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1.  Vitamin D Receptor Mutations in Patients with Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets 
Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns.
Objectives, Patients, and Methods
We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)2D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)2D3-mediated transactivation in COS-7 monkey kidney cells.
Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2 bp deletion in exon 3 5’-splice site (IVS3Δ+4–5) leading to a premature stop.
These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.
PMCID: PMC3933290  PMID: 24246681
Vitamin D; rickets; hypocalcemia; mutations; vitamin D receptor; HVDRR
2.  Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention 
Calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D exerts anti-proliferative, pro-apoptotic, anti-inflammatory effects and other anticancer actions in breast cancer (BCa) cell cultures and animal models of BCa. Our research is focused on investigating the potential beneficial effects of dietary vitamin D3 compared to calcitriol and the underlying mechanisms in BCa treatment and chemoprevention. We recently found that dietary vitamin D3 exhibits significant tumor inhibitory effects in xenograft models of BCa that are equivalent to those elicited by the administration of the active hormone calcitriol. At the easily achievable dose tested in our studies, dietary vitamin D3 exhibited substantial tumor inhibitory activity and, unlike calcitriol, did not cause hypercalcemia demonstrating its relative safety. We found elevations in circulating calcitriol as well as increased CYP27B1 expression in the tumor and the intestine in tumor-bearing mice ingesting a vitamin D3-supplemented diet. We hypothesize that the elevation in circulating 25(OH)D induced by dietary vitamin D3 supplements stimulates local synthesis of calcitriol in the mammary tumor microenvironment and the ensuing paracrine/autocrine actions play a major role in the anticancer activity of dietary vitamin D3. Our findings suggest that the endocrine activity of calcitriol derived from tumor and other extra-renal sources such as the intestine, probably also plays a role in mediating the anticancer effects of dietary vitamin D3. Thus it appears that multiple sites of 1α-hydroxylation contribute to the anticancer effects of dietary vitamin D3. Our data strongly suggest that dietary vitamin D will be useful in the chemoprevention and treatment of BCa since it is a safe, economical and easily available nutritional agent that is equivalent to calcitriol in exerting anticancer effects, at least in mouse models. Furthermore, adequate vitamin D nutrition and avoidance of vitamin D deficiency appear to be important in reducing BCa risk. These findings warrant clinical trials in BCa patients and in women at high risk for BCa to evaluate the benefits of dietary vitamin D3 supplementation.
PMCID: PMC3554854  PMID: 22939886
3.  Direct Renin Inhibition Prevents Cardiac Dysfunction in a Diabetic Mouse Model: Comparison with an Angiotensin Receptor Antagonist and Angiotensin Converting Enzyme Inhibitor 
Hyperglycemia upregulates intracellular angiotensin II production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than angiotensin receptor blockers (ARBs) or ACE inhibitors. Here we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACE inhibitor. Diabetes was induced in adult mice for 10 wks by streptozotocin. Diabetic mice were treated with insulin, aliskiren (renin inhibitor), benazeprilat (ACE inhibitor), or valsartan (ARB) via subcutaneous minipumps. Significant impairment in diastolic and systolic cardiac function was observed in diabetic mice, which was completely prevented by all three RAS inhibitors. Hyperglycemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, while valsartan was partially effective. Diabetes increased cardiac (pro)renin receptor (PRR) expression and nuclear translocation of promyelocytic zinc finger protein (PLZF), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function as ARBs and ACE inhibitors. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines, and PRR expression suggested subtle differences in their mechanism of action.
PMCID: PMC3982397  PMID: 23116220
Diabetic cardiomyopathy; intracrine; prorenin receptor
4.  Combination of Calcitriol and Dietary Soy Exhibits Enhanced Anticancer Activity and Increased Hypercalcemic Toxicity in a Mouse Xenograft Model of Prostate Cancer 
The Prostate  2012;72(15):1628-1637.
The potential role of vitamin D and soy in prostate cancer (PCa) prevention/treatment has gained much attention in recent years. In this study, we evaluated the anticancer activity of calcitriol, the active form of vitamin D, dietary soy, and their combinations in a mouse model of PCa.
Athymic male nude mice bearing PC-3 human PCa xenografts received diets containing 10 kcal% or 20 kcal% soy, calcitriol injections, or a combination of dietary soy and calcitriol. Changes in tumor growth, serum levels of 1,25(OH)2D and calcium, and regulation of tumor gene expression were examined.
The combination treatments resulted in substantially greater inhibition of tumor growth than either agent alone. Soy diets alone caused a modest elevation in serum 1,25(OH)2D, whereas the calcitriol-soy combinations led to substantially elevated serum 1,25(OH)2D, hypercalcemia, and in some cases lethal toxicity. The combinations enhanced calcitriol activity in regulating target gene expression, including greater up-regulation of anti-proliferative (p21, IGFBP-3) and pro-apoptotic (Bax) genes, increased inhibition of anti-apoptotic (Bcl-2) and cell cycle promoting (cyclin D1) genes, and suppression of prostaglandin (PG) synthesis and signaling (COX-2, 15-PGDH, PG receptors). Increases in serum calcium were accompanied by elevated expression of intestinal calcium absorption genes (TRPV6, calbindin-9k).
Soy increases the bioavailability of endogenous and administered calcitriol, thereby enhancing its anticancer effects and risk of hypercalcemia. Since both agents are easily available as dietary supplements, the increased potential for hypercalcemic toxicity becomes an important factor when considering the combined use of vitamin D and soy in PCa therapy.
PMCID: PMC3389566  PMID: 22457201
Vitamin D; calcitriol; soy; prostate cancer; CYP24A1; hypercalcemia
5.  The Potential Therapeutic Benefits of Vitamin D in the Treatment of Estrogen Receptor Positive Breast Cancer 
Steroids  2012;77(11):1107-1112.
Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+ BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+ BCa in women.
PMCID: PMC3429709  PMID: 22801352
Calcitriol; breast cancer; anti-proliferative effects; anti-inflammatory effects; aromatase; prostaglandins; aromatase inhibitors; estrogen receptor; dietary vitamin D
6.  The Role of Vitamin D Receptor Mutations in the Development of Alopecia 
Hereditary Vitamin D Resistant Rickets (HVDRR) is a rare disease caused by mutations in the vitamin D receptor (VDR). The consequence of defective VDR is the inability to absorb calcium normally in the intestine. This leads to a constellation of metabolic abnormalities including hypocalcemia, secondary hyperparathyroidism and hypophosphatemia that cause the development of rickets at an early age in affected children. An interesting additional abnormality is the presence of alopecia in some children depending on the nature of the VDR mutation. The data indicate that VDR mutations that cause defects in DNA binding, RXR heterodimerization or absence of the VDR cause alopecia while mutations that alter VDR affinity for 1,25(OH)2D3 or disrupt coactivator interactions do not cause alopecia. The cumulative findings indicate that hair follicle cycling is dependent on unliganded actions of the VDR. Further research is ongoing to elucidate the role of the VDR in hair growth and differentiation.
PMCID: PMC3196847  PMID: 21693169
7.  Vitamin D Metabolism and Action in the Prostate: Implications for Health and Disease 
Prostate cancer (PCa) is the second most common cancer in men worldwide. Epidemiological, molecular, and cellular studies have implicated vitamin D deficiency as a risk factor for the development and/or progression of PCa. Studies using cell culture systems and animal models suggest that vitamin D acts to reduce the growth of PCa through regulation of cellular proliferation and differentiation. However, although pre-clinical studies provide a strong indication for anti-cancer activity, proof of therapeutic benefits in men is still lacking. The anti-proliferative and pro-differentiating properties of vitamin D have been attributed to calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D, acting through the vitamin D receptor (VDR). Metabolism of vitamin D in target tissues is mediated by two key enzymes: 1α-hydroxylase (CYP27B1), which catalyzes the synthesis of calcitriol from 25(OH)D and 24-hydroxylase (CYP24), which catalyzes the initial step in the conversion of calcitriol to less active metabolites. Many factors affect the balance of calcitriol synthesis and catabolism and several maneuvers, like combination therapy of calcitriol with other drugs, have been explored to treat PCa and reduce its risk. The current paper is an overview addressing some of the key factors that influence the biological actions of vitamin D and its metabolites in the treatment and/or prevention of PCa.
PMCID: PMC3189327  PMID: 21664249
Prostate cancer; vitamin D; calcitriol; vitamin D receptor (VDR); 1α-hydroxylase; 24-hydroxylase; combination therapy
8.  Calcium Plus Vitamin D Supplementation and the Risk of Nonmelanoma and Melanoma Skin Cancer: Post Hoc Analyses of the Women's Health Initiative Randomized Controlled Trial 
Journal of Clinical Oncology  2011;29(22):3078-3084.
In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.
Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.
Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; Pinteraction = .038), which was not observed in women without history of NMSC.
Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.
PMCID: PMC3157967  PMID: 21709199
9.  The Anti-Cancer and Anti-Inflammatory Actions of 1,25(OH)2D3 
Various epidemiological studies have shown an aetiological link between vitamin D deficiency and cancer incidence. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has potent anti-cancer activities both in vitro and in vivo. These anti-cancer effects are attained by regulating the transcription of numerous genes that are involved in different pathways to reduce tumorigenesis and are dependent on the cancer cell type. Besides reducing cell growth and inducing apoptosis, 1,25(OH)2D3 also inhibits angiogenesis and metastasis. Moreover, its potency to inhibit inflammation also contributes to its anti-tumoral activity. Here, we report the different ways in which 1,25(OH)2D3 interferes with the malignant processes that are activated in cancer cells.
PMCID: PMC3164534  PMID: 21872801
Vitamin D; Cancer; Proliferation; Apoptosis; Metastasis; Angiogenesis; Inflammation
10.  Pelvic Positioning Creates Error in CT Acetabular Measurements 
CT allows for accurate measurement of acetabular orientation and shape, but malpositioning of the pelvis may lead to measurement variance.
We therefore sought to determine: (1) whether acetabular anteversion measurements using the femoral head centers differed from those using the posterior ischia, and (2) the extent to which changing obliquity, rotation, and tilt of a pelvis in a CT scanner affected the measurement of acetabular variables.
A radiopaque human pelvis model with articulated hips was suspended from a plastic sheet as part of an adjustable frame. Changes in the transverse and sagittal planes created rotation and tilt, while rotating the frame in the coronal plane created obliquity. CT scans were obtained, varying the combinations of obliquity, rotation, and tilt by intervals of 5°, up to 20°. Acetabular anteversion (AA), anterior acetabular sector angle (AASA), posterior acetabular sector angle (PASA), and horizontal acetabular sector angle (HASA) were measured.
The two methods for measuring AA yielded values differing by 1° to 4° but correlated (r = 0.981) across the spectrum of pelvis positioning. Pelvic obliquity and tilt were linearly associated with changes in the measurements. For each 1°-increase in pelvic obliquity, AA changed −0.4°, and AASA, PASA, and HASA changed 1.93°, 0.99°, and 2.80°, respectively. For each 1°-increase in pelvic tilt, AA changed 0.8°, and AASA, PASA, and HASA changed −1.07°, 0.52°, and −0.51°, respectively. Rotation had no affect on the variables.
Small changes in pelvic obliquity and tilt were associated with variances in acetabular measurements. The measured changes were directly proportional to the changes in obliquity and tilt, and were additive. Pelvic rotation created no changes in measurement.
Clinical Relevance
Incorrect interpretation of acetabular anteversion and coverage may lead to unsatisfactory acetabular fragment positioning during reorientational surgery. Although intraoperative positioning of an acetabular fragment may not be as precise as the tools for preoperative planning, it is important for a surgeon to have the most precise data available for planning a procedure, and know where error can occur in collecting the data.
PMCID: PMC3094628  PMID: 21365336
11.  Inhibitory Effects of Calcitriol on the Growth of MCF-7 Breast Cancer Xenografts in Nude Mice: Selective Modulation of Aromatase Expression in vivo 
Hormones & cancer  2011;2(3):190-202.
Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.
PMCID: PMC3114631  PMID: 21686077
Calcitriol; Selective aromatase modulator; Estrogen synthesis; Aromatase; Aromatase inhibitors; Breast cancer; Xenografts
12.  Genetic Disorders and Defects in Vitamin D Action 
PMCID: PMC2879401  PMID: 20511055
1α-hydroxylase deficiency; hereditary vitamin D resistant rickets; vitamin D receptor; mutations; rickets; alopecia
13.  Improved Characterization of Focal Liver Lesions With Liver-Specific Gadoxetic Acid Disodium–Enhanced Magnetic Resonance Imaging: A Multicenter Phase 3 Clinical Trial 
To evaluate the safety of gadoxetic acid disodium (Gd-EOB-DTPA) magnetic resonance imaging (MRI) and its efficacy in characterizing liver lesions.
Lesion characterization and classification using combined (unenhanced and Gd-EOB-DTPA–enhanced) MRI were compared with those using unenhanced MRI and contrast-enhanced spiral computed tomography (CT) using on-site clinical and off-site blinded evaluations for patients with focal liver lesions.
Gadoxetic acid disodium was well tolerated in this study. For the clinical evaluation, more lesions were correctly characterized using combined (unenhanced and Gd-EOB-DTPA–enhanced) MRI than using unenhanced MRI and spiral CT (96% vs 84% and 85%, respectively; P ≤ 0.0008). For the blinded evaluation, more lesions were correctly characterized using combined MRI compared with using unenhanced MRI (61%–76% vs 48%–65%, respectively; P ≤ 0.0012 for 2/3 readers); when compared with spiral CT, a similar proportion of lesions were correctly characterized.
Gadoxetic acid disodium–enhanced MRI is of clinical benefit relative to unenhanced MRI and spiral CT for a radiological diagnosis of liver lesions.
PMCID: PMC3036163  PMID: 20351497
liver lesion; magnetic resonance; computed tomography; contrast agent; Gd-EOB-DTPA
14.  Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor 
The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3 or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone x-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient’s cultured skin fibroblasts and found to exhibit normal [3H]1,25-(OH)2D3 binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)2D3 as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)2D3-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRα and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE).
In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia.
PMCID: PMC2794978  PMID: 19815438
calcitriol; resistance; calcium; intravenous; hairless; retinoid X receptor
15.  Cardiomyopathy: An Overview 
American family physician  2009;79(9):778-784.
Cardiomyopathy is an anatomic and pathologic diagnosis associated with muscle or electrical dysfunction of the heart. Cardiomyopathies represent a heterogeneous group of diseases that often lead to progressive heart failure with signifcant morbidity and mortality. Cardiomyopathies may be primary (i.e., genetic, mixed, or acquired) or secondary (e.g., infltrative, toxic, infammatory). Major types include dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although cardiomyopathy is asymptomatic in the early stages, symptoms are the same as those characteristically seen in any type of heart failure and may include shortness of breath, fatigue, cough, orthopnea, paroxysmal nocturnal dyspnea, and edema. Diagnostic studies include B-type natriuretic peptide levels, baseline serum chemistries, electrocardiography, and echocardiography. Treatment is targeted at relieving the symptoms of heart failure and reducing rates of heart failure–related hospitalization and mortality. Treatment options include pharmacotherapy, implantable cardioverter-defbrillators, cardiac resynchronization therapy, and heart transplantation. Recommended lifestyle changes include restricting alcohol consumption, losing weight, exercising, quitting smoking, and eating a low-sodium diet.
PMCID: PMC2999879  PMID: 20141097
16.  Hereditary Vitamin D Resistant Rickets 
Bone  2009;45(4):743-746.
To study the vitamin D receptor (VDR) gene in a young girl with severe rickets and clinical features of hereditary vitamin D resistant rickets, including hypocalcemia, hypophosphatemia, partial alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D.
Study design
We amplified and sequenced DNA samples from blood for the patient, her mother, and the patient’s two siblings. We amplified and sequenced the VDR cDNA from RNA isolated from the patient’s blood.
DNA sequence analyses of the VDR gene showed that the patient was homozygous for a novel guanine to thymine substitution in the 5′-splice site in the exon 8-intron J junction. Analysis of the VDR cDNA using reverse transcriptase-polymerase chain reaction showed that exons 7 and 9 were fused, and that exon 8 was skipped. The mother was heterozygous for the mutation and the two siblings were unaffected.
A novel splice site mutation was identified in the VDR gene that caused exon 8 to be skipped. The mutation deleted amino acids 303-341 in the VDR ligand-binding domain, which is expected to render the VDR non-functional. Nevertheless, successful outpatient treatment was achieved with frequent high doses of oral calcium. (190 words)
PMCID: PMC2782671  PMID: 19523546
Hereditary Vitamin D Resistant Rickets; Vitamin D Receptor; 1,25-dihydroxyvitamin D; Bone; Alopecia
We have recently shown that cigarette smoking is associated with lesser responses to potent antiretroviral therapies. Certain Cytochrome P-450 enzymes activate compounds derived from tobacco smoke into toxic forms that may promote HIV-1 gene expression through promotion of DNA-adduct formation by the oxidation of chemical constituents of cigarette smoke, such as potyaromatic hydrocarbons and dioxins. To explore the association between environmental and genetic factors to viral replication in women who smoke and receive highly active anti-retroviral therapy (HAART), we assessed the impact of polymorphisms in a panel of four Cytochrome P-450 genes (CYP1A1, CYP2A6, CYP2D6, and CYP2E1) and two Glutathione S-transferase genes (GSTM1 and GSST1) in 924 participants of the Women’s Interagency HIV Study (WIHS). Our findings showed that GSTM1 and GSST1 deletions were not associated with HAART effectiveness. By contrast, homozygosity for the CYP1A1-m1 polymorphism, was associated with impaired viral response to treatment among smokers (relative hazard (RH) = 0.54; 95% confidence interval = 0.31-0.94) after adjustment for pretreament viral load, CD4 count, age, hepatitis C infection, prior HAART therapy and race, although it had no effect among nonsmokers. We conclude that the association of the CPY1A1-m1 variant with a reduced response to HAART therapy in HIV infected smokers is consistent with this enzyme’s role in the metabolic conversion of environmental toxins to DNA adducts, which may directly promote HIV-1 gene expression.
PMCID: PMC2754267  PMID: 19537956
18.  Heart rate control with adrenergic blockade: Clinical outcomes in cardiovascular medicine 
The sympathetic nervous system is involved in regulating various cardiovascular parameters including heart rate (HR) and HR variability. Aberrant sympathetic nervous system expression may result in elevated HR or decreased HR variability, and both are independent risk factors for development of cardiovascular disease, including heart failure, myocardial infarction, and hypertension. Epidemiologic studies have established that impaired HR control is linked to increased cardiovascular morbidity and mortality. One successful way of decreasing HR and cardiovascular mortality has been by utilizing β-blockers, because their ability to alter cell signaling at the receptor level has been shown to mitigate the pathogenic effects of sympathetic nervous system hyperactivation. Numerous clinical studies have demonstrated that β-blocker-mediated HR control improvements are associated with decreased mortality in postinfarct and heart failure patients. Although improved HR control benefits have yet to be established in hypertension, both traditional and vasodilating β-blockers exert positive HR control effects in this patient population. However, differences exist between traditional and vasodilating β-blockers; the latter reduce peripheral vascular resistance and exert neutral or positive effects on important metabolic parameters. Clinical evidence suggests that attainment of HR control is an important treatment objective for patients with cardiovascular conditions, and vasodilating β-blocker efficacy may aid in accomplishing improved outcomes.
PMCID: PMC2882891  PMID: 20539841
adrenergic beta-antagonists; heart failure; hypertension; myocardial infarction
19.  The role of vitamin D and SLCO1B1*5 gene polymorphism in statin-associated myalgias 
Dermato-endocrinology  2010;2(2):77-84.
Myalgias are the most common side effect of statin use and the commonest cause for discontinuing therapy. Vitamin D has known physiologic functions in muscle and vitamin D deficiency is known to cause myalgias, with its correction leading to disappearance of muscle symptoms. The 521T>C SLCO1B1*5 gene polymorphism decreasing function in the gene coding for a liver anion transporter that is responsible for statin uptake has been found to explain the majority of statin-associated muscle symptoms. Patients with statin-associated myalgias have been reported to improve with vitamin D supplementation. We therefore investigated (i) whether repletion of vitamin D in deficient patients with myalgias could lead to tolerance for subsequent statin therapy and (ii) whether vitamin D status modifies the effect of the SLCO1B1*5 genotype on myalgia risk. Using a retrospective cohort of 64 patients in whom 25-hydroxyvitamin D [25(OH)D] had been measured for any reason while on statin therapy, including 46 patients who consented to be genotyped, we found strong evidence showing that repletion of vitamin D in vitamin D deficient patients improved myalgias. Of 21 vitamin D deficient patients with intolerable statin-associated myalgias, 14 of 15 rechallenged with statins were subsequently symptomfree, with one patient experiencing mild and tolerable symptoms, far exceeding expected rates of acquired tolerability with no therapy (p = 0.01). In addition, while the SLCO1B1*5 genotype was associated with a three-fold increased risk of myalgias (p = 0.07), this risk was not found to differ by vitamin D status (p = 0.60).
PMCID: PMC3081682  PMID: 21547103
vitamin D; statin; myalgias; SLCO1B1 genotype; vitamin D deficiency; SNPs
20.  Femoral Deformity Correction in Children and Young Adults Using Taylor Spatial Frame 
The Taylor spatial frame (TSF) has been used commonly in children and young adults. Its use in the tibia is more extensively studied and applied than in the femur. We asked whether normal alignment can be achieved with accuracy during correction of femoral deformities while avoiding major complications in children and young adults. We retrospectively reviewed the clinical and radiographic records of 20 patients (22 limbs), ages 5.9 to 24.6 years, who underwent a TSF for femoral deformity. Etiology included a number of diagnoses of the pediatric age. Minimum followup was 4.5 months (mean, 15.7 months; range, 4.5–35 months). The mean time in frame was 6.2 months (range, 2.6–19 months). Frontal and sagittal plane deformities were corrected to within normal values. A mean limb lengthening of 4.9 cm (range, 1.5–9 cm) was performed in eight femora in seven of which the limb length discrepancy was a secondary concern. External fixation index in the lengthening subgroup was 2.2 months/cm. The 15 complications in 13 limbs included pin tract infection, knee stiffness, delayed union, skin irritation, and posterior knee subluxation. No complications occurred in nine limbs. Computer-assisted femoral deformity correction with six-axis deformity analysis and the TSF is an accurate and safe technique in children and young adults.
Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2628244  PMID: 18810569
21.  Prostatic soy isoflavone concentrations exceed serum levels after dietary supplementation 
The Prostate  2009;69(7):719-726.
The effects of soy isoflavones on prostate cancer may be concentration dependent. The impact of soy supplementation on isoflavone concentrations in prostate tissues and serum remain unclear.
To assess and compare concentrations of soy isoflavones in prostate tissue and serum among nineteen men with prostate cancer who had elected to undergo radical prostatectomy.
Participants were randomized to receive either daily soy supplements (82 mg/day aglycone equivalents) or placebos for two weeks (14 days) prior to surgery. Serum samples were obtained at the time of the surgery. Isoflavone concentrations were measured by HPLC/ESI-MS-MS.
The median (25th, 75th percentile) total isoflavone concentration in the isoflavone supplemented group was 2.3 μmol/L (1.2, 6.9) in the prostate tissue and 0.7 μmol/L (0.2, 1.2) in the serum. Total isoflavone concentrations in this group were an average of ∼6-fold higher in prostate tissue compared to serum; the tissue vs. serum ratio was significantly lower for genistein than daidzein, 4-fold vs. 10-fold, p=0.003. Tissue and serum levels of isoflavones among the placebo group were negligible with a few exceptions.
The findings from the present study suggest that prostate tissue may have the ability to concentrate dietary soy isoflavones to potentially anti-carcinogenic levels. (199 words, 8/19/08)
PMCID: PMC2734961  PMID: 19180569
22.  Adoption of Exercise and Readiness to Change Differ Between Whites and African-Americans with Hypertension: A Report from The Ohio State University Primary Care Practice-Based Research Network (OSU-PCPBRN) 
Hypertension is a major cause of morbidity and mortality in the United States and disproportionately affects African-Americans. A cornerstone to treatment is nonpharmacologic lifestyle modifications. Despite such recommendations, many patients fail to exercise.
An anonymous survey (n = 285) of hypertensive patients cared for at 2 offices within the Ohio State University Primary Care Practice-Based Research Network. Survey questions included demographics, recommendations for diet, and exercise lifestyle modification for reducing blood pressure. Questions were phrased as multiple choice or based on Prochaska and DiClemente's readiness to change model.
Of the 244 respondents, 57% were women and 43% were African-American. The income of African-Americans was significantly lower than that of whites. Exercise and increased fruit/vegetable consumption were the preferred lifestyle modifications and did not differ by race. Race and exercise were associated; a majority of whites were engaged in exercise whereas this was not so for African Americans.
Although exercise as a preferred lifestyle modification habit does not differ by race, implementation of such a behavior does. This may be related to differing income levels. When counseling patients, physicians must be prepared to ask what may hinder the adoption of such behavior and be prepared to offer possible solutions to overcoming such factors. (J Am Board Fam Med 2008;21: 358–360.)
PMCID: PMC2744419  PMID: 18612064
23.  Socioeconomic Position, Race/Ethnicity, and Inflammation in the Multi-Ethnic Study of Atherosclerosis 
Circulation  2008;117(20):e344.
PMCID: PMC2703708  PMID: 18490530
25.  Management Strategies for Stage-D Patients with Acute Heart Failure 
Clinical cardiology  2008;31(7):297-301.
Heart Failure (HF) accounted for 3.4 mill ambulatory visits in 2000. Current guidelines from the American Heart Association (AHA) and the American College of Cardiology (ACC), the Heart Failure Society of America (HSFA), and the International Society for Heart & Lung Transplantation (ISHLT) recommend aggressive pharmacologic interventions for patients with HF. This may include a combination of diuretics, angiotensin-converting enzyme (ACE) inhibitors, β-blockers, angiotensin-receptor blockers (ARBs), aldosterone antagonists, and digoxin. Nitrates and hydralazine are also indicated as part of standard therapy in addition to β-blockers and ACE inhibitors, especially but not exclusively, for African Americans with left ventricular (LV) systolic dysfunction. For those with acute decompensated HF, additional treatment options include recombinant human B-type natriuretic peptide, and in the future possible newer agents not yet approved for use in the United States, such as Levosimendan. Medical devices for use in patients with advanced HF include LV assist devices, cardiac resynchronization therapy, and implantable cardioverter defibrillators. For refractory patients heart transplantation, the gold-standard surgical intervention for the treatment of refractory HF, may be considered. Newer surgical options such as surgical ventricular restoration may be considered in select patients.
PMCID: PMC2692105  PMID: 17957741
heart failure; cardiac transplantation; cardiomyopathy; myocarditis

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