Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study.

OBJECTIVES: The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels. BACKGROUND: Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)-gamma agonists lower inflammatory markers and reduce CVD in type 2 diabetes. METHODS: In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman's rank test. RESULTS: At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 +/- 2.42 mg/l to 2.48 +/- 1.77 mg/l and 3.26 +/- 2.02 mg/l to 2.81 +/- 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 +/- 1.97 mg/l to 2.06 +/- 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group. CONCLUSIONS: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.     

Ex vivo targeting of p21Cip1/Waf1 permits relative expansion of human hematopoietic stem cells

Relative quiescence is a defining characteristic of hematopoietic stem cells. Reasoning that inhibitory tone dominates control of stem cell cycling, we previously showed that mice engineered to be deficient in the cyclin-dependent kinase inhibitor, p21Cip1/Waf1 (p21), have an increased stem cell pool under homeostatic conditions. Since p21 was necessary to maintain stem cell quiescence and its absence sufficient to permit increased murine stem cell cycling, we tested whether reduction of p21 alone in human adult-derived stem cells could affect stem cell proliferation. We demonstrate here that interrupting p21 expression ex vivo resulted in expanded stem cell number and in vivo stem cell function compared with control, manipulated cells. Further, we demonstrate full multilineage reconstitution capability in cells where p21 expression was knocked down. Therefore, lifting the brake on cell proliferation by altering cell cycle checkpoints provides an alternative paradigm for increasing hematopoietic stem cell numbers. This approach may be useful for relative ex vivo human stem cell expansion.     

Depressive symptoms in relation to periodontal health in a Jordanian sample

Abstract:  Objectives : This cross-sectional study examines the relationship of depression symptoms to periodontal diseases and decayed (D), missing (M) and filled teeth (FT) in a sample of the Jordanian population. Methods : Subjects escorting dental patients attending two dental hospitals in North Jordan were included. Each subject received full periodontal examination, including probing pocket depth (PPD), clinical attachment level (CAL), gingival index (GI) and plaque index (PI). The numbers of M, D and F teeth were also recorded. The Zung Self-rating Depression Scale was used to determine susceptibility to depression. Results : The frequency of high susceptibility to depression among periodontitis-free subjects and those with periodontitis was found to be 48% and 50% respectively. There was no statistically significant association between susceptibility to depression symptoms and periodontal parameters, including PPD, CAL, PI and GI ( P  >   0.05 ) . However, subjects with low susceptibility to depression had significantly more FT than subjects highly susceptible to depression. Conclusions : High susceptibility to depression does not play a significant role in the aetiology and severity of periodontitis in the population studied.     

Seltene Differenzialdiagnose einer schweren Hyperkalz?mie

We report a 47-year-old women who presented to her general practitioner and our hospital with weight loss of unknown etiology. Eight years previously she had undergone a hemithyroidectomy for nodular goiter with one cold nodule. Laboratory results revealed hypercalcemia, evidence of primary hyperparathyroidism and computer tomography of the thorax showed bilateral pulmonary metastasis. After undergoing CT-guided biopsy of a metastasis, histology revealed an endocrine primary tumor with low parathyroid hormone expression. In view of the history, clinical and biochemical findings we diagnosed a recently metastasized functioning parathyroid carcinoma, which eight years previously has been labeled as a benign atypical thyroid adenoma. The patient underwent surgical resection of all detected metastases. Afterwards the serum calcium and parathyroid hormone levels normalized. Parathyroid carcinoma is an uncommon tumor. In the absence of pathognomonic diagnostic criteria a definitive pathological diagnosis of parathyroid carcinoma often is not possible. The treatment of parathyroid carcinoma is essentially surgical. Patients with parathyroid carcinoma mostly die from uncontrollable hypercalcemia rather than from other tumor-related complications.     

Increased platelet aggregation and decreased high-density lipoprotein cholesterol in women on oral contraceptives.

In vivo platelet function, serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and serum triglycerides (TG) were determined in 26 women starting oral contraceptives (OCA). Studies were run prior to, and after one and two months of therapy. Platelet aggregation time decreased by 50 percent or more in eight of the 26 women from a pre-experimental mean value of 387 +/- 136 seconds. TC did not vary but after the women were on medication for two months, HDL decreased from 56 +/- 14.4 mg/dl to 52 +/- 12.3 mg/dl (p less than 0.05). There was a progressive increase in TG under treatment, 74 +/- 23.3 mg/dl on the pre-experimental measurement to 93 +/- 31.0 mg/dl after two months of therapy (p less than 0.005). Women planning to use OCA might best be advised to have aggregation and serum lipid studies done before and early in usage.     

Differential cytosolic delivery and presentation of antigen by listeriolysin O-liposomes to macrophages and dendritic cells

Delivery of antigenic protein to the cytosol of antigen-presenting cells (APCs), such as macrophages (MPhi) and dendritic cells (DCs), is required for an efficient CD8 T-cell-mediated immune response. We have previously shown that co-encapsulation of antigenic protein inside pH-sensitive liposomes with listeriolysin O (LLO), a pore-forming protein of Listeria monocytogenes, generates efficient major histocompatibility complex class I (MHC I)-restricted immune responses both in vitro and in vivo. In this study, we sought to analyze the relative efficiency of LLO-mediated cytosolic delivery of liposomal antigen in two important APCs, macrophages and dendritic cells, by examining the sequential steps involved in antigen presentation to T-cells in cultured mouse bone marrow-derived MPhis (BMMPhis) and DCs (BMDCs). BMMPhis overall presented liposomal antigen better than BMDCs at a given concentration of liposomal antigen incubated with cells, and the trend was also observed after the presentation was normalized by the uptake of antigen. When soluble antigen was directly introduced into the cytosol, however, BMDCs presented the antigen more efficiently than BMMPhis. In addition, when the APCs were externally loaded with the antigenic peptide of the protein, BMDCs displayed a higher level of cell surface MHC I-peptide complexes and presented the peptide more efficiently than BMMPhis. These results combined together suggest that LLO-mediated release of liposomal antigen from the endosomal/lysosomal compartment may be more pronounced in BMMPhis than in BMDCs, and further implicates differential activity of LLO and varying efficiency of LLO-mediated endosomal escape in different antigen-presenting cell types.     

出血热误诊为上呼吸道感染1例

1病例报告患者,男,22岁,因间歇性全身乏力、肌肉酸痛2 wk,发冷1 wk,发热4 d入院.曾在我院查WBC 4.5×109/L,N 0.60,L 0.4,体温波动在38～40℃.初步诊断"上呼吸道感染",用阿莫西林、VC银翘片、清热解毒冲剂等治疗无效.查体:T 38.9℃,BP面性12/8 kPa.全身皮肤无出血点,双眼球结膜轻度充血,咽部充血,软腭未见充血点,心肺腹部未见阳性体征.实验室检查:WBC 7.85 × 109/L,N 0.79,L 0.21,HGB 150g/L,PCL30×109/L,尿蛋白3.2g/L,流行性出血热抗体( ).诊断:流行性出血热.入院后立即按照流行性出血热的治疗原则给予抗病毒、抗渗出、抗出血治疗.具体包括卧床休息,给予高热量,多维生素,易消化饮食;维持水、电解质、酸碱及血浆渗透压平衡;给予大剂量(5 g)Vit.C和Vit.E.同时给予氢化可地松100 mg/d,稀释后缓慢静脉滴注.入院后3 d患者的尿量由450 mL/d增至750 mL/d,肌酐204.6μmol/L,BUN 13.3 mmol/L.5 d尿量增加至4000 mL/d.经综合治疗10 d,肌酐和BUN检查等正常,痊愈出院,随访1 mo未见异常.