25(OH)D and other nutritional factors is warranted.

There are few data on the skeletal health of Hispanic men. We observed differences in vitamin D deficiency and low BMD between Hispanic ethnic subgroups that persisted with adjustment for risk factors. Our data indicate a substantial burden of low BMD and vitamin D deficiency among Hispanic men. Disparities within ethnic groups are generally ignored, but in evolving populations they may have implications for public health. We examined ethnic variation in serum 25-hydroxyvitamin D [25(OH)D] and bone mineral density (BMD) among Hispanic American men. Three hundred and fifty-eight Hispanic males 30 to 79 years of age were studied. Logistic regression models assessed variation in odds of vitamin D deficiency (

Vitamin D deficiency may have implications for cardiovascular health. The purpose of this study was to determine the relationship of 25-hydroxyvitamin D (25[OH]D) to cholesterol and lipoprotein particles and to determine whether increasing 25(OH)D through ultraviolet (UV) irradiation impacted on these parameters in healthy young men and women. This was a randomized trial of 51 adults exposed to suberythemal doses of whole-body irradiation using UV lamps that emitted UV-A and UV-B radiation, compared with a control group, twice weekly for 12 weeks. 25-Hydroxyvitamin D, cholesterol, and lipoprotein subfractions were measured at baseline and after 12 weeks. There was a significant (P < .03) positive association between 25(OH)D and apolipoprotein A-I (Apo A-I) and lipoprotein A-I (Lp A-I). The ratio of low-density lipoprotein to high-density lipoprotein was significantly (P < or = .044) negatively correlated with 25(OH)D levels. The levels of 25(OH)D increased significantly in the treated compared with control group (P < .05). Overall, there were no significant differences between the treated and control groups in any lipoproteins or apolipoproteins after administration of UV irradiation. Subgroup analysis for Apo A-II confined to those with 25(OH)D insufficiency (25[OH]D

Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D 3 )

OBJECTIVES: To determine the effect of four vitamin D supplement doses on falls risk in elderly nursing home residents. DESIGN: Secondary data analysis of a previously conducted randomized clinical trial. SETTING: Seven hundred twenty-five-bed long-term care facility. PARTICIPANTS: One hundred twenty-four nursing home residents (average age 89). INTERVENTION: Participants were randomly assigned to receive one of four vitamin D supplement doses (200IU, 400IU, 600IU, or 800IU) or placebo daily for 5 months. MEASUREMENTS: Number of fallersand number offalls assessed using facility incident tracking database. RESULTS: Over the 5-month study period, the proportion of participants with falls was 44% in the placebo group (11/ 25), 58% (15/26) in the 200IU group, 60% (15/25) in the 400IU group, 60% (15/25) in the 600IU group, and 20% (5/23) in the 800IU group. Participants in the 800IU group had a 72% lower adjusted-incidence rate ratio of falls than those taking placebo over the 5 months (rate ratio 50.28; 95% confidence interval 50.11‐0.75). No significant differences were observed for the adjusted fall rates compared to placebo in any of the other supplement groups. CONCLUSION: Nursing home residents in the highest vitamin D group (800IU) had a lower number of fallers and a lower incidence rate of falls over 5 months than those taking lower doses. Adequate vitamin D supplementation in elderly nursing home residents could reduce the number of falls experienced by this high falls risk group. JA m Geriatr Soc 55:234–239, 2007.

To investigate the relation of circulating concentrations of vascular endothelial growth factor (VEGF) for the risk of developing cardiovascular disease (CVD) in a large community-based sample.We prospectively assessed the relation of circulating VEGF concentrations with the incidence of CVD among 3041 Framingham Heart Study participants (mean age 63.4±11.1 years, 59% women). Multivariable Cox proportional hazards models were estimated adjusting for standard risk factors to VEGF quartiles to incident CVD. Restricted cubic splines were used to examine the linearity of the association.After a mean follow-up of 8.8 (±2.8) years, 527 individuals experienced a first CVD event. Compared with participants in the first VEGF quartile, individuals in the second VEGF quartile had a 34% increased risk for future CVD (HR 1.34, 95% CI 1.03 to 1.74; p value=0.03) and individuals in third quartile had a 59% higher risk (HR 1.59; 95% CI 1.23 to 2.05, p value=0.0003). Individuals in the highest VEGF quartile had a similar cardiovascular risk as compared with those in the lowest VEGF quartile (HR 1.18, 95% CI 0.91 to 1.53, p value=0.21). Evaluation of restricted cubic splines confirmed the nonlinear, inverted U-shaped relation of serum VEGF and CVD events (p0.0001 for model fit, p=0.006 for non-linearity).Circulating VEGF concentrations exhibit a complex non-linear (inverted U-shaped) relation with the risk of developing CVD events, with the lowest risk experienced at the lower and upper end of the distribution. The underlying pathophysiological mechanisms remain to be elucidated.

To determine vitamin D status and bone mineral density (BMD) in patients admitted to a subacute rehabilitation facility.Cross-sectional cohort study.Subacute rehabilitation facility.Fifty-three community-dwelling patients admitted from June through February 2005.Not applicable.BMD, 25-hydroxyvitamin D (25[OH]D), C-telopeptide (CTX), osteocalcin, and dietary milk intake.Prevalence of vitamin D deficiency (25[OH]D20 ng/mL) was 49.1%, while a total of 83% of patients were either vitamin D deficient or insufficient (25[OH]D30 ng/mL). The prevalence of osteopenia (T score,-1) was 52.8%; osteoporosis (T score,-2.5) was 17.0%. CTX (bone resorption marker) was elevated in 60.4% of patients. Osteocalcin (bone formation marker) was elevated in 13.2% of patients. Measurements of bone resorption and formation positively correlated (R2 = .22) indicating increased bone remodeling.Vitamin D deficiency and osteopenia and osteoporosis were highly prevalent in patients admitted for rehabilitation. Elevated bone resorption and remodeling were evident. This could be due to vitamin D deficiency that should be corrected before antiresorptive therapy is considered. The study emphasizes the need for vigilance for vitamin D status and BMD testing in patients admitted to rehabilitation facilities.

The 25-hydroxyvitamin D3 (25-OH-D3) is a nontoxic and low-affinity vitamin D receptor (VDR)-binding metabolic precursor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We hypothesized that covalent attachment of a 25-OH-D3 analog to the hormone-binding pocket of VDR might convert the latter into transcriptionally active holo-form, making 25-OH-D3 biologically active. Furthermore, it might be possible to translate the nontoxic nature of 25-OH-D3 into its analog. We showed earlier that 25-hydroxyvitamin D3-3-bromoacetate (25-OH-D3-3-BE) alkylated the hormone-binding pocket of VDR. In this communication we describe that 10−6 mol/L of 25-OH-D3-3-BE inhibited the growth of keratinocytes, LNCaP, and LAPC-4 androgen-sensitive and PC-3 and DU145 androgen-refractory prostate cancer cells, and PZ-HPV-7 immortalized normal prostate cells with similar or stronger efficacy as 1,25(OH)2D3. But its effect was strongest in LNCaP, PC-3, LAPC-4, and DU145 cells. Furthermore, 25-OH-D3-3-BE was toxic to these prostate cancer cells and caused these cells to undergo apoptosis as shown by DNA-fragmentation and caspase-activation assays. In a reporter assay with COS-7 cells, transfected with a 1α,25-dihydroxyvitamin D3-24-hydroxylase (24-OHase)-construct and VDR-expression vector, 25-OH-D3-3-BE induced 24-OHase promoter activity. In a “pull down assay” with PC-3 cells, 25-OH-D3-3-BE induced strong interaction between VDR and general transcription factors, retinoid X receptor, and GRIP-1. Collectively, these results strongly suggested that the cellular effects of 25-OH-D3-3-BE were manifested via 1,25(OH)2D3/VDR signaling pathway. A toxicity study in CD-1 mice showed that 166 μg/kg of 25-OH-D3-3-BE did not raise serum-calcium beyond vehicle control. Collectively, these results strongly suggested that 25-OH-D3-3-BE has a strong potential as a therapeutic agent for androgen-sensitive and androgen-refractory prostate cancer.

Testosterone therapy for osteoporosis has not been studied extensively in women because of its potential to cause virilization. Female-to-male transsexuals are genetic females who suffer from gender dysphoria and thus take supra-physiologic doses of testosterone to change from the female to male phenotype. The aim of this study is to examine the effects of testosterone treatment on the genetic female skeleton.A group of 15 female-to-male transsexuals was prospectively enrolled for observation over a 2-year period. The subjects had a mean age of 37.0 +/- 3.0 years. All of the subjects self-administered testosterone esters intramuscularly at a mean dose of 70.7 +/- 4.5 mg weekly.The subjects had measurements of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) of the femoral neck and spine (L2-L4) at 12-month intervals. They had determinations of serum oestradiol, testosterone, soluble RANKL (sRANKL), osteoprotegerin (OPG) and urine N-telopeptide (NTX) at the date of enrolment and at the end of 2 years. results There was a significant positive increase in mean BMD of 7.8% at the femoral neck and a nonsignificant increase in mean BMD of 3.1% at the spine over 2 years. The levels of testosterone reached the upper normal range for males and the levels of oestradiol declined to near the postmenopausal range. sRANKL levels decreased significantly in female-to-male transsexuals who newly initiated testosterone therapy. There was no significant change in urine NTX or serum OPG during the study.We conclude that supra-physiologic testosterone therapy increases BMD at the hip while maintaining BMD at the spine in female-to-male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis.

The hormonal form of vitamin D, 1 alpha,25-dihydroxyvitamin D [1 alpha,25(OH)(2)D] promotes the differentiation and inhibits the proliferation, invasiveness and metastasis of prostate cells. However, 1 alpha,25(OH)(2)D is not suitable as a chemopreventive agent because its administration can cause hypercalcemia. Serum levels of 1 alpha,25(OH)(2)D are tightly regulated by the renal enzyme, 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-OHase), which synthesizes 1 alpha,25(OH)(2)D from the prohormone, 25-hydroxyvitamin D [25(OH)D]. Normal prostate epithelial cells in primary culture, as well as several prostate cancer cell lines, also express 1 alpha-OHase and synthesize the hormone intracellularly. We now investigated the regulation of the prostate 1 alpha-OHase by the three most important regulators of the renal 1 alpha-OHase: calcium, 1 alpha,25(OH)(2)D and parathyroid hormone (PTH). The 1 alpha-OHase activity in the primary cultures of prostate epithelial cells was inhibited by 1 alpha,25(OH)(2)D(3) at 10 and 100 nM, whereas PTH at 10 and 100 nM had no significant effect. Calcium at 1.2 and 2.4 mM had no significant effect on the enzyme activity in the PZ-HPV-7 cell line, a prostate epithelial cell line derived from normal prostate tissue. Conversely, 1.2 or 2.4 mM calcium markedly inhibited 1 alpha-OHase activity in a human kidney cell line used as a positive control. Furthermore, PTH at 100 nM and calcium at 1.2 and 2.4 mM had no effect on the 1 alpha-OHase gene promoter activity in prostate cells, whereas the promoter activity was inhibited 48 +/- 5% by 100 nM 1 alpha,25(OH)(2)D(3). Our findings suggest that, unlike the renal enzyme, the prostate 1 alpha-OHase appears to be largely unregulated by serum levels of PTH and calcium. These findings support the hypothesis that vitamin D or 25(OH)D may be useful as chemopreventive agents for prostate cancer because their administration should cause an increased synthesis of 1 alpha,25(OH)(2)D within prostate cells.

Methylecgonidine is formed from cocaine base when smoked and has been identified in biological fluids of crack smokers. Ecgonidine, a metabolite of methylecgonidine formed via esterase activity, also has been identified in similar samples collected from crack smokers. Methylecgonidine and ecgonidine can be used as biomarkers to differentiate smoking from cocaine use via other routes of administration. We determined the pharmacokinetic properties of methylecgonidine and ecgonidine in sheep after intravenous administration of methylecgonidine at doses of 3.0, 5.6, and 10.0 mg/kg using gas chromatography-mass spectrometric assays. Methylecgonidine clears quickly from blood with a half-life of 18 to 21 min, whereas ecgonidine has a longer half-life of 94 to 137 min. Because ecgonidine clears more slowly, it may be a more effective biomarker of cocaine smoking. The cardiovascular stimulant effects of cocaine contrast with reported in vitro muscarinic agonist effects of methylecgonidine, decreasing contractility and stimulating nitric oxide production in cardiac cells and tissues. To test the hypothesis that methylecgonidine produces cardiovascular effects in vivo consistent with muscarinic agonism, methylecgonidine was administered to sheep intravenously (0.1-3.0 mg/kg) while monitoring heart rate and blood pressure. Significant hypotension and tachycardia occurred in all three sheep. Two of the three sheep demonstrated mild bradycardia 3 to 5 min after methylecgonidine injection. Intravenous pretreatment with atropine methyl bromide (15 microg/kg) antagonized methylecgonidine-induced hypotension in all three sheep, supporting the hypothesis that methylecgonidine acts as a muscarinic agonist in vivo.

Background: Exposure to drugs and toxins is a major cause for patients’ visits to the emergency department (ED).Methods: Recommendations for the use of clinical laboratory tests were prepared by an expert panel of analytical toxicologists and ED physicians specializing in clinical toxicology. These recommendations were posted on the world wide web and presented in open forum at several clinical chemistry and clinical toxicology meetings.Results: A menu of important stat serum and urine toxicology tests was prepared for clinical laboratories who provide clinical toxicology services. For drugs-of-abuse intoxication, most ED physicians do not rely on results of urine drug testing for emergent management decisions. This is in part because immunoassays, although rapid, have limitations in sensitivity and specificity and chromatographic assays, which are more definitive, are more labor-intensive. Ethyl alcohol is widely tested in the ED, and breath testing is a convenient procedure. Determinations made within the ED, however, require oversight by the clinical laboratory. Testing for toxic alcohols is needed, but rapid commercial assays are not available. The laboratory must provide stat assays for acetaminophen, salicylates, co-oximetry, cholinesterase, iron, and some therapeutic drugs, such as lithium and digoxin. Exposure to other heavy metals requires laboratory support for specimen collection but not for emergent testing.Conclusions:Improvements are needed for immunoassays, particularly for amphetamines, benzodiazepines, opioids, and tricyclic antidepressants. Assays for new drugs of abuse must also be developed to meet changing abuse patterns. As no clinical laboratory can provide services to meet all needs, the National Academy of Clinical Biochemistry Committee recommends establishment of regional centers for specialized toxicology testing.

Background: The cholecalciferol inputs required to achieve or maintain any given serum 25-hydroxycholecalciferol concentration are not known, particularly within ranges comparable to the probable physiologic supply of the vitamin. Objectives: The objectives were to establish the quantitative relation between steady state cholecalciferol input and the resulting serum 25-hydroxycholecalciferol concentration and to estimate the proportion of the daily requirement during winter that is met by cholecalciferol reserves in body tissue stores. Design: Cholecalciferol was administered daily in controlled oral doses labeled at 0, 25, 125, and 250 � g cholecalciferol for � 20 wk during the winter to 67 men living in Omaha (41.2� N latitude). The time course of serum 25-hydroxycholecalciferol concentration was measured at intervals over the course of treatment. Results: From a mean baseline value of 70.3 nmol/L, equilibrium concentrations of serum 25-hydroxycholecalciferol changed during the winter months in direct proportion to the dose, with a slope of � 0.70 nmol/L for each additional 1 � g cholecalciferol input. The calculated oral input required to sustain the serum 25-hydroxycholecalciferol concentration present before the study (ie, in the autumn) was 12.5 � g (500 IU)/d, whereas the total amount from all sources (supplement, food, tissue stores) needed to sustain the starting 25-hydroxycholecalciferol concentration was estimated at � 96 � g( � 3800 IU)/ d. By difference, the tissue stores provided � 78‐82 � g/d. Conclusions: Healthy men seem to use 3000‐5000 IU cholecalciferol/d, apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D. Am J Clin Nutr 2003;77:204‐10.

Long-term vitamin D insufficiency can cause secondary hyperparathyroidism and osteomalacia (1). In addition, there is increasing evidence that vitamin D may protect against common cancers, such as cancer of the colon (2–4), prostate (5), and breast (6). Young adults aged 17 to 35 years drink inadequate amounts of milk (7) and are concerned about exposure to the sun because of the fear of developing skin cancer (8,9), which increases the risk of vitamin D insufficiency (10). We sought to examine the prevalence of vitamin D insufficiency in a group of free-living healthy young adults, consisting of mostly health care professionals, in Boston, Massachusetts.

Several disease syndromes in captive rhinoceroses have been linked to low vitamin status. Blood samples from captive and free-ranging black (Diceros bicornis) and white rhinoceros (Ceratotherium simum) and tissue samples of captive individuals from four rhinoceros species were analysed for vitamins A and E. Circulating vitamin A levels measured as retinol for free-ranging versus captive black and white rhinoceros were 0.04 (+/- 0.03 SD) vs. 0.08 (+/- 0.08) and 0.07 (+/- 0.04) vs. 0.06 (+/- 0.02) microgram/ml, respectively. Circulating vitamin E levels measured as alpha-tocopherol were 0.58 (+/- 0.30) vs. 0.84 (+/- 0.96) and 0.62 (+/- 0.48) vs. 0.77 (+/- 0.32) microgram/ml, respectively. In contrast to earlier findings, there was no significant difference in vitamin E concentration between captive and free-ranging black rhinoceros. When the samples of captive black rhinoceros were grouped into those taken before 1990 and after 1990, however, those collected before 1990 had significantly lower (P < 0.001) vitamin E levels (0.46 +/- 0.83 microgram/ml) and those collected in 1990 or later significantly higher (P < 0.001) vitamin E levels (1.03 +/- 1.04 micrograms/ml) than the captive population as a whole. This is probably due to increased dietary supplementation. There were significant differences in circulating vitamin concentrations in black rhinoceroses from different regions in the wild. Serum 25-hydroxy (OH) vitamin D3 averaged 55.7 ng/ml in free-ranging rhinoceroses; no carotenoids were detected in any blood samples. Captive black and white rhinoceroses appear to be adequately supplemented in vitamin A and E. Captive Indian rhinoceroses (Rhinoceros unicornis) had significantly lower vitamin A concentrations in blood (P < 0.001) and higher vitamin A concentrations in liver tissue samples (P < 0.001) than other rhinoceros species. Equine requirements are not recommended as a model for rhinoceros vitamin requirements.

Nutrition most certainly affects health and may play a role in the etiology of growth and reproductive problems in captive cheetah (Acinonyxjubatus) populations. The objective of our research was to examine nutritional differences between two dietary regimens and quantify their physiologic effects on cheetahs held in captivity. Twelve cheetahs were randomly assigned to either a commercial diet (COM) or a supplemented meat diet (SMD) group. These cats were physically examined and had blood samples taken three times over the course of a year. Representative samples of COM and four separate components of the SMD treatment were analyzed over the same time frame for proximate nutrient composition, digestibility, and concentrations of taurine, fat-soluble vitamins, and selected minerals. Concentrations of fat, vitamins A and E, Se, Fe, Cu, Na, and Mn were significantly higher in COM compared with those in SMD samples, with the exception of fat content in turkey. Mg content was lower in COM than in SMD; other nutrients did not differ. Mean concentrations of vitamins A and E in COM were markedly higher than in SMD samples (408,140 vs. 29,696 IU/kg dry matter [DM] and 431 vs. 48 IU/kg DM, respectively) and varied dramatically between sampling periods. Percent crude protein and protein-to-fat ratios were high for SMD compared with either whole prey-based or commercial food preparations. Blood urea nitrogen and serum creatinine levels were above normal reference means for domestic cats. Plasma concentrations of vitamins A, D, and E were significantly higher in COM-fed than in SMD-fed cheetahs. Both plasma retinol and tocopherol levels were almost three times higher in COM-fed cats (1.26 +/- 0.06 vs. 0.53 +/- 0.03 microg/ml and 17.5 +/- 0.7 vs. 6.4 +/- 0.02 microg/ml, respectively) and exceeded the normal ranges expected for domestic felids. Significant differences between male and female cheetahs were found for plasma concentrations of vitamin E, Se, and Fe after allowing for effects of diet and time of collection. Excess fat-soluble dietary vitamins can result in direct toxicities as well as nutrient antagonisms and may be linked to reproductive and health issues in captive cheetahs. The high protein levels found in SMD may be linked to chronic renal disease, which was detected in some of these cheetahs.

Purpose The current epidemic of prescription opioid abuse and misuse in the United States is discussed, with an emphasis on the pharmacist’s role in ensuring safe and effective opioid use. Summary U.S. sales of prescription opioids increased fourfold from 1999 to 2010, with an alarming rise in deaths and emergency department visits associated with the use of fentanyl, hydrocodone, oxycodone, and other opioid medications. Signs and symptoms of opioid toxicity may include altered mental status, hypoventilation, decreased bowel motility, central nervous system and respiratory depression, peripheral vasodilation, pulmonary edema, hypotension, bradycardia, and seizures. In patients receiving long-term opioid therapy for chronic pain, urine drug testing is an important tool for monitoring and assessment of therapy; knowledge of opioid metabolic pathways and assay limitations is essential for appropriate use and interpretation of screening and confirmatory tests. In recent years, there has been an increase in federal enforcement actions against pharmacies and prescription drug wholesalers involved in improper opioid distribution, as well as increased reliance on state-level prescription drug monitoring programs to track patterns of opioid use and improper sales. Pharmacies are urged to implement or promote appropriate guidelines on opioid therapy, including the use of pain management agreement plans; policies to ensure adequate oversight of opioid prescribing, dispensing, and waste disposal; and educational initiatives targeting patients as well as hospital and pharmacy staff. Conclusion Pharmacists in hospitals and health systems can play a key role in recognizing the various forms of opioid toxicity and in preventing inappropriate prescribing and diversion of opioids.

Pancreatic cancer (PDA) is a devastating disease and there is no effective treatment available at present. To develop new regiments against PDA is urgently needed. Previously we have shown that vitamin D analog, MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), exerted potent antiproliferative effect on PDA in vitro and in vivo without causing hypercalcemia. Since metastasis is the major cause of PDA-related death, we therefore investigate the anti-metastasis effect of MART-10 on PDA. Our results showed that both 1α,25(OH)2D3 and MART-10 repressed migration and invasion of BxPC-3 and PANC cells with MART-10 much more potent than 1α,25(OH)2D3. 1α,25(OH)2D3 and MART-10 inhibited epithelial-mesenchymal transition (EMT) in pancreatic cancer cells through downregulation of Snail, Slug, and Vimentin expression in BxPC-3 and PANC cells. MART-10 further blocked cadherin switch (from E-cadherin to N-cadherin) in BxPC-3 cells. The F-actin synthesis in the cytoplasm of BxPC-3 cells was also repressed by 1α,25(OH)2D3 and MART-10 as determined by immunofluorescence stain. Both 1α,25(OH)2D3 and MART-10 decreased MMP-2 and -9 secretion in BxPC-3 cells as determined by western blot and zymography. Collectively, MART-10 should be deemed as a promising regimen against PDA.