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In Switzerland, the COVID-19 incidence during the first pandemic wave was high. Our aim was to assess the association of the outbreak with acute stroke care in Switzerland in spring 2020. This was a retrospective analysis based on the Swiss Stroke Registry, which includes consecutive patients with acute cerebrovascular events admitted to Swiss Stroke Units and Stroke Centers. A linear model was fitted to the weekly admission from 2018 and 2019 and was used to quantify deviations from the expected weekly admissions from 13 March to 26 April 2020 (the "lockdown period"). Characteristics and 3-month outcome of patients admitted during the lockdown period were compared with patients admitted during the same calendar period of 2018 and 2019. In all, 28,310 patients admitted between 1 January 2018 and 26 April 2020 were included. Of these, 4491 (15.9%) were admitted in the periods March 13-April 26 of the years 2018-2020. During the lockdown in 2020, the weekly admissions dropped by up to 22% compared to rates expected from 2018 and 2019. During three consecutive weeks, weekly admissions fell below the 5% quantile (likelihood 0.38%). The proportion of intracerebral hemorrhage amongst all registered admissions increased from 7.1% to 9.3% (p = 0.006), and numerically less severe strokes were observed (median National Institutes of Health Stroke Scale from 3 to 2, p = 0.07). Admissions and clinical severity of acute cerebrovascular events decreased substantially during the lockdown in Switzerland. Delivery and quality of acute stroke care were maintained.

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naive postmenopausal women with low bone mass, romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L1 vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L1 and L2 entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p

Previously, we reported the effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone formation based on biochemical markers and bone histomorphometry of the cancellous envelope at month 6 in postmenopausal women with osteoporosis who participated in the 12-month primary Skeletal Histomorphometry in Subjects on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study. Patients were eligible to enter a 12-month extension on their original treatment regimen: TPTD 20 μg/day (s.c. injection) or ZOL 5 mg/year (i.v. infusion). A second biopsy was performed at month 24. Here we report longitudinal changes between and within each treatment group in the cancellous, endocortical, intracortical, and periosteal bone envelopes in patients with evaluable biopsies at months 6 and 24 (paired data set: TPTD, n = 10; ZOL, n = 9). Between-group differences are also reported in the larger set of patients with evaluable biopsies at month 6 (TPTD, n = 28; ZOL, n = 30). Data from the cancellous envelope at month 6 or month 24 provided a reference to compare differences across envelopes within each treatment group. The 24-month results extend our earlier report that TPTD and ZOL possess different tissue-level mechanisms of action. Moreover, these differences persisted for at least 2 years in all four bone envelopes. Few longitudinal differences were observed within or across bone envelopes in ZOL-treated patients, suggesting that the low bone formation indices at month 6 persisted to month 24. Conversely, the magnitude of the effect of TPTD on bone formation varied across individual envelopes: median values for mineralizing surface (MS/BS) and bone formation rate (BFR/BS) at month 6 were approximately 3-fold to 5-fold higher in the endocortical and intracortical envelopes compared to the cancellous envelope. Although MS/BS and BFR/BS declined in these envelopes at month 24, median values continued to exceed, or were not significantly different from, those in the cancellous envelope. This study demonstrates for the first time that bone formation indices are higher with TPTD treatment than with ZOL in all four bone envelopes and the difference persists for at least 2 years. Moreover, the magnitude of the effect of TPTD in cortical bone remains robust at 24 months. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.

Denosumab reduced bone resorption, increased bone mineral density (BMD), and decreased new vertebral, hip, and nonvertebral fracture risk in postmenopausal women with osteoporosis in the FREEDOM trial. Consistent with its mechanism of action, transiliac crest bone biopsies from subjects treated with denosumab for 1 to 3 years demonstrated reduced bone turnover that was reversible upon treatment cessation. Long-term denosumab treatment for up to 6 years in the FREEDOM extension provides sustained bone turnover reduction and continued low fracture incidence. Here, we evaluate 5 years of denosumab treatment on bone remodeling at the tissue level. Transiliac crest bone biopsies were obtained from 41 subjects (13 cross-over and 28 long-term from the FREEDOM placebo and denosumab groups, respectively) at year 2 of the FREEDOM extension, representing up to 5 years of denosumab treatment. Demographics for this subset were comparable to the overall extension cohort. The mean (SD) duration from the last denosumab dose to the first dose of tetracycline was 5.7 (0.5) months. Qualitative bone histology assessed in all biopsy samples was unremarkable, showing normally mineralized lamellar bone. Structural indices, including trabecular bone volume, number, and surface, were similar between cross-over and long-term groups. Bone resorption was decreased as reflected by eroded surface in cross-over and long-term subjects. A total of 11 of 13 (85%) cross-over subjects and 20 of 28 (71%) long-term subjects had specimens with double or single tetracycline label in trabecular and/or cortical compartments; specimens from 5 cross-over subjects and 10 long-term subjects were evaluable for dynamic trabecular bone parameters. Dynamic remodeling indices were low for both groups and consistent with reduced bone turnover with denosumab. In conclusion, denosumab treatment through 5 years resulted in normal bone quality with reduced bone turnover. These observations are consistent with its mechanism of action and associated with continued BMD increases and low fracture incidence.

Objectives To perform an updated meta-analysis comparing biodegradable polymer drug eluting stents (BP-DES) and durable polymer drug eluting stents (DP-DES). Background BP-DES have been suggested to reduce late stent thrombosis (LST) rates as compared to first generation DP-DES. Recently, second generation DP-DES have replaced older DES, but comparison of these stents with BP-DES has not yielded consistent results. Methods Medline/Web databases were searched for studies comparing BP-DES and DP-DES, and reporting rates of overall/cardiac mortality, myocardial infarction (MI), LST, target lesion revascularization (TLR) and target vessel revascularization (TVR) and late lumen loss (LLL), with a follow-up ≥6 months. Results Twenty studies (20,005 patients) were included in the meta-analysis. Median follow-up time was 1 year. Compared with DP-DES, BP-DES showed lower LLL (in stent: weighted mean difference WMD −0.45 mm, 95% CI −0.66 to −0.24 mm, P = 0.00001; in segment: WMD −0.15 mm, 95% CI = −0.24 to −0.06 mm, P = 0.001) and lower rates of LST (OR 0.51, 95% CI = 0.30 to 0.86, P = 0.01), although they did not improve mortality, MI, TLR, and TVR rates. BP-DES coated with sirolimus or novolimus, in comparison with biolimus or paclitaxel, were associated with reduced LLL (P

Microwave (MW) irradiation allows to prepare a mini-library of pyridophenoxazinone derivatives, that are crucial intermediates in the synthesis of new antiproliferative compounds, active for human lymphoma/leukemia. The optimized procedure, consisting of a continuous input power of 50 W (80 °C) and a reaction time of 30 min, leads in very satisfactory yields to both regioisomers 5H-pyrido[2,3-a]phenoxazin-5-ones and isomeric 5H-pyrido[3,2-a]phenoxazin-5-ones, starting from readily available quinoline-5,8-dione and substituted 2-aminophenols (APhOHs). Broad functional group tolerance was observed. The availability of derivatives carrying a carboxyl group at the C-9 and C-10 positions enables the synthesis of a new family of 5H-pyridophenoxazin-5-one conjugates that were shown to exhibit good anti-cancer activity.

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. © 2012 American Society for Bone and Mineral Research.

Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not < -4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95% CI: 39%-66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95% CI: 24% - >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab. Copyright © 2012 American Society for Bone and Mineral Research. Fil: Austin, Matthew. Amgen Incorporated; Estados Unidos Fil: Yang, Yu Ching. Amgen Incorporated; Estados Unidos Fil: Vittinghoff, Eric. University of California; Estados Unidos Fil: Adami, Silvano. Universita di Verona; Italia Fil: Boonen, Steven. Katholikie Universiteit Leuven; Bélgica Fil: Bauer, Douglas C. University of California; Estados Unidos Fil: Bianchi, Gerolamo. Azienda Sanitaria Genovese; Italia Fil: Bolognese, Michael A.. Bethesda Health Research Center; Estados Unidos Fil: Christiansen, Claus Bohn. Center For Clinical And Basic Research As; Estados Unidos Fil: Eastell, Richard. University Of Sheffield; Reino Unido Fil: Grauer, Andreas. Amgen Incorporated; Estados Unidos Fil: Hawkins, Federico. Hospital Universitario 12 de Octubre; España Fil: Kendler, David L.. University of British Columbia; Canadá Fil: Oliveri, María Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: McClung, Michael R.. Oregon Osteoporosis Center; Estados Unidos Fil: Reid, Ian R.. The University of Auckland; Nueva Zelanda Fil: Siris, Ethel S.. Columbia University; Estados Unidos Fil: Zanchetta, Jose. Universidad del Salvador; Argentina Fil: Zerbini, Cristiano A.F.. Centro Paulista de Investigação Clinica; Brasil Fil: Libanati, Cesar. Amgen Incorporated; Estados Unidos Fil: Cummings, Steven R.. University of California; Estados Unidos

BACKGROUND: The present article reports the anthocyanin content in the berry skin and wine of the Italian red grape cultivar Aglianico (clone VCR11 grafted onto 1103 Paulsen), one of the most ancient vines and famous for its deep-red colour. Anthocyanins were extracted from frozen berry skin in an acidified methanol solution. The extraction mixtures, monitored for 120 h, were analysed by high-performance liquid chromatography. RESULTS: The extraction from berry skin of delphinidin, petunidin and malvidin appeared to be a time-independent process, whereas the concentration of peonidin increased linearly with time. Peonidin-O-acetyl-glucoside was transferred from skin moreslowlythanpetunidin-O-acetyl-glucosideandmalvidin-O-acetyl-glucoside.Theanthocyanincompositionoftheresulting wine showed that the total anthocyanin content was about one-tenth of the corresponding berry skin content. The ratio acetyl/coumaroyl anthocyanins in the wine was sharply higher than the value in berry skin (0.85 and 0.10, respectively), indicating an enrichment of acetyl derivatives in the wine. CONCLUSION: Levels of single anthocyanins in wine were not always correlated with those detected in grapes, as they were affected by winemaking. The high values of some anthocyanins in Aglianico wine could ameliorate its quality, increasing the chromatic properties, aging stability and product acceptance. c � 2011 Society of Chemical Industry

Objectives: The aim of the present study was to evaluate the anti-Streptococcus mutans activity of Hyptis pectinata essential oil, and present its promising potential against oral diseases. Materials and methods: The essential oil of H. pectinata was obtained by hydrodistillation from dried leaves and analyzed by GC / MS. The effectiveness of this essential oil regarding the antimicrobial activity against several S. mutans strains was investigated by the agar diffusion and microdilution methods, and chlorohexidine was used as a standard control. Results: The H. pectinata essential oil exhibited considerable inhibitory effect against either all the clinical isolates obtained from patients’ saliva or the ATCC strains tested, with minimum inhibitory and bactericidal concentrations of 200 μg ml−1. The study also compared the efficiency of the emulsifying agents Tween 20, Tween 80, dimethyl sulfoxide and propylene glycol in H. pectinata essential oil when tested against S. mutans. The data obtained confirmed the better inhibitory effect of the oil when using all tested diluents, although Tween 80 seemed to be more suitable for emulsification. Conclusion: According to our results, H. pectinata essential oil can be considered a promising alternative to chlorhexidine for the control of oral bacteria-related diseases and hygiene.

Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo-controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women. Introduction: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD. Materials and Methods: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of −1.8 to −4.0 or femoral neck/total hip T-scores of −1.8 to −3.5 were randomly assigned to receive double-blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety. Results: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and ≥60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment. Conclusions: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo.

Objectives— To describe a cranioplasty procedure used in conjunction with foramen magnum decompression (FMD) for the treatment of canine caudal occipital malformation syndrome (COMS), and to evaluate the clinical outcome. Study Design— Prospective clinical study. Animals— Dogs (n=21) with COMS diagnosed by magnetic resonance imaging (MRI). Methods— After FMD, titanium screws were placed around the perimeter of the foramen magnum defect and a skull plate fashioned from titanium mesh and polymethylmethacrylate was attached to the back of the skull, using the titanium screws as anchor posts. Follow-up was obtained by direct examination by the authors, telephone interviews with owners and referring veterinarians, and a questionnaire sent to owners of surviving dogs designed to assign objective measures of response to surgical intervention. Surgical success was defined as improvement in ≥1 aspects of clinical dysfunction (e.g. scratching, pain) postoperatively. Owner-assigned pre- and postoperative quality-of-life (QOL) scores (1–5) for surviving dogs were compared using a Wilcoxon's signed rank test for paired data (P≤.05). Results— No intraoperative complications occurred and postoperative complications were limited to transient worsening of a pre-existing head tilt and ataxia in 1 dog, and the need for oral pain medication for 1–4 weeks in 3 dogs. Seventeen dogs (81%) had clinical improvement after surgery. Although clinical signs resolved in 1 dog, it died after being hit by a car, 5 months after surgery. One dog had no change in clinical signs; this patient's clinical signs were not severe and the owners had opted for surgery primarily to prevent progression of disease. Two dogs were euthanatized; 1 because of no improvement of severe clinical signs, and 1 because of sustained recurrence of apparent head and neck pain 7 months later. One dog required a dorsal laminectomy at a second site (C1/C2 vertebral level), 2 months later. Four dogs has transient “flare-ups” of apparent head/neck pain 2–13 months later; all resolved with transient re-institution of oral analgesic therapy. Further surgery at the FMD was not needed. Based on the returned questionnaires, there was an overall significant improvement in QOL scores. Conclusions— FMD with cranioplasty was well tolerated, with no intraoperative complications, and minor postoperative complications. Most dogs improved clinically, and none required further surgery at the original FMD site. Clinical Relevance— FMD with cranioplasty may be an effective surgical method of treating dogs with COMS and is well tolerated. Based on prior reports of FMD for this disorder, it appears that cranioplasty may reduce the rate of surgical failure caused by formation of compressive scar tissue at the FMD site in the short term. Results of this preliminary study support further evaluation of the cranioplasty procedure in a larger group of dogs over a more extended follow-up period.

BACKGROUND: Single median maxillary central incisor (SMMCI) is a rare anomaly that may occur alone or associated with other conditions, frequently as part of the holoprosencephaly (HPE) spectrum. However, it has been suggested that SMMCI alone, or associated with some midline defects, may be considered a different entity from HPE (OMIM: 147250). Families with SMMCI, without HPE cases, are difficult to counsel for the risk of HPE in future generations because the same midline defects described as part of the “SMMCI syndrome” can also be part of the HPE spectrum. METHODS: We screened five cases of SMMCI for mutations in three HPE genes, SHH, TGIF, and SIX3. RESULTS: A missense mutation c.686C>T was found in the gene SIX3 of one patient, which did not differ from the accepted 20% of known HPE gene mutations among all HPE cases. Our results and an extensive literature review of gene mutations in patients with SMMCI showed that 27/28 of them were in HPE genes: SHH (n = 21), SIX3 (n = 3), TGIF (n = 1), GLI2 (n = 1), and PTCH (n = 1), and only one in the SALL4 gene. CONCLUSIONS: The clinical findings in patients with SMMCI without HPE in families with mutations in HPE genes cannot be distinguished from the findings reported in the SMMCI syndrome. Therefore, persons with SMMCI and their relatives should be carefully investigated for related midline disorders, especially of the HPE spectrum, and all known HPE genes screened. Birth Defects Research (Part A), 2007. © 2007 Wiley-Liss, Inc.

AIMS: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. METHODS AND RESULTS: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. CONCLUSION: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity. Fil: McMurray, John J. V.. University of Glasgow; Reino Unido Fil: Anand, Inder S.. University of Minnesota; Estados Unidos Fil: Diaz, Rafael. Estudios Clínicos Latinoamérica; Argentina Fil: Maggioni, Aldo P.. Associazione Nazionale Medici Cardiologi Ospedalieri; Italia Fil: O'Connor, Christopher. University of Duke; Estados Unidos Fil: Pfeffer, Marc A.. Brigham and Women’s Hospita; Estados Unidos Fil: Solomon, Scott D.. Brigham and Women’s Hospital; Estados Unidos Fil: Tendera, Micha. Medical University of Silesia; Polonia Fil: van Veldhuisen, Dirk J.. University of Groningen; Países Bajos Fil: Moetaz, Albizem. Amgen Inc.; Estados Unidos Fil: Cheng, Sunfa. Amgen Inc.; Estados Unidos Fil: Scarlata, Debra. Amgen Inc.; Estados Unidos Fil: Swedberg, Karl. University of Gothenburg; Suecia Fil: Young, James B.. Cleveland Clinic. Endocrinology and Metabolism Institute; Estados Unidos Fil: Toblli, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: RED-HF Committees Investigators. No especifíca

Objective Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. Methods In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55–80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2−L4] bone mineral density [BMD] T score less than −2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. Results At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. Conclusion As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.

Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.

Background: Highly selective inhibitors of the inducible cyclooxygenase-2 enzyme (coxibs) have been associated with less gastrotoxicity than nonselective NSAIDs in clinical studies. Aim: To evaluate the influence of risk factors for NSAID-induced gastrotoxicity on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen. Methods: We analysed pooled data from two identical double-blind, randomized, 12-week endoscopy studies which compared the gastroduodenal toxicity of placebo (n=371), rofecoxib 25 mg (n=390), rofecoxib 50 mg (n=379), and ibuprofen 2400 mg daily (n=376) in patients with osteoarthritis. The potential risk factors evaluated were: age (

Some clinical trials aim to demonstrate therapeutic equivalence on multiple primary endpoints. For example, therapeutic equivalence studies of agents for the treatment of osteoarthritis use several primary endpoints including investigator's global assessment of disease activity, patient's global assessment of response to therapy, and pain. In this paper, thoughts on simultaneous equivalence assessment on three endpoints are presented. As pointed out by Berger and Hsu (1996), the conventional intersection-union test can be conservative. Simulation and computation are conducted to provide an insight on the conservativeness. We also provide a method to lower the confidence level and at the same time maintain the type I error when endpoints have normal distributions and are independent. If, in a particular analysis, the goal is to demonstrate equivalence on as many endpoints as possible, a step-up procedure can be used for selecting those endpoints for which equivalence may be demonstrated. This step-up procedure at the same time controls experimentwise error rate. The techniques are illustrated by a data example.

The Carbostent is a new balloon-expandable, stainless steel, tubular stent with innovative multicellular design and unique turbostratic carbon coating. The aim of this study was to assess clinical and angiographic outcomes after Carbostent implantation in 112 patients poorly suitable for an effective treatment with stenting because of the high risk of thrombosis, late restenosis, and clinical target vessel failure. The inclusion criteria were age > 75 years, diabetes mellitus, a lesion length > 10 mm, a reference vessel diameter < 3.0 mm, an ostial location of the target lesion, and chronic total occlusion. Overall, a total of 175 stents ranging from 9 to 25 mm in length were placed in 147 lesions. There were no stenting attempt failures. The acute gain after stent implantation was 2.46 ± 0.51 mm, and the residual stenosis 0 ± 4%. No stent thrombosis occurred, nor myocardial infarction. The 6-month event-free survival rate was 74% ± 5%. The 6-month angiographic follow-up showed a late loss of 0.81 ± 0.88 mm and a binary (≥ 50%) restenosis rate of 25%. The results of this study suggest that the Carbostent may be highly effective in patients at high risk of restenosis and target vessel failure. Cathet Cardiovasc Intervent 2001;54:420–426. © 2001 Wiley-Liss, Inc.

Intravascular ultrasound studies have shown that additional stent implantation is the only percutaneous technique that allows for recovery of all the lumen area of the original implantation procedure. Despite this theoretical advantage, information on systematic additional stent implantation is still forthcoming, especially concerning the impact of new stent designs. This prospective study evaluated the efficacy of routine additional stent implantation for treatment of in-stent restenosis in 68 consecutive patients. Repeat stenting was successful in all cases, and second-generation tubular stents were used in 84% of patients. The mean additional stent length was 19.2 ± 9.4 mm, and 15% of patients had multiple stent implantation. The postprocedure minimum lumen diameter was 3.11 ± 0.41 mm, and the percentage residual stenosis was 2% ± 7%. At a mean clinical follow-up of 10 ± 8 months (follow-up rate 100%), the incidence of major adverse events was 21% (1 death, 13 target vessel revascularizations). Overall, angiographic restenosis rate was 32% (angiographic follow-up rate 79%). By multivariate analysis, the only predictors of recurrence after additional stenting were unstable angina at the second procedure (OR 8.70, 95% CI 1.50–50.33, P = 0.019), and early clinical recurrence after the first stent procedure (OR 4.83, 95% CI 1.13–20.71, P = 0.038). Additional stenting is a safe and effective treatment modality for the majority of patients with in-stent restenosis. Alternative treatments should be considered only for patients with in-stent restenosis presenting as unstable angina or early recurrence after a first stent procedure. Cathet. Cardiovasc. Intervent. 49:376–381, 2000. © 2000 Wiley-Liss, Inc.

Most randomized trials comparing primary stenting with primary coronary angioplasty (PTCA) excluded patients at high risk from enrollment, thus arising the important question about the generalizability of the randomized trial results to all patients with AMI. The aim of this study was to assess the feasibility and effectiveness of a primary infarct-related artery (IRA) stenting strategy using a second-generation tubular stent in nonselected patients with acute myocardial infarction (AMI). All patients with AMI were considered eligible for primary IRA stenting. No restriction was made based on age or clinical status on presentation, or coronary anatomy, except in cases of a reference IRA diameter < 2.5 mm. The primary endpoint of the study was clinical target vessel failure defined as death, reinfarction, or repeat TVR due to restenosis or reocclusion of the IRA. Between June 1998 and March 1999, 201 consecutive patients with AMI underwent mechanical recanalization of the IRA. The mean age was 64 ± 12, and 16% of patients were aged 75 years or over. The incidence of shock was 9%. Primary IRA stenting was performed in 89% of the patients. Patients who underwent PTCA alone had a smaller IRA diameter as compared to patients with a stented IRA (2.48 ± 0.46 mm vs. 3.15 ± 0.37 mm; P < 0.001). There were no stent deployment failures. The 6-month primary endpoint rate was 15% (2 deaths, 27 repeat TVR, 0 reinfarctions), while the 6-month angiographic restenosis rate was 22%. Primary IRA stenting in nonselected patients with AMI is highly feasible and associated with favorable clinical and angiographic outcomes. Cathet. Cardiovasc. Intervent. 51:273–279, 2000. © 2000 Wiley-Liss, Inc.

Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin-like growth factor I (IGF-I). We determined the effect of chronic administration of the GH secretagogue, MK-677, on serum IGF-I and markers of bone turnover in 187 elderly adults (65 years or older) enrolled in three randomized, double-blind, placebo-controlled clinical studies lasting 2–9 weeks. Urine was collected for determination of N-telopeptide cross-links (NTXs), a marker of bone resorption, and blood was collected for determination of serum osteocalcin and bone-specific alkaline phosphatase (BSAP), as bone formation markers, and serum IGF-I levels pre- and post-treatment. Dose response data were initially obtained in healthy elderly subjects who received oral doses of 10 mg or 25 mg of MK-677 or placebo for 2 weeks (n = 10–12/group). Treatment with 10 mg and 25 mg of MK-677 for 2 weeks increased mean urine NTXs 10% and 17%, respectively (p < 0.05 vs. placebo). Additionally, 50 healthy elderly subjects received either placebo (n = 20) for 4 weeks or 25 mg of MK-677 (n = 30) daily for 2 weeks followed by 50 mg daily for 2 weeks. MK-677 increased mean serum osteocalcin by 8% (p < 0.05 vs. placebo). In both studies, MK-677 increased serum IGF-I levels significantly (55–94%). Subsequently, the biological effects of MK-677 were studied in 105 elderly subjects who met objective criteria for functional impairment. Subjects were randomized to receive oral doses of placebo for 9 weeks or either 5, 10, or 25 mg of MK-677 daily for an initial 2 weeks followed by 25 mg of MK-677 daily for the next 7 weeks(n = 63 on MK-677 and n = 28 on placebo completed 9 weeks of therapy). Treatment with MK-677 (all MK-677 groups combined) for 9 weeks increased mean serum osteocalcin by 29.4% and BSAP by 10.4% (p < 0.001 vs. placebo) and mean urinary NTX excretion by 22.6% (p < 0.05 vs. placebo). The change from baseline serum osteocalcin correlated with the change from baseline serum IGF-I in the MK-677 group (r = 0.37; p < 0.01). In conclusion, once daily dosing with MK-677, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.

Background : Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxy- genase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. Aim : To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. Methods Healthy subjects (n = 170; age range 18–54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score ≥ 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. Results The percentage of subjects who developed a mucosal score ≥ 2 in the MK-0966 group (12%) was significantly lower (P

CD23, the low-affinity IgE receptor, is up-regulated on interleukin (IL)-4-stimulated B cells and monocytes, with a concomitant increase in the release of soluble fragments of CD23 (sCD23) into the medium by proteolytic processing of the surface-bound intact CD23. The effect of inhibition of the processing of CD23 on IgE production in human and mouse cells and in a mouse model in vivo was evaluated. CD23 processing to sCD23 from RPMI 8866 (a human Epstein-Barr virus-transformed B cell line) cell membranes was inhibited by a broad-spectrum matrix-metalloprotease inhibitor, batimastat, with an IC50 of 0.15 microM. Batimastat also inhibited CD23 processing in whole RPMI 8866 cells as well as in IL-4-stimulated purified human monocytes with similar IC50. Batimastat inhibited IgE production from IL-4/anti-CD40-stimulated human tonsil B cells as well as mouse splenic B cells in a manner consistent with inhibition of CD23 processing. Release of soluble fragments of CD23 in the cell supernatants of tonsil B cells was inhibited over the concentration range of 1-10 microM batimastat and intact cell surface CD23 was increased on mouse splenic B cells in the presence of these concentrations of batimastat. IgE production of IL-4-stimulated human peripheral blood mononuclear cells was also blocked by 1-10 microM batimastat, again with comparable inhibition of sCD23 release over the same concentration range. Finally, in a mouse model of IgE production, batimastat inhibited IgE production in response to ovalbumin challenge as determined by serum IgE levels. Taken together, the data support a role of CD23 in IgE production and point to CD23 processing to sCD23 as a therapeutically relevant control point in the regulation of IgE synthesis.

The effects of urinary symptoms on health-related quality of life (HRQL) are important in therapeutic decision making. Few have evaluated the treatment effects on HRQL in men with benign prostatic hyperplasia (BPH), even though increased urinary symptoms are associated with greater worry, bother, and interference with living activities. We report on patient assessments of such disease-specific measures as well as general HRQL measures from two placebo-controlled clinical trials of finasteride in the treatment of symptomatic BPH. Patients treated with finasteride appeared to have greater improvement than placebo-treated patients in disease-specific measures and in patient global assessment. The treated group appeared to have a greater mean increase in sexual domain scores. As expected, general measures (health rating, life satisfaction, ladder of life) changed little. Thus, treatment with finasteride appears to reduce bother, worry, and activity interference due to symptoms but in a small percentage of men may lead to slightly reduced sexual function.

1. Cultured elicited-peritoneal macrophages release a soluble type II 14 kDa phospholipase A2 (PLA2) over time, reaching a plateau by 20-24 h of incubation and maintaining these levels over 72 h. Prostaglandin E2 (PGE2) is also produced but does not plateau until 48-72 h. 2. Transforming growth factor beta 1 (TGF beta 1) reduces cellular 14 kDa PLA2 and its subsequent release by approximately half, but does not alter PGE2 production. Co-incubation of TGF beta 1 with indomethacin interfered, in a concentration-dependent manner, with the ability of TGF beta 1 to reduce cellular 14 kDa PLA2 and its subsequent release over 24 h. The regulation of TGF beta 1 was not specific to indomethacin since other non-steroidal anti-inflammatory drugs had the same effect. This suggested that cyclooxygenase activity was essential for TGF beta 1 to exert its effect and indeed, the addition of exogenous PGE2 restored the TGF beta 1 action. 3. PGE2 alone exerted a concentration-dependent negative feedback action on elicited-macrophage 14 kDa PLA2 release. The inhibitory concentration (IC50 = approximately 180 ng PGE2 ml-1) approximated the PGE2 levels measured in the 24 h macrophage conditioned media (85-140 ng PGE2 ml-1) where PLA2 release began to plateau. Further, incubation of cells with indomethacin over 48 h resulted in the enhancement of 14 kDa PLA2 activity compared to that released from untreated cells. Forskolin failed to inhibit 14 kDa PLA2 release, suggesting PGE2 was not acting through an increase in adenylate cyclase. 4. Taken together, the data are consistent with the immunosuppressive aspects reported for both mediators during inflammation and demonstrates the requirement of PGE2 for TGF beta 1 action on the elicited macrophage.