Effects of ultra-low-dose estrogen therapy on muscle and physical function in older women

OBJECTIVES: To determine the effects of ultra-low-dose hormone therapy on muscle mass and physical function in community-dwelling women. DESIGN: Double-blind, placebo-controlled trial. SETTING: Clinical research center in Connecticut. PARTICIPANTS: Healthy, community-dwelling women aged 65 and older (n=167). INTERVENTION: Eligible women were randomly assigned to treatment with 0.25 mg 17-beta estradiol or placebo for 36 months. All women (estradiol or placebo) with an intact uterus received micronized progesterone 100 mg/d for 2 weeks every 6 months. All participants received 1,300 mg elemental calcium with 1,000 IU vitamin D per day. MEASUREMENTS: Appendicular skeletal muscle mass (ASM), lean body mass (LBM), and percentage body fat were measured using dual x-ray absorptiometry. Sarcopenia was defined as skeletal muscle mass (ASM/height2) 2 standard deviations or less than young, healthy reference population mean. Physical activity (Physical Activity Scale in the Elderly (PASE)) and performance were measured. Serum estrone, estradiol, and sex hormone-binding globulin were measured. RESULTS: The prevalence of sarcopenia at baseline was 13%. There were no baseline differences between groups except for PASE score and chair rise time, in which the estrogen group had better performance. No changes in ASM, LBM, percentage of body fat, or physical performance were found after 3 years of estrogen therapy. CONCLUSION: Sarcopenia was present in 13% of this group of community-dwelling, postmenopausal older women. Ultra-low-dose estrogen therapy neither improves nor harms ASM. Similarly, no changes in body fat or physical performance were detected.     

Osteoporosis. Pathogenesis, diagnosis, and treatment in older adults

Osteoporosis is a major cause of disability and excess mortality in older men and women. Hip fracture incidence accelerates approximately 10 years after menopause in women and after age 70 in men. Approximately 1 million Americans suffer fragility fractures each year at a cost of over 14 billion dollars. The disability, mortality, and cost of hip and vertebral fractures are substantial in the rapidly growing, aging population so that prevention of osteoporosis is a major public health concern. BMD is used to make the diagnosis of osteoporosis before incident fracture and predict fracture risk. Recommendations for treatment and prevention of osteoporosis based on BMD score have been published by the World Health Organization and the National Osteoporosis Foundation. In a process that continues throughout life, bone repairs itself by the coupled action of bone resorption followed by bone formation, sometimes referred to as bone turnover. Osteoblasts and osteoclasts are the primary cells involved in bone formation and resorption, respectively. The process of bone turnover is regulated by hormones, such as PIH and local factors such as IL-1 and prostaglandins. Following attainment of peak bone mass at age 25, bone loss begins, accelerates in women at menopause and slows again but continues into advanced years at a rate of 1% to 2% per year, similar to premenopausal bone loss rate. The leading theories of the mechanism of bone loss in older individuals is calcium deficiency leading to secondary hyperparathyroidism and sex hormone deficiency. Risk factors such as age, gender, ethnic background, smoking, exercise, and nutrition, and medical conditions associated with osteoporosis should be evaluated and modified when possible to prevent further bone loss. Osteoporosis treatment and prevention include weight-bearing exercise, calcium and vitamin D supplementation, estrogen replacement, bisphosphonates, selective estrogen receptor antagonists, and calcitonin. Although there is no currently approved treatment for osteoporosis in men, many of the treatments approved for osteoporosis in women hold promise to be beneficial in men.     

Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+Thy-1+Lin- primitive progenitor cells

Thrombopoietin (TPO) or MpI ligand is known to stimulate megakaryocyte (MK) proliferation and differentiation. To identify the earliest human hematopoietic cells on which TPO acts, we cultured single CD34+Thy- 1+Lin- adult bone marrow cells in the presence of TPO alone, with TPO and interleukin-3 (IL-3), or with TPO and c-kit ligand (KL) in the presence of a murine stromal cell line (Sys1). Two distinct growth morphologies were observed: expansion of up to 200 blast cells with subsequent differentiation to large refractile CD41b+ MKs within 3 weeks or expansion to 200-10,000 blast cells, up to 25% of which expressed CD34. The latter blast cell expansions occurred over a 3- to 6-week period without obvious MK differentiation. Morphological staining, analysis of surface marker expression, and colony formation analysis revealed that these populations consisted predominantly of cells committed to the myelomonocytic lineage. The addition of IL-3 to TPO-containing cultures increased the extent of proliferation of single cells, whereas addition of KL increased the percentage of CD34+ cells among the expanding cell populations. Production of multiple colony- forming unit-MK from single CD34+Thy-1+Lin- cells in the presence of TPO was also demonstrated. In limiting dilution assays of CD34+Lin- cells, TPO was found to increase the size and frequency of cobblestone areas at 4 weeks in stromal cultures in the presence of leukemia inhibitory factor and IL-6. In stroma-free cultures, TPO activated a quiescent CD34+Lin-Rhodamine 123lo subset of primitive hematopoietic progenitor cells into cycle, without loss of CD34 expression. These data demonstrate that TPO acts directly on and supports division of cells more primitive than those committed to the MK lineage.     

Charlson Co‐morbidity Index and albumin significantly associated with fracture risk in peritoneal dialysis patients

Published literature on fracture in dialysis patients seldom addressed the effect of co‐morbidity and malnutrition. In this study, we reported the incidence and risk factors for fracture in peritoneal dialysis patients. Peritoneal dialysis patients who had fractures between 2006 and 2011 were recruited. Demographic data, details of fracture, Charlson Co‐morbidity Index (CCI) and biochemical parameters were also collected. Non‐fracture controls, matched for age, gender and duration of dialysis, were also recruited at ratio 1:1 for fracture risk analysis. The incidence of fracture was 1 in 37 patient‐years. The commonest site of fracture was neck of femur (n = 16, 55.2%). Twenty‐four patients (82.8%) developed fracture after slip and fall injury. Eight out of 17 self‐ambulatory patients (47.1%) became non‐ambulatory after fracture. Infection was the commonest complication during hospitalization. Univariant analysis demonstrated high CCI (P = 0.001), hypoalbuminaemia (P < 0.001), loss of self autonomy (P = 0.006) and non‐ambulatory state (P = 0.011) significantly associated with increased fracture risk. However, only CCI (odds ratio (OR) 1.373, P = 0.028) and albumin (OR 0.893, P = 0.025) increased fracture risk significantly on multivariant analysis. Bone profile and parathyroid hormone were not significant risk factors. To conclude, fracture associated with adverse outcome in peritoneal dialysis patients. High CCI score and hypoalbuminaemia significantly increase risk of fracture.     

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Optimizing dose and scheduling of filgrastim (granulocyte colony- stimulating factor) for mobilization and collection of peripheral blood progenitor cells in normal volunteers [see comments]

To define an optimal regimen for mobilizing and collecting peripheral blood progenitor cells (PBPC) for use in allogeneic transplantation, we evaluated the kinetics of mobilization by filgrastim (recombinant met- human granulocyte colony-stimulating factor [r-metHuG-CSF]) in normal volunteers. Filgrastim was injected subcutaneously for up to 10 days at a dose of 3 (n = 10), 5 (n = 5), or 10 micrograms/kg/d (n = 15). A subset of volunteers from each dose cohort underwent a 7L leukapheresis on study day 6 (after 5 days of filgrastim). Granulocyte-macrophage colony-forming cell (GM-CFC) numbers in the blood were maximal after 5 days of filgrastim; a broader peak was evident for CD34+ cells between days 4 and 6. The 95% confidence intervals (CI) for mean number of PBPC per milliliter of blood in the three dose cohorts overlapped on each study day. However, on the peak day, CD34+ cells were significantly higher in the 10 micrograms/kg/d cohort than in a pool of the 3 and 5 micrograms/kg/d cohorts. Mobilization was not significantly influenced by volunteer age or sex. Leukapheresis products obtained at the 10 micrograms/kg/d dose level contained a median GM-CFC number of 93 x 10(4)/kg (range, 50 x 10(4)/kg to 172 x 10(4)/kg). Collections from volunteers receiving lower doses of filgrastim contained a median GM- CFC number of 36 x 10(4)/kg (range, 5 x 10(4)/kg to 204 x 10(4)/kg). The measurement of CD34+ cells per milliliter of blood on the day of leukapheresis predicted the total yield of PBPC in the leukapheresis product (r = .87, P < .0001). Assuming a minimum GM-CFC requirement of 50 x 10(4)/kg (based on our experience with autologous PBPC transplantation), all seven leukapheresis products obtained at the 10 micrograms/kg/d dose level were potentially sufficient for allogeneic transplantation purposes. We conclude that in normal donors, filgrastim 10 micrograms/kg/d for 5 days with a single leukapheresis on the following day is a highly effective regimen for PBPC mobilization and collection. Further studies are required to determine whether PBPC collected with this regimen reliably produce rapid and sustained engraftment in allogeneic recipients.     

Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.     

Epidemiology of tuberculosis and HIV coinfections in Singapore, 2000–2014

Cross‐matching of records between Singapore's tuberculosis and HIV registries showed that 3.3% of individuals with tuberculosis (TB) were coinfected with HIV (2000?2014), the TB incidence among individuals with HIV infection was 1.65 per 100 person‐years, and 53% of coinfections were diagnosed within 1 month of each other. The findings supported joint prevention programmes for early diagnosis and treatment.     

图形翻转视觉诱发电位在视神经管减压后视神经损伤不同时期的变化特征

目的:观察视神经损伤动物模型在损伤后和不同时期视神经管减压后视觉诱发电位的变化,了解创伤性视神经损伤的手术时机与疗效的关系。方法:实验于2005-03/05在解放军南京军区南京总医院动物实验中心完成。①实验分组:30只新西兰白兔随机分为正常对照组、术后2d减压组、术后7d减压组、术后14d减压组、术后不减压组,每组6只。②造模:除正常对照组外,其余各组在视神经孔中塞入一细端为2mm直径的圆锥软硅胶,阻塞视神经孔,造成视神经的挤压伤。③指标检测:采用图形翻转视觉诱发电位检测损伤前、损伤后1h、减压前1h、减压后2周视功能变化,记录NPN曲线主波(P波)的绝对潜伏期、绝对波幅。正常对照组仅采集一组数据作为对照。结果:30只实验动物均进入结果分析。①正常对照组家兔图形翻转视觉诱发电位检查均引出典型NPN波型曲线,视神经挤压伤后1hNPN波形低阔扁平,P波潜伏期延长,波幅降低。②P波潜伏期:术后2d减压组减压后短于减压前[(71.25±8.51),(86.47±14.28)ms,P<0.05];术后7d减压组减压前后比较差异无显著性(P>0.05);术后14d减压组减压后明显长于减压前[(158.73±15.16),(116.35±17.13)ms,P<0.05]。术后2d减压组和术后7d减压组短于术后不减压组(P<0.01)。术后7,14d减压组和术后不减压组明显长于正常对照组(P<0.01)。③P波波幅:术后2d减压组减压后高于减压前[(5.25±0.78),(4.42±0.42)μV,P<0.05]。术后2d减压组减压后低于术后7d减压组、术后14d减压组(P<0.01),术后14d减压组低于术后7d减压组(P<0.05);术后7d减压组、术后14d减压组、术后不减压组低于正常对照组(P<0.01)。结论:神经元继发性损伤是视功能进行性下降的重要原因,视神经减压术有利于减轻视神经间接损伤,较早期(损伤后48h以内)减压可阻止轴突继发性损伤,避免视功能进一步下降,并在一定程度上逆转视功能的损害。