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Recent genome-wide association studies of schizophrenia reported a novel risk variant, rs2312147 at vaccinia-related kinase 2 gene (VRK2), in multiple Asian and European samples. However, its effect on the brain structure in schizophrenia is little known. We analyzed the brain structure of 36 schizophrenia patients and 18 healthy subjects with regard to rs2312147 genotype groups. Brain magnetic resonance scans for gray matter (GM) and white matter (WM) analysis, and genotype analysis for VRK2 rs2312147, were conducted. The Positive and Negative Syndrome Scale and the Digit Symbol Test were assessed for schizophrenia patients. There was no significant difference in either GM volume or WM connectivity with regard to rs2312147 genotype in healthy subjects. In contrast, we found significant differences in the WM connectivity between rs2312147 CC and CT/TT genotype groups of schizophrenia patients. The related brain areas included the splenium of corpus callosum, the left occipital lobe WM, the internal capsule (left anterior limb and right retrolenticular part), the bilateral temporal lobe WM, the left fornix/stria terminalis, the left cingulate gyrus WM, and the left parietal lobe WM. Voxelwise correlation analysis revealed that the Digit Symbol Test scores (age corrected) correlated with the fractional anisotropy in WM tracts that previously showed significant group differences between the CT/TT and CC genotypes in the rs2312147 CT/TT genotype group, while no significant correlation was found in the CC genotype group. Our data may provide evidence for the effect of VRK2 on WM connectivity in patients with schizophrenia.

Context: The detrimental effect of moisture on orthodontic bonding has long been known. Hydrophilic bonding materials have been introduced suggesting the possibility of obtaining successful orthodontic bonding to a moisture contaminated enamel surface., Aims: This study has been performed with an aim to compare the in vitro shear bond strength (SBS) and debonding characteristic of moisture-insensitive primer (MIP) (Transbond MIP) (3M Unitek, South Peck Road, Monrovia, California, USA) and self-etching primer (SEP) (Transbond Plus SEP) (3M Unitek, South Peck Road, Monrovia, California, USA) in combination with a color changing adhesive system (Transbond Plus Color Change) (3M Unitek, South Peck Road, Monrovia, California, USA) under both dry and contaminated condition., Settings and Design: Randomized controlled clinical study., Subjects and Methods: One hundred and twenty freshly extracted teeth for the purpose of orthodontic treatment were collected. Teeth were randomly assigned into four groups, each consisting of 30 specimen and stainless steel brackets were bonded using each primer-adhesive combination under different enamel conditions, that is, dry and enamel contaminated with natural saliva. SBS and adhesive remnant index were calculated for each group., Results: Analysis of variance of SBS for both MIP and SEP under dry and contaminated condition showed no statistical significance (P = 0.5). Chi-square test showed significant difference in debonding characteristics among the test groups (P < 0.001). All the groups showed typical debonding characteristics of separation either at the bracket-adhesive interface or within the adhesive itself., Conclusions: Moisture contamination did not affect the SBS and adhesive remaining on tooth for both MIP and SEP.

The frontal cortex might play an important role in the fear network, and white matter (WM) integrity could be related to the pathophysiology of panic disorder (PD). A few studies have investigated alterations of WM integrity in PD. The aim of this study was to determine frontal WM integrity differences between patients with PD without comorbid conditions and healthy control (HC) subjects by using diffusion tensor imaging. Thirty-six patients with PD who had used medication within 1 week and 27 age- and sex-matched HC subjects participated in this study. Structural brain magnetic resonance imaging was performed on all participants. Panic Disorder Severity Scale and Beck Anxiety Inventory (BAI) scores were assessed. Tract-based spatial statistics (TBSS) was used for image analysis. TBSS analysis showed decreased fractional anisotropy (FA) in frontal WM and WM around the frontal lobe, including the corpus callosum of both hemispheres, in patients with PD compared to HC subjects. Moreover, voxel-wise correlation analysis revealed that the BAI scores for patients with PD were positively correlated with their FA values for regions showing group differences in the FA of frontal WM of both hemispheres. Altered integrity in frontal WM of patients with PD without comorbid conditions might represent the structural pathophysiology in these patients, and these changes could be related to clinical symptoms of PD.

Objective: Serotonin-1A receptors (5-HTR1A) is suggested to be involved in the etiology of several psychiatric disorders including panic disorder (PD). A few imaging studies have suggested the alterations of the cingulum bundle in PD. The objective of this study is to examine the structural changes of cingulum related to the 5-HTR1A polymorphism rs6295 in the patients with PD., Methods: Thirty-two right-handed patients with PD [11 men, 21 women; 40.34±13.17 (mean±SD) age] who met the diagnostic criteria in Structured Clinical Interview for DSM-IV were examined by means of MRI at 3 Tesla. We divided the patients with PD into CC genotype group and non CC genotype group (GG/CG genotype group) of the 5-HTR1A rs6295 polymorphism to compare the cingulum white matter connectivity., Results: Tract-based spatial statistics showed significantly increased fractional anisotropy (FA) values in cingulate gyrus process of left cingulum in 5-HTR1A CC genotype compared to GG/CG genotype in PD. Significant positive correlations were shown between the Albany Panic and Phobia Questionnaire (APPQ) interoceptive fear subscale scores, the Anxiety Sensitivity Inventory-Revised fear of publicly observable anxiety reaction subscale scores and FA values of cingulate gyrus process of left cingulum in 5-HTR1A rs6295 GG/CG genotype group. In CC genotype group, APPQ total, APPQ agoraphobia subscale and APPQ social phobia subscale scores also showed significant positive correlations with FA values of hippocampal process of right cingulum., Conclusion: This preliminary study suggests that 5-HTR1A polymorphism may be associated with the cingulum white matter connectivity in PD.

Purpose: Although the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) for panic disorder (PD) has been studied previously, data on the predictors of treatment outcomes in MBCT for PD are scarce., Materials and Methods: Eighty patients with PD were screened to analyze treatment outcomes such as MBCT completion, treatment response, and remission after undergoing MBCT for PD. Sociodemographic characteristics, comorbid personality disorders, and baseline medication doses were examined. The study administered the Panic Disorder Severity Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale and Anxiety Sensitivity Inventory-Revised to patients at baseline and at eight weeks., Results: Sixty-five participants were enrolled in the present study. Comorbid personality disorder was significantly associated with MBCT non-completion. We found that anxiety sensitivity (AS) improvement after an eight week MBCT program was a statistically significant factor associated with treatment response. Using logistic regression analysis, AS improvement after MBCT showed significant association with PD remission after MBCT., Conclusion: Comorbid personality disorders of participants could be a potential predictor of MBCT non-completion. Furthermore, AS improvement after MBCT may predict treatment response and remission after MBCT for PD. However, better designed studies with a larger number of patients are needed to confirm our findings.

Background: Strong lifetime and current comorbidity occur between panic disorder and depression. However, no study has examined the influence of comorbid depression on brain structural characteristics in panic disorder patients. We aimed to compare gray matter (GM) volume and white matter (WM) connectivity in panic disorder patients with and without depression., Methods: Twenty-one panic disorder patients without comorbid major depression (PD-D) and seventeen panic disorder patients with major depression (PD+D) were investigated. The Panic Disorder Severity Scale (PDSS) and Beck Depression Inventory (BDI) were assessed for all subjects. Voxel Based Morphometry 5 toolbox and Tract-Based Spatial Statistics were used., Results: Compared to the PD-D group, GM volumes of patients with PD+D were significantly increased in a cluster located across the left cingulate gyrus, right medial frontal gyrus, and left paracentral lobule. Clinical symptom severity such as PDSS and BDI scores showed positive correlation with GM volumes in the PD+D group. Of the highlighted regions, the left posterior cingulate gyrus demonstrated both a GM volume difference between the groups and a positive correlation of GM volume with symptom severity in the PD+D group. Fractional anisotropy values were significantly higher across almost all the WM tracts in the PD+D group compared to the PD-D group., Conclusion: Alteration of GM volume and WM connectivity was associated with comorbid depression in panic disorder patients in this study. These findings suggest that distinct structural characteristics may be related to comorbid depression occurring in the context of panic disorder., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The functional imaging technique of ¹⁸F-fluoride positron emission tomography (¹⁸F-PET) allows the noninvasive quantitative assessment of regional bone formation at any skeletal site, including the spine and hip. The aim of this study was to determine if ¹⁸F-PET can be used as an early biomarker of treatment efficacy at the hip. Twenty-seven treatment-naive postmenopausal women with osteopenia were randomized to receive teriparatide and calcium and vitamin D (TPT group, n = 13) or calcium and vitamin D only (control group, n = 14). Subjects in the TPT group were treated with 20 µg/day teriparatide for 12 weeks. ¹⁸F-PET scans of the proximal femur, pelvis, and lumbar spine were performed at baseline and 12 weeks. The plasma clearance of ¹⁸F-fluoride to bone, K(i), a validated measurement of bone formation, was measured at four regions of the hip, lumbar spine, and pelvis. A significant increase in K(i) was observed at all regions of interest (ROIs), including the total hip (+27%, p = 0.002), femoral neck (+25%, p = 0.040), hip trabecular ROI (+21%, p = 0.017), and hip cortical ROI (+51%, p = 0.001) in the TPT group. Significant increases in K(i) in response to TPT were also observed at the lumbar spine (+18%, p = 0.001) and pelvis (+42%, p = 0.001). No significant changes in K(i) were observed for the control group. Changes in BMD and bone turnover markers were consistent with previous trials of teriparatide. In conclusion, this is the first study to our knowledge to demonstrate that ¹⁸F-PET can be used as an imaging biomarker for determining treatment efficacy at the hip as early as 12 weeks after initiation of therapy., (Copyright © 2013 American Society for Bone and Mineral Research.)

Background: The catechol-O-methyltransferase (COMT) gene val158met polymorphism (rs4680) has been found to be associated with various psychiatric phenotypes including panic disorder. Considering the probable genetic influence of COMT on the pathogenesis of panic disorder and white matter connectivity, the present study investigated white matter connectivity using diffusion tensor imaging in relation to the COMT genotype in panic disorder., Methods: Twenty-six patients with panic disorder and twenty-six age- and gender-matched healthy controls participated in this study. Brain magnetic resonance scans and genotype analysis for COMT rs4680 were conducted. Panic Disorder Severity Scale, Albany Panic and Phobia Questionnaire, and Anxiety Sensitivity Inventory-Revised were assessed. Tract-based spatial statistics (TBSS) were used for image analysis., Results: There was no significant difference in white matter analysis between panic disorder and healthy controls. However, TBSS analysis showed increased fractional anisotropy (FA) in posterior thalamic radiation, posterior and superior corona radiata, superior longitudinal fasciculus, and sagittal stratum, all located in the right hemisphere in COMT AA/AG genotype group compared to GG genotype in panic disorder. Voxelwise correlational analysis revealed the symptom severity scores are correlated with the FA in white matter tracts that previously showed significant group differences between AA/AG and GG genotypes in COMT AA/AG genotype group, while no significant correlation was found in GG genotype group., Limitations: The sample size in each group was small, hence, further studies with larger numbers of patients are needed to confirm our findings., Conclusions: These data suggested that COMT rs4680 could affect the white matter connectivity in panic disorder., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The polymorphisms of serotonergic genes (5-HTTLPR and HTR1A rs6295) and separation life events have been studied to find an association with panic disorder, respectively. However, there are no studies that have yet evaluated the interaction effect between serotonergic genes and separation life events for panic disorder., Methods: For this study, 194 panic disorder patients and 172 healthy controls were included for genotyping and environmental factor analysis. Separation life events were assessed using the Stressful Life Events Scale and clinical interviews. To evaluate the potential endophenotypes of panic disorder, the Anxiety Sensitivity Index-revised (ASI-R), harm avoidance in the Temperament and Character Inventory (HA), and neuroticism in the Eysenck Personality Questionnaire (neuroticism) scales were administered., Results: For 5-HTTLPR and HTR1A rs6295, there was no significant main effect of each genotype on panic disorder alone. However, the number of separation life events and their interaction with 5-HTTLPR showed a statistically significant effect on panic disorder. In addition, the interaction between 5-HTTLPR and the number of separation life events significantly affected the HA for potential endophenotypes., Conclusion: This study could suggest the effect of the interaction between 5-HTTLPR and separation life events on panic disorder and its potential endophenotype., (Copyright © 2013 S. Karger AG, Basel.)

Objective: Since 1999, patients with low risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. Here we prospectively assess survival, sites of recurrence, morbidity, and cost in this low risk cohort., Methods: Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Classification. Thirty-day cost analyses were expressed in 2010 Medicare dollars., Results: Among 1393 consecutive surgically managed cases, 385 (27.6%) met inclusion criteria, accounting for 34.1% of type I EC. There were 80 LND and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5% vs. 19.3%; P<0.001). The prevalence of lymph node metastasis was 0.3% (1/385). Over a median follow-up of 5.4 years only 5 of 31 deaths were due to disease. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was $15,678 for LND cases compared to $11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was $327,866 to $439,990, adding an additional $1,418,189 if all 305 non-LND cases had undergone LND., Conclusion: Lymphadenectomy dramatically increases morbidity and cost of care without discernible benefits in low-risk EC as defined by the Mayo criteria. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be standard of care., (Copyright © 2012. Published by Elsevier Inc.)

Purpose: The incidence of hospital acquired adverse events in radical cystectomy and their implications for hospital outcomes and costs remain poorly described. We describe the incidence of hospital acquired adverse events in radical cystectomy, and characterize its relationship with in-hospital mortality, length of stay and hospitalization costs., Materials and Methods: We identified 10,856 patients who underwent radical cystectomy for bladder cancer at 1,175 hospitals in the Nationwide Inpatient Sample from 2001 to 2008. We used hospital claims to identify adverse events for accidental puncture, decubitus ulcer, deep vein thrombosis/pulmonary embolus, methicillin-resistant Staphylococcus aureus, Clostridium difficile, surgical site infection and sepsis. Logistic regression and generalized estimating equation models were used to test the associations of hospital acquired adverse events with mortality, predicted prolonged length of stay and total hospitalization costs., Results: Hospital acquired adverse events occurred in 11.3% of all patients undergoing radical cystectomy (1,228). Adverse events were associated with a higher odds of in-hospital death (OR 8.07, p<0.001), adjusted prolonged length of stay (41.3%) and total costs ($54,242 vs $26,306; p<0.001) compared to no adverse events on multivariate analysis. The incremental total costs attributable to hospital acquired adverse events were $43.8 million. Postoperative sepsis was associated with the highest risk of mortality (OR 17.56, p<0.001), predicted prolonged length of stay (62.22%) and adjusted total cost ($79,613)., Conclusions: With hospital acquired adverse events occurring in approximately 11% of radical cystectomy cases, they pose a significant risk of in-hospital mortality and higher hospitalization costs. Therefore, increased attention is needed to reduce adverse events by improving patient safety, while understanding the economic implications for tertiary referral centers with possible policy changes such as denial of payment for hospital acquired adverse events., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined differences in temperament and character dimensions of personality between patients with Hwa-byung (HB) and those with major depressive disorder (MDD)., Method: Of 144 participants, 96 completed the Korean version of the Temperament and Character Inventory-Revised Short (TCI-RS) and the Hwa-byung Scale. We diagnosed participants according to the DSM-IV and the Research Diagnostic Criteria for Hwa-byung. We compared TCI scores between the HB group (with or without MDD; N=55) and the MDD-only group (N=41) and correlated them with the total scores on six HB-specific symptoms (global HB severity) on the Hwa-byung Scale., Results: Compared to patients with only MDD, patients with HB with or without MDD exhibited significantly higher scores on Impulsiveness; Harm Avoidance (HA) and its subscales of Anticipatory Worry; and Self-Transcendence (ST), with its subscale of Self-Forgetfulness. However, HB patients had lower scores on Self-Directedness, with its subscales of Responsibility, and Self-Acceptance; and Acceptance. Moreover, Global HB Severity had significant, positive correlations with ST, its subscale Self-Forgetfulness, and Anticipatory Worry but negative correlations with Attachment and Compassion., Limitations: Our data are cross-sectional and self-reported, so they are subject to personal perceptual bias. The number of participants may be too low for us to generalize the results., Conclusion: These results suggest that HB is a different clinical entity from MDD in relation to personality traits, and that symptoms unique to HB are closely correlated with ST., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Cerium-doped Titanium dioxide (TiO(2)) nanoparticles are prepared by sol-gel method. Doping shifts the UV absorption edge of TiO(2) to the visible region, making it efficient for visible light photocatalysis. Incorporation of cerium decreases the effective band gap of TiO(2) and increases the Urbach energy levels. At the dopant concentrations of 0.015 and 0.025 mol the luminescence intensity increases compared to undoped TiO(2); however, the luminescence is quenched at 0.035 mol. Quenching of luminescence indicates efficient separation of charge carriers. Undoped TiO(2) is showing poor performance in the photocatalytic degradation of methyl orange under visible light. However, on cerium doping its photoactivity is increased, and is drastically enhanced at 0.035 mol of cerium. Further increase in Ce(3+) doping level to 0.045 mol results in the reduction of the photodegradation of the dye. On UV irradiation, entire samples show good photocatalytic activity up to 30 min, but their efficiency decreases when irradiation time is increased to 45 min. Irradiation for longer time results in negative charging of the TiO(2) surface with migrating electrons. The negatively charged surface repels the OH(-) ion and O(2) molecule from adsorbing on its surface thus decreasing the availability of hydroxyl and superoxide radical for dye degradation., (© 2011 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2011 The American Society of Photobiology.)

Clinical and psychosocial deterioration associated with schizophrenia occurs within the first few years following the onset of the illness. Therefore, to improve the long-term prognosis, it is important to provide schizophrenia patients with intensive treatment following their first episode. Relapse is highly associated with partial medication adherence or nonadherence in patients with first-episode schizophrenia. Recent studies suggest that long-acting injectable (LAI) antipsychotics compared with oral antipsychotics are more effective for medication adherence and relapse prevention. Moreover, some clinical guidelines for the treatment of schizophrenia suggested that LAI antipsychotics should be considered when patients are nonadherent "at any stage." Decreased compliance is a common cause of relapse during the initial stages of the disease. Therefore, LAI antipsychotics should be highly considered when treating patients with first-episode schizophrenia. In the present paper, clinical trial data and current guidelines on the use of LAI antipsychotics for first-episode schizophrenia are discussed as well as the pros and cons of this treatment option.

Objective: Some patients with schizophrenia may need mirtazapine augmentation to improve negative and cognitive symptoms. However there have been a few studies about the tolerability of mirtazapine augmentation to antipsychotics such as akathisia, extrapyramydal symptoms, weight gain, and body mass index (BMI)., Methods: This study was an eight-week double-blind, randomized controlled trial (RCT) of mirtazapine augmentation to risperidone. Twenty-one stabilized participants diagnosed with schizophrenia and undergoing treatment with risperidone were randomized to adjunctive treatment with mirtazapine (15 mg/day for the first two weeks, 30 mg/day for the next six weeks) or placebo. Eleven patients were assigned to the mirtazapine group, and nine patients were given placebo., Results: There was no significant difference between the mirtazapine and placebo groups with respect to Barnes Akathisia rating Scale (BAS) and Sympsom-Angus Scale (SAS). However, the mirtazapine group exhibited a statistically significant increase in weight and BMI (p<0.05)., Conclusion: These results suggest that mirtazapine augmentation can be tolerable in schizophrenic patients treated with risperidone; however, we should pay attention to the weight gain with mirtazapine. Our results should be replicated in a large-scale lengthy trial.

This preliminary study aimed to determine if adding mirtazapine to risperidone might improve negative and cognitive symptoms in schizophrenia. In an 8-week, double-blind clinical trial, we randomly assigned 21 stabilized outpatients with schizophrenia undergoing risperidone treatment to adjunctive treatment with either mirtazapine or a placebo. The mirtazapine group exhibited a statistically significant improvement in cognitive function, including vocabulary and immediate memory, and negative symptoms (as measured by negative symptom scales) and showed an adverse effect of 5.83 kg mean weight gain. This study suggests augmenting risperidone with mirtazapine can effectively improve both negative and some cognitive symptoms of schizophrenia., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A widespread leaf deformity disease of mentha (mint), accompanied by whiteflies, the vectors of begomoviruses, was observed in Punjab in the last few years. The presence of begomovirus was indicated by DNA dot-blot analysis using the conserved coat protein and replication-associated protein genes of another begomovirus, Sri Lankan cassava mosaic virus (SLCMV). A DNA fragment (2.0 kb), representing a partial genomic DNA of a begomovirus, amplified from the symptomatic mentha leaves was used to design end-primers and further amplify an additional 0.9 kb fragment, representing the remaining portion of the resident viral DNA. The two sequences, assembled together (2.7 kb), showed that they represented the complete sequence of an isolate of Tomato leaf curl Karnataka virus (ToLCKV) DNA. Using universal betasatellite primers, a 1.4 kb fragment was amplified from the same sample. This cloned DNA fragment showed complete sequence identity with the previously reported Cotton leaf curl Multan betasatellite (CLCuMB). Majority of the symptomatic mentha leaf samples, collected from four districts of Punjab, showed cross-hybridization in DNA dot-blot using cloned SLCMV and CLCuMB DNA, indicating the presence of one or more begomoviruses related to SLCMV and the betasatellite, CLCuMB. The begomovirus and betasatellite could be mechanically transmitted to Nicotiana benthamiana. Whitefly transmission of the resident begomovirus could also be demonstrated on mentha. The evidence indicates the association of ToLCKV and CLCuMB, a hitherto new combination of a begomovirus and a betasatellite associated with a leaf deformity disease in mentha in Punjab.

Mindfulness-based cognitive therapy (MBCT) has been studied to treat patients with depressive or anxiety disorders. The aim of this study was to examine whether MBCT is effective as an adjunct to pharmacotherapy in the treatment of patients with panic disorder. Twenty-three patients with panic disorder were included in a MBCT program for a period of 8 weeks. The Hamilton Anxiety Rating Scale (HAM-A), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Anxiety Sensitivity Index-Revised (ASI-R), Albany Panic and Phobia Questionnaire (APPQ), and Panic Disorder Severity Scale (PDSS) were used to assess the patients during the MBCT program. Both HAM-A and PDSS scores were significantly decreased at the 2nd, 4th and 8th weeks compared to baseline in the patients with panic disorder (HAM-A, p<0.01; PDSS, p<0.01). Also, BAI, APPQ and ASI-R were improved significantly after MBCT program (BAI, p<0.01; APPQ, p<0.01; ASI-R, p<0.01). In addition, all subscale scores of ASI-R decreased significantly. MBCT could be effective as an adjunct to pharmacotherapy in patients with panic disorder. However, randomized controlled trials are needed., ((c) 2010 Elsevier Ltd. All rights reserved.)

Objectives: Treatment effectiveness depends upon administering medications as prescribed, and adherence is critical for Alzheimer's disease (AD) patients to receive optimal benefit from therapy. The objective of this study was to investigate factors associated with adherence to AD oral medications., Methods: This retrospective claims analysis identified AD patients who initiated oral AD therapy (rivastigmine, donepezil, galantamine, or memantine) between January 1, 2006 and December 31, 2007 from a large US health plan. Patient baseline characteristics were assessed during the 6-month pre-index period; outcomes were assessed during the 1-year post-index period. Pill burden was measured as a count of unique units of medication/day. Adherence was measured by medication possession ratio (MPR), with MPR >or=80% defined as adherent. Multivariate logistic regression was used to assess how potential covariates affect adherence probability., Results: A total of 3091 AD patients (36% male; mean age 80 [8.25 SD]) were identified. Only 58% of patients were adherent to oral AD medications. Compared to patients <75 years, patients >or=86 years were likely to be more adherent (OR = 1.401, p < 0.001). Other factors found to be positively associated with the probability of adherence to AD medications were male gender (OR = 1.175, p < 0.05), overall pill burden (OR = 1.192, p < 0.001), and a lower formulary tier status of the AD medication (OR = 1.332, p < 0.001)., Conclusion: Among the several variables assessed, being male, >or=86 years of age, having a greater overall daily pill burden, or using a lower formulary tier AD medication was associated with better adherence to oral AD medication in patients diagnosed with AD. The database had no information on caregiver support, medication management interventions, or use of adherence aids that may have affected adherence in this cohort, yet, a substantial proportion of patients (42%) remained non-adherent. A better understanding of the causes of non-adherence is necessary, and methods to improve adherence, such as transdermal medications and educational programs, should be considered.

An attempt was undertaken to investigate the efficacy of Ovsynch protocol for timed artificial insemination (TAI) with or without Norprolac (antiprolactin) treatment during non-breeding season (winter months) in yaks (n = 25). During non-breeding season, plasma prolactin profile has been reported high due to cold and nutritional stress. The Norprolac dose of i.m. administration was standardized for prolactin suppression. Three different doses viz. 2.5, 5.0 and 7.5 mg were attempted and the dose of 7.5 mg Norprolac i.m. per animal was found to be suitable for suppression of prolactin levels up to 30 h. Ovsynch treatment with Norprolac induced more number of oestrous symptoms per animal (4.8 vs 2.1), higher LH peak concentration (24.01 vs 16.16 ng/ml), longer duration of LH surge (6.8 vs 5.2 h) and higher conception rate (70 vs 30%) in Ovsynch plus Norprolac treated animals compared with animals treated with Ovsynch alone. Therefore, this study clearly indicates the opportunity for practical application of the Ovsynch plus Norprolac protocol for TAI in yaks during non-breeding seasons.

An attempt was made to determine plasma concentrations of, 13, 14-dihydro-15-keto-prostaglandin F(2alpha) (PGFM), cortisol and progesterone during periparturient period in yak. Plasma PGFM level showed an increasing trend beginning day 5 prior to parturition (0.48 +/- 0.14 ng/ml) and increased steeply thereafter to reach a peak level (17.16 +/- 1.31 ng/ml) on the day of parturition. The levels, then, declined sharply on day 1 postpartum to reach 1.20 +/- 0.40 ng/ml and thereafter declined gradually over the days to reach 0.28 +/- 0.09 ng/ml on day 20 postpartum and this level was maintained with fluctuation within narrow limits thereafter till conclusion of the blood sampling on day 90 post-calving. The plasma progesterone concentration on days 7 and 6 before parturition was high (2.10 +/- 0.10 and 2.12 +/- 0.10 ng/ml, respectively). The level then decreased gradually and abrupt fall was observed 1-2 days before parturition and became basal on day of parturition (0.24 +/- 0.04 ng/ml). This basal level was maintained till the end of the blood sampling on day 90 postpartum. Plasma cortisol level showed an increasing trend beginning day 2 prior to parturition (2.36 +/- 0.65 ng/ml) and increased steeply thereafter to reach a peak level (26.65 +/- 5.28 ng/ml) on the day of parturition. The levels, then, declined gradually over the days and touched 2.36 +/- 0.25 ng/ml on day 3 postpartum and this level was maintained with fluctuation within narrow limits thereafter till day 7 post-calving.

Schizophrenia is a chronic disorder that is usually characterized by relapses alternating with periods of full or partial remission. We examined whether combined therapy with a psychosocial intervention for relapse prevention (PIRP) and risperidone administered by long-acting injection (RLAI) would be more effective in reducing relapses than RLAI with treatment-as-usual (TAU) among outpatients with schizophrenia. We conducted a prospective, controlled study over 2 years in 46 patients with schizophrenia receiving RLAI, of which 21 and 25 patients were assigned to the PIRP and TAU control groups, respectively. The 1- and 2-year relapse rates were lower and medication compliance was higher in the PIRP group than in the TAU group. Cox proportional analysis revealed that time from baseline to relapse was associated with RLAI discontinuation. These results indicate that PIRP can be effective in maintaining medication compliance, and that discontinuation of long-acting atypical antipsychotics might be predictive of the next relapse. However, these results need to be replicated in studies with larger samples., (2008 Elsevier Ireland Ltd. All rights reserved.)

Previous antiresorptive treatment may influence the anabolic response to teriparatide. The OPTAMISE (Open-label Study to Determine How Prior Therapy with Alendronate or Risedronate in Postmenopausal Women with Osteoporosis Influences the Clinical Effectiveness of Teriparatide) study reported greater increases in biochemical markers of bone turnover and volumetric bone mineral density (BMD) when 12 months of teriparatide treatment was preceded by 2 years or more of risedronate versus alendronate treatment. The objective of this study was to use quantitative computed tomography (CT)-based nonlinear finite element modeling to evaluate how prior therapy with alendronate or risedronate in postmenopausal women with osteoporosis influences the biomechanical effectiveness of teriparatide. Finite element models of the L1 vertebra were created from quantitative CT scans, acquired before and after 12 months of therapy with teriparatide, from 171 patients from the OPTAMISE study. These models were subjected to uniaxial compression. Total BMD-derived bone volume fraction (BV/TV(d), i.e., bone volume [BV]/total volume [TV]), estimated from quantitative CT-based volumetric BMD, vertebral stiffness, and failure load (strength) were calculated for each time measurement point. The results of this study demonstrated that 12 months of treatment with teriparatide following prior treatment with either risedronate or alendronate increased BMD-derived BV/TV(d), the predicted vertebral stiffness, and failure load. However, the effects of teriparatide were more pronounced in patients treated previously with risedronate, which is consistent with the findings of the OPTAMISE study. The mean (+/-standard error) increase in stiffness was greater in the prior risedronate group than the prior alendronate group (24.6+/-3.2% versus 14.4+/-2.8%, respectively; p=0.0073). Similarly, vertebral failure load increased by 27.2+/-3.5% in the prior risedronate group versus 15.3+/-3.1% in the prior alendronate group (p=0.0042). The mechanical variables increased in greater proportion than BV/TV(d), which increased by 6.9+/-0.9% versus 4.6+/-0.8% in the prior-risedronate and prior-alendronate groups, respectively (p=0.0290). Our finding indicated that while teriparatide can be used with success on patients who have previously undergone treatment with risedronate and alendronate, it demonstrated greater anabolic effect on biomechanical properties in prior-risedronate patients in the first year of teriparatide treatment., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Nonvertebral fractures account for 80% of all fractures and their accompanying morbidity and mortality. Despite this, the effect of drug therapy on cortical morphology has received limited attention, partly because cortical bone is believed to remodel less and decrease less with age than trabecular bone. However, the haversian canals traversing the cortex provide a surface for remodeling that produces bone loss, porosity, and cortical fragility. We developed a new method of 3D micro-computed tomography (microCT) to quantify intracortical porosity and the effects of treatment. Women with osteoporosis randomized to risedronate (5 mg/day, n = 28) or placebo (n = 21) had paired transiliac biopsies at baseline and 5 years imaged using 3D microCT. Pores determined from 8 to 12 slices were stratified by their minor axis length into those 25 to 100 microm (closing cone of haversian canals), 100 to 300 microm (cutting cone of haversian canals), and >300 microm (coalescent cavities). Porosity was analyzed as pore area (percent bone area) and pore density (pore number/mm(2)). Medians are reported. Risedronate reduced pore area in the 25 to 100, 100 to 300, and 300 to 500 microm ranges over 5 years (p = .0008, .04, NS, respectively) corresponding to an 18% to 25% reduction. In the placebo group, pore area was unchanged. At 5 years, pore area and pore number/mm(2) in the 25 to 100 microm range were each 17% lower in the risedronate group than in the placebo group (p = .02 and .04, respectively). Risedronate is likely to maintain bone strength and reduce nonvertebral fracture risk in part by reducing remodeling and therefore the number and size of intracortical cavities., (2010 American Society for Bone and Mineral Research)

Introduction: The use of androgen deprivation therapy (ADT) for prostate cancer is on the rise, but its adverse side effects may include increased fat mass and decreased lean muscle mass. The net effect of ADT on BMI is unknown., Methods: Primary, incident cases of early stage prostate cancer (n = 473) were identified from the Buffalo VA Medical Center tumor registry and matched to body size, demographic, comorbidity, and treatment exposure data from veteran medical records. Multilevel modeling was used to assess the association between ADT and changes in BMI., Results: On average, survivors were overweight at diagnosis and showed small, non-significant changes in BMI over time. However, among those survivors with a history of ADT, a significant decrease of 0.05 BMI units per year was associated with each additional dose of ADT (p < 0.001). When the association between BMI rate of change and ADT was allowed to vary with respect to age, additional doses of ADT predicted stronger decreases in BMI for younger survivors as compared to older survivors (p < 0.05). Neither a history of surgery nor radiation influenced the association between ADT use and BMI., Conclusions: Declines in BMI in relation to ADT exposure may be reflective of unfavorable changes in body composition, especially decreased muscle mass, that is most pronounced in younger survivors., Implications for Cancer Survivors: Survivors on ADT may benefit from close monitoring of physical functioning and referral for exercise interventions to preserve muscle mass and improve health related quality of life.

Seasonal changes in plasma testosterone concentration and semen quality were evaluated in yak bulls throughout a 1-year period. Blood samples were collected every week from adult yak bulls (n=15). These blood samples were analyzed for testosterone using a highly sensitive enzyme-linked immunoassay. Ejaculates were collected from five representative bulls each week. Ejaculate volume, progressive motility, live sperm count and sperm concentrations were determined. Mean testosterone in plasma was 1.03+/-0.25 ng/ml. Concentrations of testosterone changed throughout the year (P<0.05) and were found to be highest during the winter. It was also higher during the autumn than in summer and spring (P<0.05). Mean ejaculate volume, progressive motility, live sperm count and spermatozoa concentration were 2.7+/-0.3 ml, 72.8+/-1.4%, 82.3+/-0.9% and 968+/-233 x 10(6)ml(-1), respectively. Ejaculate volume and sperm concentration were higher (P<0.05) in autumn than in other seasons. To conclude, a highly sensitive EIA for testosterone was developed and validated for yak plasma. Seasonal changes in semen quality were associated with changes in the concentration of testosterone in plasma from yak bulls.

Ovulatory response to the first GnRH of Ovsynch is the critical determinant for successful synchronization of ovulation in animals. An attempt was made in this study to design a pre-Ovsynch hormonal strategy in yaks to increase the ovulatory response to the first GnRH injection of Ovsynch so that overall synchronization rate to Ovsynch could be improved. Non-lactating cyclic yak cows (n=33) were assigned to receive either no treatment before Ovsynch (control) or 0.375 mg of PGF2alpha (PreP) followed 2 d later by 10 microg of GnRH (PreG), administered 4 (G4G), 5 (G5G), or 6 (G6G) d before initiating the Ovsynch protocol. Rectal palpation was performed to assess ovulation and blood samples were collected to measure progesterone concentrations during pre-treatment, treatment and post-treatment periods. All the animals received timed AI 12 and 24h after the final GnRH of Ovsynch. Diagnoses for pregnancy were performed by rectal palpation and profiles of plasma progesterone 35 d after AI. Percentage of yak cows that ovulated in response to the first GnRH injection of Ovsynch, synchronized to Ovsynch treatment, had a functional CL at PGF2alpha of Ovsynch, had circulating concentrations of P4 at PGF2alpha of Ovsynch and likely to be pregnant after 35 d after AI, were greater in G6G and G5G compared with control, whereas G4G did not differ from controls. In addition, animals that ovulated in response to first GnRH of Ovsynch had greater response to PGF2alpha of Ovsynch and greater synchronization rate to the overall protocol than those that did not ovulate. In summary, PGF2alpha-and-GnRH-based pre-Ovsynch strategies consisting of 5 or 6-d interval between PreG and first GnRH of Ovsynch resulted in a greater ovulatory and luteolytic response to first GnRH andPGF2alpha of Ovsynch, respectively, compared with control animals. These, in turn, optimized synchronization rate to Ovsynch in yaks.

Background: Mindfulness-based cognitive therapy (MBCT) has been widely used to treat patients with depressive disorder to prevent relapse. The objective of this study was to examine the effectiveness of newly developed MBCT program as an adjuvant to pharmacotherapy in the treatment of patients with panic disorder or generalized anxiety disorder., Methods: Forty-six patients with panic disorder or generalized anxiety disorder were assigned to either MBCT or an anxiety disorder education (ADE) program for a period of 8 weeks. The Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Symptom Checklist-90-Revised (SCL-90-R) were used to assess the patients at 0 week and after the two programs had been running for 2, 4, and 8 weeks., Results: The MBCT group demonstrated significantly more improvement than the ADE group according to all anxiety (HAM-A, p<0.01; BAI, p<0.01; anxiety subscale of SCL-90-R, p=0.01) and depression (HAM-D, p<0.01; BDI, p<0.01; depression subscale of SCL-90-R, p<0.01) scale scores. The obsessive-compulsive and phobic subscales of the SCL-90-R also showed significantly more improvement in the MBCT group. However, no significant improvement was observed in the MBCT group versus the ADE group in terms of the somatization, interpersonal sensitivity, paranoid ideation, or psychoticism subscale scores of the SCL-90-R., Conclusions: MBCT may be effective at relieving anxiety and depressive symptoms in patients with panic disorder or generalized anxiety disorder. However, well-designed, randomized controlled trials are needed.

As an alternative to radioimmunoassays, a simple, highly sensitive and quick enzymeimmunoassay (EIA) for determination of testosterone in blood plasma of yaks on microtitreplates using second antibody coating technique and testosterone-horseradish peroxidase as a label has been developed for the first time. The wells of the microtitreplate were coated with affinity-purified goat immunoglobulin (antirabbit IgG) that binds the hormone specific antibody. The EIA was carried out directly in 20 mICROl of plasma after 1:10 dilution with assay buffer. The testosterone standard curve ranged from 0.2 to 200 pg/well. The sensitivity of the assay was 0.20 pg/well. Testosterone standard curve in buffer showed parallelism with serially diluted yak plasma containing high endogenous testosterone. Intra- and inter-assay coefficients of variation (CV) determined using pooled plasma was found 5.24 and 8.54%, respectively. Recovery of known concentrations of added testosterone in charcoal stripped plasma was linear (r=0.98). For biological validation of testosterone enzymeimmunoassay, the blood samples were collected from yak cows at -2h before and thereafter at 2h interval until 24h. after gonadotropin releasing hormone (GnRH) administration. There was a rapid increase (p<0.01) of luteinizing hormone (LH) and testosterone 2 and 6h after GnRH administration. Plasma testosterone concentration in normal adult yak bulls was found to be 0.52+/-0.09 ng/ml. In conclusion, the EIA developed in this study is simple, highly sensitive, valid and sufficiently reliable method for estimation of testosterone directly in yak plasma.

Patients with first-episode schizophrenia frequently relapse during the first years of the illness. This may be associated with clinical deterioration. It is important to prevent relapses in first-episode schizophrenia. We examine whether risperidone long-acting injection (RLAI) could effectively act to prevent relapse in first-episode schizophrenia. We conducted a prospective, naturalistic, controlled, and open-label study over 2 years in 50 patients with first-episode schizophrenia. 22 patients with schizophrenia were assigned to the RLAI group and 28 patients with schizophrenia to the oral risperidone group as control. We compared medication adherence, time to non-adherence, and relapse rate between the RLAI and control groups. There were no significant difference in sociodemographic findings and initial psychometric measures between two groups. The RLAI group showed significantly lower relapse rate and higher medication adherence than the control group. The result demonstrated by Kaplan-Meier survival analysis that time to non-adherence is associated with the difference in the groups. Cox proportional survival analysis revealed that time from baseline to relapse was associated with time to non-adherence. This result showed that RLAI could be effective in maintaining medication adherence and preventing relapse. However, studies with a larger sample size will be needed to examine whether these results are applicable to schizophrenic population.

Background: Little is known about the specific cost effect of rhinitis on third-party payers. No recently reported studies have examined the economic burden of rhinitis in managed care. Furthermore, the direct costs of chronic rhinitis have not been evaluated and potential differences in health care use and costs of allergic rhinitis have not been examined., Objective: To evaluate the economic burden of allergic rhinitis and chronic rhinitis to third-party payers in a large US managed care plan., Methods: In a retrospective analysis using pharmacy and medical claims data from a US health plan covering approximately 15 million members, health care use and cost data were summarized for patients with allergic or chronic rhinitis (n = 301,001) for the 13-month study period (January 1, 2004, to January 31, 2005)., Results: Average rhinitis-related total costs were $657 per patient each year ($319 in medical costs and $338 in pharmacy costs). Ambulatory visits were the primary contributor to rhinitis-related medical costs. Antihistamines were the most common rhinitis medication, followed by intranasal corticosteroids (INSs) and montelukast. Many patients (37% with at least 1 filled prescription for an antihistamine, an INS, or montelukast) used combination therapy. Of the 3 main pharmacotherapy categories, montelukast was associated with the highest pharmacy cost ($353 vs $198 for antihistamines and $231 for INSs per patient each year for monotherapy) and drove the average annual cost of combination therapy regardless of the concomitant medication(s). The most common comorbidities were sinusitis and asthma, present in 51.1% and 27.9% of patients, respectively. Comorbidities increased rhinitis-related health care costs., Conclusions: Allergic rhinitis and chronic rhinitis imposed a significant financial burden on third-party payers in a large US managed care plan. The presence of comorbidities further increased the rhinitis-related treatment costs.

Objective: Primary spontaneous pneumothorax (PSP) is a frequent and problematic disease, but its underlying causes and pathophysiology remain unclear. This study examined whether anger, which is related to many psychosomatic diseases, is a psychosocial factor associated with first-onset PSP., Method: We administered the State-Trait Anger Expression Inventory, Stress Response Inventory, Coping Scale, Beck Depression Inventory and Global Assessment of Recent Stress to 91 patients with first-onset PSP and to 77 patients with recent minor trauma as controls., Results: The scores on anger-in, anger-out, state anger and trait anger were significantly higher in the PSP group than in the control group. Logistic regression analysis revealed that low body mass index and trait anger could be associated with PSP., Conclusion: We hypothesize that anger could play a role in the pathophysiology of PSP.

The objective of this study was to examine the usefulness of a mindfulness-based cognitive therapy (MBCT) for treating insomnia symptoms in patients with anxiety disorder. Nineteen patients with anxiety disorder were assigned to an 8-week MBCT clinical trial. Participants showed significant improvement in Pittsburgh Sleep Quality Index (Z = -3.46, p = 0.00), Penn State Worry Questionnaire (Z = -3.83, p = 0.00), Ruminative Response Scale (Z = -3.83, p = 0.00), Hamilton Anxiety Rating Scale (Z = -3.73, p = 0.00), and Hamilton Depression Rating Scale scores (Z = -3.06, p = 0.00) at the end of the 8-week program as compared with baseline. Multiple regression analysis showed that baseline Penn State Worry Questionnaire scores were associated with baseline Pittsburgh Sleep Quality Index scores. These findings suggest that MBCT can be effective at relieving insomnia symptoms by reducing worry associated sleep disturbances in patients with anxiety disorder. However, well-designed, randomized, controlled trials are needed to confirm our findings.

Background: The ability to track dynamic changes in myocardial blood flow (MBF) and wall motion with serial gated perfusion imaging may be a limiting factor in assessing new therapies. The purpose of this study was to determine whether gated Tc-99 m sestamibi (MIBI) SPECT imaging can track small changes in MBF in a model of progressive ischemia., Methods: Eight pigs (20 kg) underwent lateral thoracotomy for placement of an ameroid constrictor on the left circumflex coronary artery (LCX) and indwelling femoral and left atrial catheters for serial microsphere determinations of absolute MBF. Animals underwent concurrent left atrial microsphere and Tc-99 m sestamibi (0.3 mCi/Kg IV) injections at weekly intervals over 6 weeks per animal. Gated SPECT imaging was acquired for each injection using high resolution collimation and standard processing. The animals were sacrificed on day 42. Mean signal intensity (SI) from regions of interest (ROI) corresponding to control and ischemic MBF by microspheres was measured for three SPECT short-axis images. Mean contrast ratio (MCR) was calculated from the ratio of ischemic to control SI per slice. Regional wall motion (RWM) from gated images was scored 1-5 using a 16 segment model and a score index (RWMI) was calculated., Results: MBF decreased progressively (27% below resting values [P < 0.0001]) but with a clear and significant partial recovery by day 42 (13% improvement from peak ischemia, [P < 0.01]). SPECT perfusion and gated RWM closely paralleled the dynamic pattern of MBF caused by the ameroid constrictor. SPECT MCR decreased 21% from baseline scans in the LCX territory (P < 0.0001) and improved 11% from peak ischemia (P < 0.01) while the gated RWMI (1.0 at baseline) peaked at 1.36 and improved to 1.13 by day 42., Conclusion: Gated SPECT-a technique readily available-tracks dynamic changes in MBF closely with both perfusion and RWM. For trials of new therapies for the alleviation of chronic ischemia, these findings have direct implications for measuring efficacy.

The objective of the study was to assess the time course of changes in bone mineralization and architecture using sequential triple biopsies from women with postmenopausal osteoporosis (PMO) who received long-term treatment with risedronate. Transiliac biopsies were obtained from the same subjects (n = 7) at baseline and after 3 and 5 years of treatment with 5 mg daily risedronate. Mineralization was measured using 3-dimensional (3D) micro-computed tomography (CT) with synchrotron radiation and was compared to levels in healthy premenopausal women (n = 12). Compared to the untreated PMO women at baseline, the premenopausal women had higher average mineralization (Avg-MIN) and peak mineralization (Peak-MIN) by 5.8% (P = 0.003) and 8.0% (P = 0.003), respectively, and lower ratio of low to high-mineralized bone volume (BMR-V) and surface area (BMR-S) by 73.3% (P = 0.005) and 61.7% (P = 0.003), respectively. Relative to baseline, 3 years of risedronate treatment significantly increased Avg-MIN (4.9 +/- 1.1%, P = 0.016) and Peak-MIN (6.2 +/- 1.5%, P = 0.016), and significantly decreased BMR-V (-68.4 +/- 7.3%, P = 0.016) and BMR-S (-50.2 +/- 5.7%, P = 0.016) in the PMO women. The changes were maintained at the same level when treatment was continued up to 5 years. These results are consistent with the significant reduction of turnover observed after 3 years of treatment and which was similarly maintained through 5 years of treatment. Risedronate restored the degree of mineralization and the ratios of low- to high-mineralized bone to premenopausal levels after 3 years of treatment, suggesting that treatment reduced bone turnover in PMO women to healthy premenopausal levels. Conventional micro-CT analysis further demonstrated that bone volume (BV/TV) and trabecular architecture did not change from baseline up to 5 years of treatment, suggesting that risedronate provided long-term preservation of trabecular architecture in the PMO women. Overall, risedronate provided sustained benefits on mineralization and architecture, two key determinants of bone strength, over 5 years lending support for its long-term efficacy in fracture risk reduction.

Overexpression of antiapoptotic Bcl-2 family members is thought to contribute to chemotherapeutic resistance of neural crest tumors. Paradoxical potentiation by Bcl-2 of apoptosis induced by the antineoplastic prodrug, neocarzinostatin (NCS), has been observed in PC12 pheochromocytoma cells. Prior studies have indicated that the cleavage of Bcl-2 to its proapoptotic counterpart mediated by caspase-3 is responsible for this potentiation of apoptosis. This has led to the hypothesis that induction of caspase-3 expression in bcl-2-transfected, caspase-3-deficient MCF-7 cells, will result in Bcl-2 cleavage and Bcl-2-dependent potentiation of NCS-induced apoptosis. These studies have further led to the hypothesis that both cleavable Bcl-2 and sulfhydryl groups are required for the activity of caspase-3 in this regard. As hypothesized, co-transfection of bcl-2-transfected MCF-7 cells with a caspase-3 expression construct results in cleavage of Bcl-2 and potentiation of dose-dependent, NCS-mediated cell death. Furthermore, PC12 cells transfected with an expression construct for cleavage-resistant Bcl-2 demonstrated attenuated potentiation of apoptosis relative to their counterparts transfected with wild-type bcl-2. Finally, irreversible oxidative titration of sulfhydryl groups resulted in concentration-dependent attenuation of apoptosis in PC12 cells, along with prevention of caspase-3 activation and Bcl-2 cleavage. These results definitively demonstrate the requirement for caspase-3, cleavable Bcl-2, and available sulfhydryl groups (separate from those required for NCS activation) in potentiation of NCS-induced apoptosis by Bcl-2.

The primary goal of our study was to determine changes in bone mineralization in postmenopausal osteoporotic women treated for 3 years with risedronate or placebo. A secondary goal was to determine the relationship between mineralization and indices of bone turnover measured on the same biopsies. The degree of mineralization was measured by micro-computed tomography using Synchrotron radiation (Synchrotron microCT) in the trabecular bone of paired transiliac biopsies taken at baseline and after 3 years of treatment from patients receiving risedronate 5 mg daily (n=11) or placebo (n=8). In the risedronate-treated patients, the average mineralization (Avg-MIN) and peak mineralization (Peak-MIN) at 3 years were significantly increased from baseline by 4.7% (P<0.0001) and 5.4% (P=0.0003), respectively and showed significant negative correlation to turnover indices. In the placebo-treated patients, the increases in Avg-MIN (2.0%) and Peak-MIN (1.6%) were not significantly different from baseline and correlation to turnover indices was weaker. Risedronate significantly reduced the ratio of low- to high-mineralized bone fractions estimated by volume (BMR-V) and surface area (BMR-S) by 70.1% and 54.1%, respectively from baseline. These changes were consistent with the significant reduction of turnover from baseline assessed by reductions in mineralizing surface, MS/BS (-72.8%); activation frequency, Ac.F (-60.4%); and bone formation rate, BFR-BV (-63.6%) in the same biopsies in the risedronate-treated patients. Comparing the pair-wise changes from baseline, risedronate significantly reduced the low-mineralized bone fraction in comparison to placebo, as indicated by a larger reduction of BMR-V (P=0.015) and BMR-S (P=0.035). In the risedronate group, BMR-V and BMR-S showed significant positive correlation to MS/BS (R2: 0.83 and 0.92, respectively). The correlations to Ac.F and BFR-BV were also significant, with BMR-S showing a strong relation (R2: 0.77 and 0.79, respectively). The data suggest that BMR-V and BMR-S are markers of turnover of trabecular bone and may be used to assess treatment effect on turnover in bone biopsies. The results demonstrate that the reduction of turnover by risedronate increased the degree of mineralization and reduced the ratio of low- to high-mineralized bone fractions which may increase bone's resistance to fracture.

The deterioration of trabecular microarchitecture induced by elevated bone turnover is increasingly recognized as a factor in the pathogenesis of osteoporotic fractures. We investigated the effect of the reduction of turnover with risedronate on trabecular architecture in postmenopausal women with osteoporosis. Iliac crest bone biopsy specimens taken before and after 3 years of treatment from patients receiving risedronate 5 mg daily (n = 21) or placebo (n = 17) were analyzed using 3-D microcomputed tomography. We found a significant correlation between baseline bone turnover and bone loss in the placebo group, providing evidence that higher turnover induced higher bone loss leading to a greater degree of architectural degradation. When patients were classified into two groups based on baseline bone turnover (MS/BS less than or greater than the median value for the entire cohort), significant decreases in trabecular bone volume (BV/TV, P = 0.009) and trabecular thickness (Tb.Th*, P = 0.008) and an increase in marrow star volume (Ma.St.V, P = 0.008), a measure of trabecular porosity, were observed in the higher turnover (MS/BS> median) placebo-treated patients. The trabecular structure shifted from plates to rods as shown by an increase in structure model index (SMI, P = 0.028) and bone surface to bone volume ratio (BS/BV, P = 0.006). The changes from baseline in the lower turnover (MS/BS

Risedronate reduces the risk of vertebral fractures by up to 70% within the first year of treatment. Increases in bone mineral density or decreases in bone turnover markers explain only a portion of the anti-fracture effect, suggesting that other factors, such as changes in trabecular bone architecture, also play a role. Our objective was to determine the effects of risedronate on bone architecture by analyzing iliac crest bone biopsy specimens using three-dimensional microcomputed tomography (3-D micro CT). Biopsy specimens were obtained at baseline and after 1 year of treatment from women enrolled in a double-blind, placebo-controlled study of risedronate 5 mg daily for the prevention of early postmenopausal bone loss. Trabecular architecture deteriorated in the placebo group (n = 12), as indicated by a 20.3% decrease in bone volume (25.1% vs. 20.0%, P = 0.034), a 13.5% decrease in trabecular number (1.649 vs. 1.426 mm(-1), P = 0.052), a 13.1% increase in trabecular separation (605 vs. 684 microm, P = 0.056), and an 86.2% increase in marrow star volume (3.251 vs. 6.053 mm(3), P = 0.040) compared with baseline values. These changes in architectural parameters occurred in the presence of a concomitant decrease from baseline in lumbar spine bone mineral density (-3.3%, P = 0.002), as measured by dual energy x-ray absorptiometry. There was no statistically significant ( P < 0.05) deterioration in the risedronate-treated group (n = 14) over the 1-year treatment period. Comparing the actual changes between the two groups, the placebo group experienced decreases in bone volume (placebo, -5.1%; risedronate, +3.5%; P = 0.011), trabecular thickness (placebo, -20 microm; risedronate, +23 microm; P = 0.032), and trabecular number (placebo, -0.223 mm(-1); risedronate, +0.099 mm(-1); P = 0.010), and increases in percent plate (placebo, +2.79%; risedronate, -3.23%; P = 0.018), trabecular separation (placebo, +79 microm; risedronate, -46 microm; P = 0.010) and marrow star volume (placebo, +2.80 mm(3); risedronate, -2.08mm(3); P = 0.036), compared with the risedronate group. These data demonstrate that trabecular architecture deteriorated significantly in this cohort of early postmenopausal women, and that this deterioration was prevented by risedronate. Although there is no direct link in this study between fracture and preservation of architecture, it is reasonable to infer that the preservation of bone architecture may play a role in risedronate's anti-fracture efficacy.

Risedronate reduces the risk of new vertebral fractures up to 70% within 1 year of treatment in patients with osteoporosis. Both increases in bone mass and preservation of bone architecture are thought to contribute to antifracture effects. Our objectives were to determine the effects of risedronate on trabecular bone mass and architecture and to determine the relative contributions of mass and architecture to strength in the vertebra of ovariectomized (OVX) minipigs. The minipigs were OVX at 18 months of age and were treated daily for 18 months with either vehicle or risedronate at doses of 0.5 mg/kg per day or 2.5 mg/kg per day. The three-dimensional (3D) bone architecture of the L4 vertebral cores of Sinclair S1 minipigs was evaluated by 3D microcomputed tomography (muCT). Compared with the OVX control, the vertebral bone volume (bone volume/tissue volume [BV/TV]) was higher in both treated groups (p < 0.05). The architectural changes were more significant at the 2.5-mg/kg dose and were more prevalent at the cranial-caudal ends compared with the midsection. At the higher dose, the trabecular thickness (Tb.Th), trabecular number (Tb.N), and connectivity were higher, and marrow star volume (Ma.St.V) and trabecular separation (Tb.Sp) were lower (p < 0.05). The trabecular separation variation index (TSVI), a new measure to approximate structural variations, was smaller in the 2.5-mg/kg-treated group (p < 0.05). In this group, a significant preservation of trabeculae orthogonal to the cranial-caudal axis was confirmed by a decrease in the degree of anisotropy (DA) and an increase in the percent Cross-strut (% Cross-strut; p < 0.05). Both normalized maximum load (strength) and normalized stiffness of the same vertebral cores were higher in the 2.5-mg/kg risedronate group compared with the OVX group (p < 0.05). BV/TV alone could explain 76% of the variability of the bone strength. The combination of bone volume and architectural variables explained >90% of the strength. The study showed that risedronate preserved trabecular architecture in the vertebra of OVX minipigs, and that bone strength is tightly coupled to bone mass and architecture.

Aims: To optimize the nutritional and environmental conditions for growth of and poly-beta-hydroxybutyrate (PHB) accumulation in Bacillus mycoides RLJ B-017., Methods and Results: An isolate, identified as B. mycoides, was grown on different sources of carbon and nitrogen. Among these, sucrose, beef extract and di-ammonium sulphate were found to be the most suitable for growth and PHB accumulation. The overall maximum value of PHB (%) in cells, PHB yield (Yp/s) and productivities (Qp and qp) were 69.4 +/- 0.4% dry cell weight (DCW), 0.21 gp gS(-1), 0.104 +/- 0.012 gp l(-1) h(-1) and 0.03 gp gx(-1) h(-1), respectively when grown in a medium containing 20 gs l(-1) sucrose, supplemented with di-ammonium sulphate. The addition of beef extract increased the value of PHB (%) in cells, PHB yield and productivities by 17.58 +/- 0,3, 23.8, 19.23 +/- 0.3 and 13.8 +/- 0.2% , respectively. The overall maximum values of PHB (% DCW), PHB yield and productivities were obtained at pH 7.0 +/- 0 .1, temperature 30 +/- 0.5 degrees C, agitation 650 rev min(-1) and oxygen transfer rate 3.8 mmol O(2) l(-1) h(-1)., Conclusions: Sucrose, glucose and fructose were found to be more suitable for cell growth and PHB accumulation, but sucrose was less expensive than glucose. Among the nitrogen sources, beef extract and di-ammonium sulphate promoted PHB synthesis. The accumulation of PHB was observed to be growth associated., Significance and Impact of the Study: Gram-positive bacteria have not been reported to accumulate large amounts of polyhydroxyalkanoate and hence have not been considered as potent candidates for industrial production. A number of Bacillus spp. have been reported to accumulate 9-44.5% DCW PHB. By comparison, Bacillus RLJ B-017 contained 69.4 +/- 0.4% DCW PHB. Therefore, this strain has been considered as a potent organism for industrial interest. A relatively high yield of PHB was obtained in this wild strain and PHB synthesis was independent of nutrient limitation. The conditions for the higher PHB yield and productivity will be optimized in the next phase using fed-batch culture.

With the proportion of elderly people increasing in many countries, osteoporosis has become a growing public health problem, with rising medical, social, and economic consequences. It is well recognized that a combination of low bone mass and the deterioration of the trabecular architecture underlies osteoporotic fractures. A comprehensive understanding of the relationships between bone mass, the three-dimensional (3D) architecture of bone and bone function is fundamental to the study of new and existing therapies for osteoporosis. Detailed analysis of 3D trabecular architecture, using high-resolution digital imaging techniques such as magnetic resonance microimaging (MRmicroI), micro-computed tomography (microCT), and direct image analysis, has become feasible only recently. Rapid prototyping technology is used to replicate the complex trabecular architecture on a macroscopic scale for visual or biomechanical analysis. Further, a complete set of 3D image data provides a basis for finite element modeling (FEM) to predict mechanical properties. The goal of this paper is to describe how we can integrate three-dimensional microimaging and image analysis techniques for quantitation of trabecular bone architecture, FEM for virtual biomechanics, and rapid prototyping for enhanced visualization. The integration of these techniques provide us with an unique ability to investigate the role of bone architecture in osteoporotic fractures and to support the development of new therapies., (Copyright 2001 Wiley-Liss, Inc.)

Bacillus mycoides strain RIJ B-017, a growth-associated poly-3-hydroxybutyrate (PHB) producer was grown on sucrose-containing media. PHB accumulated in cells up to 72% of dry cell mass. The overall maximum value of PHB yield (Yp/s) and productivities (Qp and qp) 250 mgp/gs, 120 mgp L-1 h-1 and 30 mgp gx-1 h-1, respectively, were obtained at 15 g/L sucrose. Differential scanning calorimeter heating curve showed two peaks, one at 95.9 degrees C and another at 165.4 degrees C with a shoulder around 154.6 degrees C. The viscosity-average molar mass in chloroform at 27 degrees C was 505 kDa. The carbon content of PHB was 55.4% of the mass.

The study objective was to analyze the three-dimensional (3D) trabecular architecture and mechanical properties in vertebral specimens of young and mature Sinclair minipigs to assess the relative contribution of architecture to bone strength. We used 3D magnetic resonance microimaging (MRmicroI) and direct image analysis to evaluate a set of standard structural measurements and new architectural descriptors of trabecular bone in biopsy specimens from L2, L3, and L4 vertebrae (n = 16 in each group) from young (mean age, 1.2 years) and mature (mean age, 4.8 years) minipigs. The measurements included bone volume/tissue volume (BV/TV), marrow star volume (Ma.St.V), connectivity density (ConnD), and two new parameters, percent platelike trabeculae (% plate) and percent bone in the load direction (% boneLD). The % plate, calculated from surface curvature, allowed the delineation of plates from rods. The % boneLD quantified the percentage of bone oriented along the long axis of the vertebral body. We showed that 3D MRmicroI can detect the subtle changes in trabecular architecture between the two age groups. ConnD, star volume, % plate, % boneLD, and BV/TV were found to be more effective than the model-based, derived indices (trabecular thickness [Tb.Th], trabecular separation [Tb.Sp], and trabecular number [Tb.N]) in differentiating the structural changes. BV/TV, % plate, and % boneLD significantly increased (p < 0.05) in all three vertebral sites of the mature minipigs. The significant decrease in ConnD and star volume in the mature vertebra was consistent with the concurrent increase of platelike trabecular bone (p < 0.05). Overall, ConnD, star volume, % plate, and % boneLD provided a coherent picture of the architectural changes between the two age groups. Apparent modulus and maximum stress were determined experimentally on biopsy specimens from L2 vertebrae (n = 16). When apparent modulus was predicted using 3D MRmicroI data sets as input for finite element modeling (FEM), the results were similar to the experimentally determined apparent modulus (p = 0.12). Both methods were then used to compare the young and the mature animals; the experimental and predicted apparent modulus were significantly higher for the mature group (p = 0.003 and 0.012, respectively). The experimental maximum stress in the vertebra of the mature animals was twice as high as that for the young animals (p = 0.006). Bone quantity (BV/TV or bone mineral content [BMC]) alone could explain approximately 74-85% of the total variability in stress and modulus. The inclusion of either ConnD or % boneLD with BV/TV in a multiple regression analysis significantly improved the predictability of maximum stress, indicating that architecture makes additional contributions to compressive strength in normal minipig vertebra.

LC-NMR and LC-MS were applied to the characterization of six degradation products of a protease inhibitor, N-hydroxy-1,3-di-[4-ethoxybenzenesulphonyl]-5,5-dimethyl-[1,3]c yclohexyldiazine-2-carboxamide, in a dosage formulation. A reversed-phase HPLC method was developed for the separation of the parent compound and its six degradation products. LC-MS was then utilized to obtain the molecular weight and fragmentation information using an electrospray ionization (ESI) interface in the positive ion mode. LC-NMR was employed to acquire detailed structural information using a selective solvent suppression pulse sequence in the stop flow mode. This work demonstrated the usefulness of this integrated approach for the rapid and unambiguous identification of drug compounds and their degradation products in dosage formulations.

3-D bone architecture can now be measured by micro-computer tomography or micro-magnetic resonance imaging. The principles of the micro-computer technique is reviewed and new architectural parameters can be computed. In addition, the method allows the contruction of polymer models by stereolithography, a method that can be used to perform repetitive mechanical studies on the same bone sample. These non destructive methods are interesting in the pre-clinical studies on bone diseases and in the investigation of animal trials on new pharmacological compounds active on bone.