Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.

Dietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius. INTRODUCTION: The putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age. MATERIALS AND METHODS: Healthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables. RESULTS: Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049). CONCLUSIONS: These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.     

Complications associated with the Esophageal-Tracheal Combitube® in the pre-hospital setting

PURPOSE: The Esophageal-Tracheal Combitube (Combitube) is widely used for the management of the airway during cardiopulmonary resuscitation in the pre-hospital setting. Although serious complications have been reported with the Combitube, there is a paucity of data relative to the frequency and nature of such complications. The objective of this retrospective study was to determine the incidence and the nature of complications associated to the Combitube in the pre-hospital setting. METHODS: Since 1993, in the Quebec City Health Region, the basic life support treatment algorithm for emergency medical technicians has included the use of a Combitube as the primary airway device for management of all patients presenting with cardiac or respiratory arrest. The database of the emergency coordination services was searched for the period between 1993 and 2003 (2,981 patients). Only those patients who survived at least 12 hr were included. Medical records of these patients were reviewed to identify complications related to the use of the Combitube. RESULTS: Two-hundred-eighty (280) patients were identified. Fifty-eight (58) patients (20.7%, confidence interval (CI)95%=16.0%-25.4%) presented 69 complications: aspiration pneumonitis (n=31), pulmonary aspiration (n=16), pneumothorax (n=6), upper airway bleeding (n=4), esophageal laceration (n=3), sc emphysema (n=2), esophageal perforation and mediastinitis (n=2), tongue edema (n=2), vocal cord injury (n=1), tracheal injury (n=1), and pneumomediastinum (n=1). Thirteen of these complications (12 patients, 4.3%, CI95%=2.0%-6.3%) were judged as most likely resulting from trauma associated with insertion of the Combitube. CONCLUSION: The use of the Combitube in the pre-hospital setting is associated with a notable incidence of serious complications.     

Are nonresorbing osteoclasts sources of bone anabolic activity?

Some osteopetrotic mutations lead to low resorption, increased numbers of osteoclasts, and increased bone formation, whereas other osteopetrotic mutations lead to low resorption, low numbers of osteoclasts, and decreased bone formation. Elaborating on these findings, we discuss the possibility that osteoclasts are the source of anabolic signals for osteoblasts. In normal healthy individuals, bone formation is coupled to bone resorption in a tight equilibrium. When this delicate balance is disturbed, the net result is pathological situations, such as osteopetrosis or osteoporosis. Human osteopetrosis, caused by mutations in proteins involved in the acidification of the resorption lacuna (ClC-7 or the a3-V-ATPase), is characterized by decreased resorption in face of normal or even increased bone formation. Mouse mutations leading to ablation of osteoclasts (e.g., loss of macrophage-colony stimulating factor [M-CSF] or c-fos) lead to secondary negative effects on bone formation, in contrast to mutations where bone resorption is abrogated with sustained osteoclast numbers, such as the c-src mice. These data indicate a central role for osteoclasts, and not necessarily their resorptive activity, in the control of bone formation. In this review, we consider the balance between bone resorption and bone formation, reviewing novel data that have shown that this principle is more complex than originally thought. We highlight the distinct possibility that osteoclast function can be divided into two more or less separate functions, namely bone resorption and stimulation of bone formation. Finally, we describe the likely possibility that bone resorption can be attenuated pharmacologically without the undesirable reduction in bone formation.     

Oral administration of taurolidine ameliorates chronic DSS colitis in mice.

Taurolidine (TRD) has antimicrobial and anti-inflammatory properties. However, the anti-inflammatory effects of TRD in inflammatory bowel diseases (IBD) have not been investigated. Here, we have analyzed the toxicity of TRD after oral long-term application in mice and examined the impact of oral TRD in a dextran sulfate sodium (DSS) model of experimental colitis. Female C57/BL6 mice received TRD in various concentrations (0.1% to 0.4%) for 60 days. Toxicity was evaluated by use of a disease activity index (DAI) and histological examination of major metabolic organs. Furthermore, the impact of 0.2% TRD on a chronic DSS colitis was examined by daily DAI, histological crypt damage score (CDS), bacterial translocation into mesenteric lymph nodes (MLN), and colonic expression of tumor necrosis factor (TNF) alpha, transforming growth factor (TGF) beta, interleukin (IL)-1beta, IL-6, cytochrome oxidase (COX)-2, and monocyte chemotactic protein (MCP)-1 by real-time polymerase chain reaction (PCR). Oral TRD administration for 60 days was well tolerated by the animals and did not show any toxic effects in terms of DAI and histological changes. TRD treatment of DSS colitis led to increased survival of 100%, compared to 33% in the untreated colitis group (p < or = .005). Clinical amelioration was mirrored by significantly reduced DAI and CDS in the TRD treated colitis. Colonic cytokine expression and bacterial translocation into MLN showed no differences between both groups. We thus report for the first time that oral application of TRD results in amelioration of an experimental IBD model. We hypothesize direct intraluminal antimicrobial effects of TRD as well as anti-inflammatory effects during the acute phase of DSS colitis.     

Treatment of anxiety disorders in older adults: a meta-analytic comparison of behavioral and pharmacological interventions.

OBJECTIVE: To reduce the morbidity attributable to anxiety disorders in old age and to improve the quality of care, data on the effectiveness of current treatments are needed. METHODS: A comparative meta-analysis of 32 studies of treatments focused on anxiety disorders in older adults (N = 2,484) receiving behavioral interventions or pharmacotherapy was conducted. RESULTS: In separate analyses of the effects of interventions, stronger improvements of anxiety symptoms are found in pharmacotherapy than in behavioral interventions (d = 1.76 versus d = 0.81 SD units). This difference disappears when computing effect sizes that control for nonspecific change in the control group (d = 0.80 and d = 0.83 SD units) because effect sizes are greater in pill-placebo controls of pharmacological studies than in control groups (e.g., wait list) of behavioral interventions (d = 1.06 versus d = 0.10 SD units). Both interventions also yield moderate reductions in depressive symptoms (d = 0.59 versus d = 0.61 SD units), and dropout rates were comparable. CONCLUSIONS: Available pharmacotherapy and behavioral interventions are reasonably effective. Given the higher average treatment effects of pharmacological interventions, pharmacotherapy may be the first choice of treatment as long as medical conditions and patients' preferences do not preclude this form of treatment.     

Allopregnanolone produces hyperphagia by reducing neophobia without altering food palatability.

The neurosteroid allopregnanolone may increase feeding by altering food palatability; however, it may also increase feeding by reducing anxiety (neophobia). Moreover, it is unclear whether this induced hyperphagia is selective to safe, palatable foods only. Male rats were injected with allopregnanolone 20 min prior to behavioral testing. The taste reactivity test was used to examine possible shifts in the palatability of a 0.3 M sucrose solution. A lickometer was used to monitor intake and licking of either a sucrose or sucrose-quinine solution. Sucrose palatability was not enhanced; however, allopregnanolone significantly increased sucrose intake and licking on Test Day 1 when the solution was novel, but not on Test Day 2 when the solution was familiar. Sucrose-quinine intake was not enhanced. Allopregnanolone-induced hyperphagia is not a result of altered sucrose palatability, but rather reflects a reduction in the neophobia elicited by a novel solution; an effect that further seems to be selective to safe, palatable foods.     

Retention weighted recall improves discrimination of Alzheimer's disease.

Impaired recall for early items (primacy) and late items (recency) on word list recall tests are seen in Alzheimer's disease (AD). We compared conventional scoring on the Telephone Instrument for Cognitive Status (TICS) recall list with scorings based on retention-weighted recall (RWR: each item weighted by its serial position) in older adults participating in a community-based aging study. Subjects with mild AD (N=18) did not differ from those without dementia (N=231) with respect to recency (46% vs. 59%, p = 0.2), but had impaired primacy (2% vs. 39%, p < .001) on word recall on the TICS. RWR scoring improved the effect size (1.52 SD) compared to conventional scoring (1.08 SD). With a fixed sensitivity of 85%, specificity was lower using conventional scoring (56%) than RWR (76%) scoring. Our findings suggest that optimized RWR scoring of word list free recall can improve detection of mild AD compared to conventional scoring.     

Comparative expression profiling in primary and immortalized endothelial cells: changes in gene expression in response to hydroxy methylglutaryl-coenzyme A reductase inhibition.

Immortalized cell lines offer significant logistical advantages over primary cells when used for in-vitro studies. Immortalized cells may, however, exhibit important differences relative to their primary cell counterparts. In this study, microarrays were used to make a genome-wide comparison between primary human umbilical vein endothelial cells (HUVECs) and EA.hy926, an immortalized HUVEC cell line, in their baseline properties and in their response to inhibition of the mevalonate pathway with an inhibitor of hydroxy methylglutaryl-coenzyme A reductase (statin). HUVECs and EA.hy926 were incubated with control medium, atorvastatin, mevalonate, or a combination of atorvastatin and mevalonate for 24 h. Gene expression profiles were obtained in duplicates using Affymetrix Human Genome U133A 2.0 arrays (Santa Clara, California, USA). Probe-sets were selected according to the following criteria: a twofold or greater increase/decrease in atorvastatin-treated cells compared with untreated cells; a twofold or greater reversal of the effect of atorvastatin by combined treatment with atorvastatin and mevalonate; no significant change in gene expression in cells treated with mevalonate alone compared with untreated cells. Most genes that were expressed by untreated HUVECs, were also expressed by untreated EA.hy926 cells. EA.hy926 cells, however, constitutively expressed a large number of additional genes, many of which were related to cell cycle control and apoptosis. Atorvastatin induced differential expression (> or = twofold) of 103 genes in HUVECs (10 up, 93 down) and 466 genes in EA.hy926 cells (198 up, 268 down). Applying the above selection criteria, thrombomodulin and tissue plasminogen activator were up-regulated in both cell types, whereas, connective tissue growth factor, thrombospondin-1, and cysteine-rich angiogenic inducer 61 were down-regulated. In conclusion, EA.hy926 cells retain most of the characteristics of endothelial cells under baseline conditions as well as after treatment with atorvastatin. It is necessary, however, to carefully select and validate changes in genes that are the focus of studies when using EA.hy926 cells. While this cell line is highly useful in studies on some genes, including genes encoding molecules involved in regulating thrombohemorrhagic homeostasis, they appear to be less suited for studies focused on other genes, particularly those involved in the regulation of cell proliferation and apoptosis.