Stabilizing effect of total ankle arthroplasty by distal translation and lateralization of talus in varus ankle deformity.

BACKGROUND: In end-stage arthritis indicated for total ankle arthroplasty (TAA), full-thickness cartilage damage, subchondral bone defect/shaving, and fluttering of the talar dome occur, shortening the distance between the tibial and talar insertions of ligaments and leading to laxity of ligaments surrounding the ankle joint. Under such conditions, medial ligaments (including the deltoid ligament) would not be expected to function properly. To stabilize the ankle joint during the stance phase, medial ligament function under tension is important. This study therefore examined whether TAA contributes to lengthening of the medial tibio-talar joint as evaluated radiographically, as a preferable method for achieving tensile effects on medial ligaments. MATERIALS AND METHODS: Twenty-four feet with end-stage varus deformity of the ankle joint that underwent TAA were retrospectively investigated, excluding cases with any malleolar osteotomy or fracture. Distance between proximal and distal insertions of medial ligaments, lateralization of the talus, and talar tilt angle under valgus/varus stress condition were evaluated pre- and postoperatively. RESULTS: Distance between proximal and distal insertions of medial ligaments was significantly elongated after TAA. At the same time, the talus showed significant lateralization. Furthermore, talar tilt under valgus/varus stress conditions was also significantly reduced after TAA. CONCLUSION: TAA affects distal translation and lateralization of the talus in cases of varus ankle deformity. These effects might contribute to re-providing tensile force on lax medial ligaments, improving ligament function.

Congenital venous anomalies associated with retrocaval ureter: evaluation using computed tomography.

BACKGROUND: Retrocaval ureter is a rare congenital anomaly resulting from anomalous development of inferior vena cava (IVC) and not from anomalous of the ureter. The anomaly always occurs on the right side due to regression of right supracardinal vein and persistence of right posterior cardinal vein. Retrocaval ureter tends to be associated with various vena cava anomalies because of the embryogenesis. We aimed to identify the prevalence of associated congenital venous anomalies (CVA) resulting from cardinal vein development in adults with retrocaval ureter using computed tomography (CT) images. MATERIALS AND METHODS: The study included 22 adults with retrocaval ureter. We evaluated CT findings and determined the incidence of associated CVA using thin slice data sets from CT scanner with 64 or more detectors. We compared the prevalence of CVA in the retrocaval ureter group (mean age: 57 ± 19 years) and in the control group of 6189 adults with normal ureter (mean age: 66 ± 14 years). RESULTS: In the retrocaval ureter group, 4 (18.2%) adults had CVA including double IVC, right double IVC, preisthmic IVC with horseshoe kidney, and preaortic iliac confluence. One of 2 adults with preaortic iliac confluence had right double right IVC. In the control group, 49 (0.79%) adults had CVA including 37 double IVC, 11 left IVC, and 1 IVC interruption azygos continuation. Fifteen horseshow kidneys were found. The prevalence of associated CVA in the retrocaval ureter group was higher than that in the control group (p < 0.001). CONCLUSIONS: Retrocaval ureter is frequently associated with CVA. Various CVA with retrocaval ureter could happen because of abnormal development of not only the right posterior or supra cardinal vein but also other cardinal veins.

Impact of switching oral bisphosphonates to denosumab or daily teriparatide on the progression of radiographic joint destruction in patients with biologic-naïve rheumatoid arthritis.

In biologic-naïve female RA patients, switching oral BPs to DMAb significantly reduced radiographic joint destruction compared to continuing oral BPs or switching to TPTD at 12 months, which were significantly associated with a decrease of a bone resorption marker at 6 months. INTRODUCTION: The aim of this study was to clarify the effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) on the progression of radiographic joint destruction in patients with biologic-naïve rheumatoid arthritis (RA). METHODS: A retrospective, case-controlled study involving 90 female RA patients (mean age 68.2 years, 96.7% postmenopausal, disease activity score assessing 28 joints with CRP (DAS28-CRP) 2.4, methotrexate treatment 81.1%, prednisolone treatment 68.9%, and prior BP treatment 44.8 months), who were allocated depending on each patient's and physician's wishes, to (1) the BP-continue group (n = 30), (2) the switch-to-DMAb group (n = 30), or (3) the switch-to-TPTD group (n = 30), was conducted. Patients were retrospectively selected to minimize the difference of possible clinical backgrounds that may affect the joint destruction of RA. The primary endpoint was to clarify the change of the modified total Sharp score (mTSS) from baseline to 12 months. RESULTS: After 12 months, the mean changes of the modified Sharp erosion score were significantly lower in the switch-to-DMAb group (0.2 ± 0.1; mean ± standard error) than in the switch-to-TPTD group (1.3 ± 0.5; P < 0.05), and mTSS was significantly lower in the switch-to-DMAb group (0.3 ± 0.2) than in the BP-continue group (1.0 ± 0.3; P < 0.05) and the switch-to-TPTD group (1.7 ± 0.6; P < 0.05). The logistic regression analysis showed that mTSS changes were significantly associated with the percent changes of TRACP-5b at 6 months (ß = 0.30, 95% CI = 0.002-0.016; P < 0.01). CONCLUSIONS: Changes of systemic bone turnover induced by switching BPs to DMAb or TPTD may affect not only systemic bone mass, but also local joint destruction, and its clinical relevance should be considered comprehensively.

Neonatal Ethanol and Choline Treatments Alter the Morphology of Developing Rat Hippocampal Pyramidal Neurons in Opposite Directions.

Some of the neurobehavioral deficits identified in children with Fetal Alcohol Spectrum Disorders (FASDs) have been recapitulated in a binge model of gestational third trimester-equivalent ethanol (EtOH) exposure, in which Sprague-Dawley rats are intragastrically intubated between post-natal day (PD) 4 and PD9 with high doses of EtOH. In this model, the ameliorating effects of choline (Chol) administration on hippocampus-dependent behaviors altered by EtOH have also been extensively documented. In the present study, we investigated the effects of EtOH (5 g/kg/day) and/or Chol (100 mg/kg/day) on morphometric parameters of CA1 pyramidal neurons by Golgi-Cox staining followed by Neurolucida tracing and analysis. We found that EtOH increased apical dendrite complexity in male and female pups neonatally exposed to EtOH. EtOH did not significantly affect basal dendrite parameters in female and male rats. Interestingly, Chol treatments decreased basal dendrites' length, number, and maximal terminal distance in male pups. When pups were co-treated with EtOH and Chol, Chol did not rescue the effect of EtOH. In conclusion, EtOH increases while Chol decreases dendritic length and arborization of hippocampal CA1 neurons in PD9 rats. We hypothesize that developmental EtOH exposure induces a premature maturation of neurons, leading to early restriction of neuronal plasticity while Chol treatments delay the normal program of neuronal maturation and therefore prolong the window of maximal plasticity. Chol does not prevent the effects of developmental alcohol exposure on hippocampal pyramidal neurons' morphology characterized in the present study, although whether prolonged Chol administration after developmental EtOH exposure rectifies EtOH damage remains to be assessed.

The effects of exercise load during development on oxidative stress levels and antioxidant potential in adulthood.

The objective of this study was to elucidate the impact of physical activity during the growth period as well as on oxidative stress and antioxidative potential in adulthood. The experimental animals used were four-week old male Wistar rats, which were randomly divided into three groups. The exercise loads were as follows: control (CON), treadmill exercise (TE), and jumping exercise (JE). The exercise was performed at the same time of day, at a frequency of five days per week, for eight weeks. Derivatives of reactive oxygen metabolites (d-ROSs) and biological antioxidant potential (BAP) were measured during periods of rest prior to commencement of the experiment and after the experiment. Analysis was conducted using a Wilcoxon signed-rank test and Schaffer's multiple comparison procedure and the significance level was set at p < 0.05. The percent increase in d-ROM levels in the JE group, which experienced short-duration intense exercise loads, was higher than that in the TE group, which experienced moderately intense exercise loads. However, BAP, which is an index of antioxidant potential, markedly decreased in adulthood in the CON group, as compared to that in the developmental period, whereas the exercise groups showed no notable changes in BAP levels. Oxidative stress levels and antioxidant potential are affected differently in adulthood, depending on the intensity of sustained exercise loads experienced during development. Results suggested that in order to increase antioxidant potential, while taking oxidative stress production into account, moderately intense exercise loads are more desirable than highly intense exercise loads.

Clinical and microarray analysis of breast cancers of all subtypes from two prospective preoperative chemotherapy studies.

BACKGROUND: We aimed to analyse clinical and gene expression profiles to predict pathologic complete response and disease-free survival using two consecutive, prospective, preoperative chemotherapy trial cohorts. METHODS: Clinicopathological and gene expression data were evaluated in a cohort from two consecutive phase II preoperative studies that included patients with stage IIA-IIIC breast cancer of all subtypes. Analysed specimens were obtained before preoperative chemotherapy, and cDNA microarray analyses were performed using the Affymetrix Gene Chip U133 plus 2.0. RESULTS: Between December 2005 and December 2010, 122 patients were analysed. The pathologic complete response rate was significantly higher in HER2+ and HR-/HER2- cancers. Age, pathologic complete response, HR-/HER2- status, and lymph node positivity (⩾4) were significant poor prognostic factors for disease-free survival. For the cDNA microarray analyses, sufficient tumour samples were available from 78 of the 107 patients (73%). An 8-gene signature predictive of pathologic complete response and a 17-gene signature predictive of prognosis were identified. Patients were categorised into low-risk (n=45) and high-risk groups (n=33) (HR 70.0, P=0.004). CONCLUSIONS: This study yielded preliminary data on the expression of specific genes predicting pathologic complete response and disease-free survival in a cohort of chemonaïve breast cancer patients. Further validation may distinguish those who would benefit most from perioperative chemotherapy as well as those needing further intervention.

pH-Dependent membrane lysis by using melittin-inspired designed peptides.

We developed a membrane-lytic peptide (LP) having 26 amino acid residues composed of a helix-promoting hydrophobic segment (Leu-Ala repetitive sequence) and a cationic segment from melittin. In the presence of liposomes, LP interacts with liposomal surfaces to form a hydrophobic helix in the lipid bilayer in a wide pH range. In order to provide LP with a weakly acidic (endosomal) pH-controlled membrane-lytic activity, we have designed an LPE peptide series (a typical peptide, LPE3-1) with a hydrophobic segment in which Leu (L) residues are replaced by acidic Glu (E) residues. To analyze the pH-selective membrane-lytic activity of the designed peptides, both calcein leakage and membrane accessibility assays were performed. In the case of membrane disruption induced by the active pore formation, the incorporated calcein would leak from the liposomes and simultaneously the aqueous solution in the membrane surrounding would be accessible to the liposome interior at pH 5.0. The assays in the presence of LPE3-1 indicated no significant leakage or accessibility at pH 7.4, but a typical leakage and some accessibility to liposomes were positively observed at pH 5.0. In order to estimate whether the weakly acidic pH-controlled lytic activity is due to a secondary structural change of the hydrophobic segment of LPE3-1 in the liposome membrane, we have measured circular dichroism spectra. In the presence of liposomes, the minimum showing the characteristic helical structure was observed at 222 nm only under weakly acidic conditions. This pH dependence is in good agreement with the results from the leakage and accessibility assays. The pH-dependent membrane disruption properties of LPE3-1 may open a new avenue to gain insight into the interaction between peptides and lipids for the development of efficient drug/gene delivery systems.

Effects of switching weekly alendronate or risedronate to monthly minodronate in patients with rheumatoid arthritis: a 12-month prospective study.

UNLABELLED: Switching weekly ALN or RIS to monthly MIN in patients with RA, of whom two-thirds were treated with low-dose PSL, significantly decreased bone turnover markers and increased BMD at 12 months, suggesting that monthly MIN may be an effective alternative treatment option of oral bisphosphonate treatment. INTRODUCTION: The aim of this prospective, observational study was to evaluate the effects of switching weekly alendronate (ALN 35 mg) or risedronate (RIS 17.5 mg) to monthly minodronate (MIN 50 mg) in patients with rheumatoid arthritis (RA). METHODS: Patient characteristics were as follows: n = 172; 155 postmenopausal women, age 65.5 (44­87) years; T-score of lumbar spine (LS), −1.4; total hip (TH), −1.8; femoral neck (FN), −2.1; dose and rate of oral prednisolone (2.3 mg/day), 69.1 %; prior duration of ALN or RIS, 46.6 months; were allocated, based on their preference, to either the (1) continue group (n = 88), (2) switch-from-ALN group (n = 44), or (3) switch-from-RIS group (n = 40). RESULTS: After 12 months, increase in BMD was significantly greater in group 3 compared to group 1: LS (4.1 vs 1.2 %; P < 0.001), TH (1.9 vs −0.7 %; P < 0.01), and FN (2.7 vs −0.5 %; P < 0.05); and in group 2 compared to group 1: LS (3.2 vs 1.2 %; P < 0.05) and TH (1.5 vs −0.7 %; P < 0.01). The decrease in bone turnover markers was significantly greater in group 3 compared to group 1: TRACP-5b (−37.3 vs 2.5 %; P < 0.001), PINP (−24.7 vs −6.2 %; P < 0.05), and ucOC (−39.2 vs 13.0 %; P < 0.05); and in group 2 compared to group 1: TRACP-5b (−12.5 vs 2.5 %; P < 0.05) at 12 months. CONCLUSIONS: Switching weekly ALN or RIS to monthly MIN in patients with RA may be an effective alternative treatment option of oral bisphosphonate treatment.

Successful Kidney Transplantation in Epstein Syndrome With Antiplatelet Antibodies and Donor-specific Antibodies: A Case Report.

An autosomal dominant hereditary disease, Epstein syndrome (ES) is characterized by sensorineural hearing impairment, macrothrombocytopenia, and hereditary nephritis, and can progress to end-stage kidney disease after puberty. Generally, kidney transplantation is difficult to perform in Epstein syndrome owing to the high risk of perioperative bleeding. Additionally, due to previous platelet transfusions, ES patients sometimes have antihuman leukocyte antigen (HLA) antibodies, including antiplatelet antibodies and donor-specific anti-HLA antibodies (DSA), which may result in refractoriness to platelet transfusion and antibody-mediated rejection (AMR). We report a case of successful kidney transplantation in a patient with ES who had DSA and antiplatelet antibodies. To prevent AMR, we used a desensitization protocol (a combination of plasmapheresis, rituximab, and basiliximab induction). Surveillance biopsy performed at 4 months and 1 year after transplantation showed no pathological findings suggesting AMR. To prevent perioperative bleeding complications, we infused the patient with HLA-matched platelets, thereby maintaining the platelet count at >10.0 × 10(4)/µL, and no postoperative episodes of bleeding occurred.

Clinical efficacy and safety of monthly oral ibandronate 100 mg versus monthly intravenous ibandronate 1 mg in Japanese patients with primary osteoporosis.

UNLABELLED: The MOVEST study evaluated the efficacy and safety of monthly oral ibandronate versus licensed monthly IV ibandronate in Japanese osteoporotic patients. Relative BMD gains after 12 months were 5.22 % oral and 5.34 % IV, showing non-inferiority of oral to IV ibandronate (primary endpoint). No new safety concerns were identified. INTRODUCTION: The randomized, phase 3, double-blind MOVEST (Monthly Oral VErsus intravenouS ibandronaTe) study evaluated the efficacy and safety of monthly oral ibandronate versus the licensed monthly intravenous (IV) ibandronate regimen in Japanese patients with osteoporosis. METHODS: Ambulatory patients aged ≥ 55 years with primary osteoporosis were randomized to receive oral ibandronate 100 mg/month plus monthly IV placebo, or IV ibandronate 1 mg/month plus monthly oral placebo. The primary endpoint was non-inferiority of oral versus IV ibandronate with respect to bone mineral density (BMD) gains at the lumbar spine after 12 months of treatment. RESULTS: Four hundred twenty-two patients were enrolled with 372 patients in the per-protocol set (183 and 189 in the oral and IV ibandronate groups, respectively). The relative change from baseline in lumbar spine BMD values for the oral and IV ibandronate groups, respectively, was 5.22 % (95 % confidence interval [CI] 4.65, 5.80) and 5.34 % (95 % CI 4.78, 5.90). The least squares mean difference between the two groups was -0.23 % (95 % CI -0.97, 0.51), showing non-inferiority of oral ibandronate to IV ibandronate (non-inferiority limit = -1.60). Changes in BMD values at other sites, and bone turnover marker levels in the oral ibandronate group, were comparable with those of the IV group. The safety profile was similar to that previously demonstrated; no new safety concerns were identified. CONCLUSIONS: This study demonstrated the non-inferiority of oral ibandronate 100 mg/month to IV ibandronate 1 mg/month (licensed dose in Japan) in increasing lumbar spine BMD in Japanese patients with primary osteoporosis.

Monocyte CD64 expression as a novel biomarker for the disease activity of systemic lupus erythematosus.

OBJECTIVE: Interferon alpha (IFN-α) is a key cytokine associated with systemic lupus erythematosus (SLE). IFN-α induces the expression of CD64 on monocytes (mCD64). Although enhanced mCD64 expression has been reported in patients with SLE, it has never been assessed quantitatively. The aim of this study was to investigate whether or not mCD64 expression correlates with SLE disease activity. METHODS: The mCD64 expression levels were assessed quantitatively in 40 patients with active or inactive SLE by using flow cytometry. The mCD64 expression levels were subsequently compared with the SLE disease activity index (SLEDAI) and levels of existing SLE activity biomarkers, such as anti-DNA antibody, complements, and so on. RESULTS: The mCD64 expression was significantly higher in active disease than in inactive disease SLE (median molecules/cell, interquartile range: 34,648, 8174-24,932 and 20,865, 6357-21,503, respectively; p < 0.001). The levels of mCD64 expression strongly correlated with SLEDAI (r = 0.68, p < 0.001). CONCLUSION: The mCD64 expression is a simple and useful biomarker for evaluating disease activity in patients with SLE.

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling.

Surfactant protein D (SP-D) is a member of the collectin family that has an important role in maintaining pulmonary homeostasis. In this study, we demonstrated that SP-D inhibited the proliferation, migration and invasion of A549 human lung adenocarcinoma cells. We found that SP-D suppressed epidermal growth factor (EGF) signaling in A549 cells, H441 human lung adenocarcinoma cells and human EGF receptor (EGFR) stable expression CHO-K1 cells. A binding study using (125)I-EGF demonstrated that SP-D downregulated the binding of EGF to EGFR. A ligand blot indicated that SP-D bound to EGFR, and a lectin blot suggested that EGFR in A549 cells had both high-mannose type and complex type N-glycans. We purified the recombinant extracellular domain of EGFR (soluble EGFR=soluble EGFR (sEGFR)), and demonstrated that SP-D directly bound to sEGFR in a Ca(2+)-dependent manner. The binding of SP-D to sEGFR was suppressed by EDTA, mannose or N-glycopeptidase F treatment. Mass spectrometric analysis indicated that N-glycans in domain III of EGFR were of a high-mannose type. These data suggest that SP-D reduces EGF binding to EGFR through the interaction between the carbohydrate recognition domain of SP-D and N-glycans of EGFR, and downregulates EGF signaling. Our finding suggests the novel type of regulation system of EGF signaling involving lectin-to-carbohydrate interaction and downregulation of ligand binding.

Understanding the addiction cycle: a complex biology with distinct contributions of genotype vs. sex at each stage.

Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety.

Comparison of the effect of 18-month daily teriparatide administration on patients with rheumatoid arthritis and postmenopausal osteoporosis patients.

UNLABELLED: Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck bone mineral density at 18 months compared to postmenopausal osteoporosis patients. INTRODUCTION: The aim of this study was to evaluate the effects of 18-month administration of daily teriparatide (TPTD) in osteoporosis patients with rheumatoid arthritis (RA) by comparing that of postmenopausal osteoporosis patients (Porosis). METHODS: The effects of TPTD were examined between RA (n = 70; age 68.4 years; disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.8; rheumatoid factor [RF] positivity 75.5 %) with 77.1 % of prior bisphosphonate (BP), 84.3 % of oral prednisolone (PSL) (4.4 mg/day at baseline), 25.7 % of biologics, and Porosis (n = 62; age 71.3 years) with 77.4 % of prior BP. RESULTS: Femoral neck (FN) bone mineral density (BMD) increase at 18 months was significantly greater in RA compared to Porosis (4.7 vs. 0.7 %, P = 0.038), whereas it was 9.7 versus 7.9 % (P = 0.736) in the lumbar spine (LS). The increase of bone formation markers (bone alkaline phosphatase [bone ALP] and N-terminal type I procollagen propeptide [PINP]) at 1 month were all significantly greater in RA compared to Porosis. A multivariate logistic regression analysis revealed that the significant indicator of 18-month BMD increase in RA was a 3-month increase of under-carboxylated osteocalcin (ucOC) for LS (ß = 0.446, P = 0.005) and baseline ucOC for FN (ß = 0.554, P = 0.001), in which both showed significant negative correlation with baseline PSL dose. CONCLUSIONS: RA showed greater response to daily TPTD administration, especially in the increase of bone formation markers at 1 month and FN BMD increase at 18 months compared to Porosis.

Clinical impact of pentraxin family expression on prognosis of pancreatic carcinoma.

BACKGROUND: Inflammatory mediators may have decisive roles at different stages of tumour development. Mediators within the pentraxin family may be used as strong biomarkers in prognosis of advanced pancreatic carcinoma patients. METHODS: Using pancreatic carcinoma cell lines and gene transfectant, we measured long pentraxin (PTX3) level in culture solution and carried out cellular migration assay in vitro. In vivo study of the treatment-naive patients with advanced pancreatic carcinoma assigned to undergo gemcitabine therapy was prospectively conducted to measure and investigate the role of plasma PTX3, C-reactive protein (CRP), and eight inflammatory mediators by using collected clinical data. RESULTS: Elevated PTX3 production was observed in several cell lines, and a direct relationship between migratory activity and PTX3 level was identified in vitro. High PTX3 level (117 days) was significantly less than that of patients with low PTX3 level (357 days, P<0.001). Multivariate analysis of the pancreatic carcinoma revealed a strong correlation between pentraxin family member expression and prognosis of pancreatic carcinoma. The relationship between PTX3 expression and the expression of other pro-inflammatory mediators indicated that PTX3 level is positively correlated with levels of CRP, interleukin-6, and macrophage-inhibitory factor. CONCLUSION: Pentraxin family members, especially PTX3, may be used as promising biomarkers in the prognosis of pancreatic carcinoma patients.

A change of osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP-5b) with the menstrual cycle.

Bone metabolism markers associated with 4 menstrual cycle phases were evaluated in 14 healthy young females without menstrual disorder. Menstrual cycle phases were confirmed with basal body temperature for 3 months, luteinizing hormone kits, and sexual hormone concentrations of serum. The bone metabolism markers used were osteocalcin (OC), which was measured by immunoradiometric assay (IRMA), and tartrate resistant acid phosphatase 5b (TRACP-5b), which was measured by enzyme immunometric assay (EIA). The highest values of OC and TRACP-5b were observed in the ovulation phase, and TRACP-5b increased significantly when compared with levels in the menstrual phase (p<0.05). Furthermore, the changes in sex-hormone secretion involved in OC and TRACP-5b showed specific patterns during the menstrual cycle. In other words, TRACP-5b levels are influenced by sex hormones produced during the menstrual period and are based on the bone-formation status. Therefore, it is presumed that the TRACP-5b levels during ovulation play a central role in bone formation and bone metabolism.

Additive impact of alfacalcidol on bone mineral density and bone strength in alendronate treated postmenopausal women with reduced bone mass.

OBJECTIVES: Assessment of additive impact of alfacalcidol 1 µg daily (Alfa) on bone mineral density (BMD) and on bone strength in postmenopausal women treated with alendronate 70 mg weekly + 500 mg calcium daily. SUBJECTS AND METHODS: In a randomized, double-blind, placebo controlled study, 279 postmenopausal women with osteoporosis or osteopenia participated (intention to treat analysis [ITT]; aged 73.6∓4.7 years) and were treated with 70 mg alendronate (ALN) weekly and 500 mg calcium daily for 36 months. In addition, these patients received either 1 µg alfacalcidol (Alfa) or placebo (PLC) daily. BMD was measured with Dual-Energy-X-ray-Absorptiometry (DXA) at the lumbar spine and proximal femur and at forearm and tibia with peripheral quantitative computed tomography (pQCT) at regular intervals for 36 months. RESULTS: DXA-BMD of lumbar spine (L1-4) increased after 36 months, by 6.65% (p<0.0001) in the Alfa/ALN group versus 4.17% (p<0.0001) in the PLC/ALN group. Group difference was significant after 3 years (p=0.026). At the end of the study, significant differences were found in favor of the Alfa/ALN group in trabecular density (tibia) (p=0.002), cortical density (midshaft tibia) (p=0.043), and bone strength (p=0.001). The remaining parameters showed no differences between the treatment arms, apart cortical bone density at midshaft radius. CONCLUSIONS: Alfacalcidol significantly increases the efficacy of alendronate treatment in osteopenic/osteoporotic postmenopausal women on spinal DXA-BMD, cortical and trabecular BMD of the tibia and also bending stiffness of the tibia.

Importance of genetic background for risk of relapse shown in altered prefrontal cortex gene expression during abstinence following chronic alcohol intoxication.

Alcoholism is a relapsing disorder associated with excessive consumption after periods of abstinence. Neuroadaptations in brain structure, plasticity and gene expression occur with chronic intoxication but are poorly characterized. Here we report identification of pathways altered during abstinence in prefrontal cortex, a brain region associated with cognitive dysfunction and damage in alcoholics. To determine the influence of genetic differences, an animal model was employed with widely divergent responses to alcohol withdrawal, the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) lines. Mice were chronically exposed to highly intoxicating concentrations of ethanol and withdrawn, then left abstinent for 21 days. Transcriptional profiling by microarray analyses identified a total of 562 genes as significantly altered during abstinence. Hierarchical cluster analysis revealed that the transcriptional response correlated with genotype/withdrawal phenotype rather than sex. Gene Ontology category overrepresentation analysis identified thyroid hormone metabolism, glutathione metabolism, axon guidance and DNA damage response as targeted classes of genes in low response WSR mice, with acetylation and histone deacetylase complex as highly dimorphic between WSR and WSP mice. Confirmation studies in WSR mice revealed both increased neurotoxicity by histopathologic examination and elevated triidothyronine (T3) levels. Most importantly, relapse drinking was reduced by inhibition of thyroid hormone synthesis in dependent WSR mice compared to controls. These findings provide in vivo physiological and behavioral validation of the pathways identified. Combined, these results indicate a fundamentally distinct neuroadaptive response during abstinence in mice genetically selected for divergent withdrawal severity. Identification of pathways altered in abstinence may aid development of novel therapeutics for targeted treatment of relapse in abstinent alcoholics.