The Effect of Proton Pump Inhibitors on Bone Formation in a Rat Spinal Arthrodesis Model.

STUDY DESIGN: Rat posterolateral arthrodesis model. OBJECTIVE: Quantify the impact of administration of a proton pump inhibitor on spine fusion. SUMMARY OF BACKGROUND DATA: Proton pump inhibitors (PPIs) are widely used for gastrointestinal disorders and for ulcer prophylaxis in patients taking non-steroidal anti-inflammatory drugs. PPIs cause chronic acid suppression which has been found to result in decreased bone mineral density, increased fracture risk, and impaired fracture healing. Despite advances in surgical techniques, pseudarthrosis still occurs in up to 24% of patients requiring revision surgery following spinal fusion procedures. Thus, there are likely many unidentified risk factors. While PPIs have been hypothesized to impact fracture healing, no study has evaluated their effect on spine arthrodesis rates. METHODS: Thirty-eight female rats underwent posterolateral lumbar spinal fusion. Rats were divided into two groups: normal saline control and pantroprazole, which was administered by daily intraperitoneal injections. At 8 weeks postoperative spines were evaluated with manual palpation, microCT, histologic analysis, and biomechanical testing. RESULTS: Fusion rates of the control group and PPI group were not significantly different (100% vs. 94%). Average fusion scores were significantly lower in the pantoprazole group. New bone formation identified on microCT imaging of bilaterally fused specimens demonstrated a lower average volume of newly generated bone in the PPI group, but this difference was not significant. Biomechanical testing demonstrated no significant difference in strength or stiffness of the fusion mass between the groups. CONCLUSION: This study demonstrates that administration of PPIs does not inhibit fusion rates, bone formation, or affect biomechanical integrity of fusion. However, lower fusion scores in the PPI group suggest that a negative impact may still exist. Future studies will explore growth factor and protein expression in the fusion masses as well as utilize higher doses of PPI to fully discern their effect on spine fusion. LEVEL OF EVIDENCE: N/A.

Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aß1-42 synaptotoxicity.

Oligomeric Amyloid ß1-42 (Aß) plays a crucial synaptotoxic role in Alzheimer's disease, and hyperphosphorylated tau facilitates Aß toxicity. The link between Aß and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aß acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aß. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aß-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

A Retrospective Analysis of Surveillance Adherence of Patients after Treatment of Primary Cutaneous Melanoma.

BACKGROUND: Melanoma surveillance serves to identify new primary melanomas and curable locoregional or early distant recurrences. Although an optimal melanoma surveillance strategy has not been determined, several clinical guidelines exist. OBJECTIVE: The aim of this study was to identify demographic and clinico-pathologic variables associated with poor adherence to National Comprehensive Cancer Network (NCCN) melanoma surveillance guidelines. DESIGN: We retrospectively reviewed the initial five-year dermatology follow-up visit frequencies of melanoma patients and extracted basic demographic and clinical data from their medical records. PARTICIPANTS: Of 186 patients included, the mean age was 55 (standard deviation=15); 47.5 percent (n=85) were female, 93.0 percent (n=173) were white, and 76.2 percent (n=141) were married. Sixty percent of patients lived at locations more than 10 miles from the clinic, and 58.6 percent had private insurance. MEASUREMENTS: "Aggressive" and "conservative" surveillance schedules were adapted from National Comprehensive Cancer Network visit frequency guidelines. RESULTS: Between 58.4 and 74.5 percent of patients adhered to "aggressive" surveillance, with decreasing rates over the five-year period. Annual rates of poor surveillance adherence (7.3-23.6%) increased over time. Based on adjusted odds ratios, patients younger than 50 years of age (odds ratios 2.11 [95% CI 1.13-3.93], p<0.05), those lacking health insurance (odds ratios 3.08 [95% CI 1.09-8.68], p<0.05), and those with at least Stage IIB disease (odds ratios 3.21 [95% CI 1.36-7.58], p<0.01) are more likely to be poorly adherent to melanoma surveillance. CONCLUSION: This study's findings highlight some variables associated with poor surveillance adherence among melanoma survivors that could help to guide efforts in counseling this at-risk population.

Modeling vitamin D insufficiency and moderate deficiency in adult mice via dietary cholecalciferol restriction.

PURPOSE: We sought to develop and characterize a model of human vitamin D nutritional insufficiency/deficiency in the adult mouse, which could have broad utility in examining health consequences of this common condition. METHODS: Adult mice were fed diets containing cholecalciferol contents of 0.05 IU/g, 0.25 IU/g, 0.5 IU/g or 1.5 IU/g for four months. We studied induction of steady-state vitamin D insufficiency, and its consequences on primary cholecalciferol metabolite levels, calcium homeostasis, parathyroid physiology, and bone morphology. RESULTS: All diets were well tolerated, without adverse effects on body weight. Diets containing 0.05 IU/g and 0.25 IU/g cholecalciferol significantly lowered serum 25-hydroxyvitamin D levels (median 25OHD, 10.5 ng/ml, and 21.6 ng/ml, respectively), starting as early as one month following initiation of the diets, maintained through the four-month experimental period. The 0.05 IU/g diet significantly decreased 1,25-dihydroxyvitamin D (1,25OH2D) levels (median, 78 pg/ml). Despite these decreased 25OHD and 1,25OH2D levels, the diets did not alter parathyroid gland morphology or parathyroid cell proliferation. There were no statistical differences in the serum total calcium and serum PTH levels among the various dietary groups. Furthermore, the 0.05 IU/g diet did not cause any alterations in the cortical and trabecular bone morphology, as determined by microCT. CONCLUSIONS: The dietary manipulations yielded states of vitamin D insufficiency or modest deficiency in adult mice, with no overtly detectable impact on parathyroid and bone physiology, and calcium homeostasis. This model system may be of value to study health effects of vitamin D insufficiency/deficiency especially on extraskeletal phenotypes such as cancer susceptibility or immune function.

Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo.

The secosteroidal hormone 1,25-dihyroxyvitamin D [1,25(OH)(2)D(3)] and its receptor, the vitamin D receptor (VDR), are crucial regulators of epidermal proliferation and differentiation. However, the effects of 1,25(OH)(2)D(3)-directed signaling on oral keratinocyte pathophysiology have not been well studied. We examined the role of 1,25(OH)(2)D(3) in regulating proliferation and differentiation in cultured oral keratinocytes and on the oral epithelium in vivo. Using lentiviral-mediated shRNA to silence VDR, we generated an oral keratinocyte cell line with stable knockdown of VDR expression. VDR knockdown significantly enhanced proliferation and disrupted calcium- and 1,25(OH)(2)D(3)-induced oral keratinocyte differentiation, emphasizing the anti-proliferative and pro-differentiation effects of 1,25(OH)(2)D(3) in oral keratinocytes. Using vitamin D(3)-deficient diets, we induced chronic vitamin D deficiency in mice as evidenced by decreased serum 25-hydroxyvitamin D (25OHD) concentrations. The vitamin D-deficient mice manifested increased proliferation of the tongue epithelium, but did not develop any morphological or histological abnormalities in the oral epithelium, suggesting that vitamin D deficiency alone is insufficient to alter oral epithelial homeostasis and provoke carcinogenesis. Immunohistochemical analyses of human and murine oral squamous cell carcinomas showed increased VDR expression. Overall, our results provide strong support for a crucial role for vitamin D signaling in oral keratinocyte pathophysiology.