预防治疗2型糖尿病药物分子作用靶点的相关研究与进展

目的:综合分析2型糖尿病新药研究的分子靶点。资料来源:应用计算机检索Springer1990-01/2005-02和Pubmed2000-01/2005-08有关预防和治疗2型糖尿病药物的文献,检索词“diabetes,drug,target”,并限定文献语言种类为English。资料选择:对检索到的有关预防和治疗2型糖尿病药物的相关信息进行整理,筛选针对性强、影响因子较大、最近几年发表的论文。资料提炼:共检索到相关文献49篇,其中15篇符合要求,排除34篇。排除的文章中6篇是关于2型糖尿病的病理生理及生化方面的基础研究,其余为2型糖尿病预防和治疗效果方面的文献。资料综合:综合文献资料发现,以往研制的治疗糖尿病的药物或者因缺乏明确的分子靶点,或者因对疾病本身的病理反应不清楚,因而存在各种弊端。有关预防和治疗2型糖尿病和代谢综合征的分子靶点为抗糖尿病药物的研发展示了光明的前景,涉及的药物包括经典受体的小分子调节剂、酶作用靶点、蛋白质制剂和反义寡核苷酸等。结论:根据2型糖尿病和代谢综合征特异的病理反应机制作为筛选药物的分子基础是未来抗糖尿病药物研发的主攻方向。     

Cell–cell interaction between vocal fold fibroblasts and bone marrow mesenchymal stromal cells in three‐dimensional hyaluronan hydrogel

Mesenchymal stromal cells (MSCs) are multipotential adult cells present in all tissues. Paracrine effects and differentiating ability make MSCs an ideal cell source for tissue regeneration. However, little is known about how interactions between implanted MSCs and native cells influence cellular growth, proliferation, and behaviour. By using an in vitro three‐dimensional (3D) co‐culture assay of normal or scarred human vocal fold fibroblasts (VFFs) and bone marrow‐derived MSCs (BM‐MSCs) in a uniquely suited hyaluronan hydrogel (HyStem–VF), we investigated cell morphology, survival rate, proliferation and protein and gene expression of VFFs and BM‐MSCs. BM‐MSCs inhibited cell proliferation of both normal and scarred VFFs without changes in VFF morphology or viability. BM‐MSCs demonstrated decreased proliferation and survival rate after 7 days of co‐culture with VFFs. Interactions between BM‐MSCs and VFFs led to a significant increase in protein secretion of collagen I and hepatocyte growth factor (HGF) and a decrease of vascular endothelial growth factor (VEGF), monocyte chemotactic protein‐1 (MCP‐1) and interleukin‐6 (IL‐6). In particular, BM‐MSCs significantly upregulated matrix metalloproteinase 1 (MMP1) and HGF gene expression for scarred VFFs compared to normal VFFs, indicating the potential for increases in extracellular matrix remodelling and tissue regeneration. Application of BM‐MSCs‐hydrogels may play a significant role in tissue regeneration, providing a therapeutic approach for vocal fold scarring. Copyright © 2013 John Wiley & Sons, Ltd.     

MEASUREMENTS OF INTERFACE PRESSURE BETWEEN BODY SITES AND THE SURFACES OF FOUR SPECIALISED AIR MATTRESSES

SUMMARY Four specialised air mattresses had interface pressure measured under six body sites prone to pressure sores in 10 subjects, supine and sitting. The mattresses were the Clinirest (SSI) and FirstStep (KCI) continuous airflow mattress overlays, and Airwave (Pegasus) and Nimbus (Huntleigh) alternating pressure air mattresses. On the mattress overlays, average supine interface pressures were 2.33 kPa (scapula), 4.15 kPa (elbow), 1.94 kPa (sacrum) and 2.79 kPa (buttock), although they were higher at the occiput (7.97 kPa) and heel (11.7 kPa). The alternating pressure air mattresses had an average minimum interface pressure close to zero for three sites, rising to 4.28 kPa under the heel. Average maximum interface pressures were 8.61 kPa (occiput), 5.21 kPa (scapula), 4.90 (elbow), 4.85 kPa (sacrum), 4.61 kPa (buttock) and 13.2 kPa (heel). No accepted scientific method exists for comparing the two types of mattress. Our data suggest a clinical benefit at the occiput and heel (supine) in using an alternating pressure air mattress and a benefit in using a continuous airflow mattress overlay at other sites.     

Blastomycosis in a young African man presenting with a pleural effusion

Blastomyces dermatitidis is a dimorphic fungus endemic to northwestern Ontario, Manitoba and some parts of the United States. The fungus is also endemic to parts of Africa. Pulmonary and extrapulmonary findings of a 24-year-old African man who presented with weight loss, dry cough and chronic pneumonia not resolving with antibiotic treatment are presented. The unusual occurrence of pulmonary blastomycosis associated with skin lesions and a moderate pleural effusion is reported.     

Chronic modifications of lung and heart development in glucocorticoid-treated newborn rats exposed to hyperoxia or room air

We assessed the mechanics and morphology of the lung in 165 rats treated neonatally with either room air (RA), O₂, RA + steroids, or O₂, + steroids. Newborn Sprague-Dawley male rats were randomly assigned to these groups. O₂,-exposure (0.96-1.0 FiO₂ lasted 5 days, and dexamethasone treatment consisted of eight daily S.C. injections of drug or buffer in successive doses of 0.5,0.4.0.3,0.2,0.1, 0.1. 0.1. and 0.1 mg/kg. At 58 days, right ventricular systolic pressure (RVP) was measured. At 60 days, all rats were sacrificed for obtaining lung weight and DNA, saline pressure-volume (P-V) curves, and morphometry. We weighed right ventricles (RV) and left ventricles + septa (LV). Hyperoxia alone did not, but steroid decreased survival rate to 79.4% (95.3% in RA rats, P < 0.02). Only 21 of 40 (52%) O₂ + steroids rats survived, less than in both RA groups (P < 0.001). RV weight, RVP and muscularization of alveolar duct arteries were significantly increased in O₂ vs. RA rats. In RA + steroids rats, weight of the LV was decreased but RV, RVP, and lung vasculature were not affected. These effects were additive in the O₂ + steroid group. Wet lung weights and DNA were increased for RA + steroid rats over all others. O₂ and steroids shifted the P-V curve to the left and O₂+ steroids still further. Maximal lung volume increased significantly with RA + steroids and still further in O₂ + steroids but not in O₂ alone. O₂ and steroids significantly increased the mean linear intercept and O₂ + steroids even more so. In O₂- and steroid-treated rats, the parenchymal air space increased. In conclusion, both neonatal hyperoxia and steroid administration caused aberrations in the growth of lung and connective tissue. The effects of the two were additive. The vascular system, maximal lung volume, and DNA responded differently, presumably by different modes of action. Pediatr Pulmonol. 1993; 16:81–88. © 1993 Wiley-Liss, Inc.     

Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation

We describe our 9-year experience with lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation (BMT) for 24 patients with severe combined immunodeficiency disease (SCID). Nineteen of 21 evaluable patients had T-cell engraftment; 2 of 11 patients tested had B-cell and monocyte engraftment. Fourteen of 24 (58%) patients are alive 7 months to 9.8 years post-BMT. Seventeen of 24 patients received pretransplant conditioning with chemotherapy and/or total body irradiation, and 8 of 24 received more than one transplant. Patients who received conditioning had a survival rate of 61% versus 57% for those who received no conditioning. None received graft-versus- host disease (GVHD) prophylaxis and no patient had acute or chronic GVHD greater than grade I. Kinetics and follow-up of immune recovery were analyzed in 14 patients who are greater than 1 year from transplant. Half of the patients showed evidence of T-cell function by 3 months and normal T-cell function by 4 to 7 months post-BMT. On average, T-cell numbers and subsets became normal 10 to 12 months posttransplant. Recovery of B-cell function was more delayed, although in most patients B-cell numbers and IgM levels were normal by 12 months post-BMT. B-cell function, as determined by isohemagglutinin titers or specific antibodies to pneumococcal polysaccharide, keyhole limpet hemocyanin, or tetanus toxoid, became normal in 10 of 14 patients 2 to 8 years post-BMT. Seven of the 14 are off gammaglobulin therapy. Production of isohemagglutinins tended to predict recovery of antibody response to pneumococcal polysaccharide (P < .064). Based on these results, we believe that haplocompatible BMT is an effective, curative treatment for patients with SCID who lack an HLA-matched related donor.     

Poikilocytic hereditary elliptocytosis associated with spectrin Alexandria: an alpha I/50b Kd variant that is caused by a single amino acid deletion

Hereditary elliptocytosis (HE) is a heterogeneous disorder of red blood cells frequently associated with abnormal limited tryptic digestion of the alpha I domain of spectrin and impaired spectrin dimer self- association. We studied two related individuals with poikilocytic hereditary elliptocytosis (HE) of different severity. Limited tryptic digestion of spectrin from these individuals showed the presence of a variant alpha I/50b Kd peptide at the expense of the normal alpha I/80 Kd peptide. Amino acid sequence analysis of the abnormal peptide showed that the proteolytic cleavage occurred after the arginine at position 470 of the alpha spectrin chain. Spectrin from these patients had an impaired ability to undergo self-association, as evidenced by increased amounts of spectrin dimers in 4 degrees C extracts of erythrocyte membrane from affected individuals. The polymerase chain reaction was used to study the DNA sequence of the alpha spectrin gene encoding the region of the alpha spectrin chain surrounding the abnormal proteolytic cleavage site. We detected the in-frame deletion of the trinucleotide CAT, encoding histidine 469, two amino acid residues to the N-terminal side of the abnormal proteolytic cleavage site between residues 470 and 471. Similar to many other defects of spectrin associated with HE, this deletion occurs in helix three of repeat 5 of the proposed triple helical model of spectrin repeats.