Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.     

DNA looping by the Sfi I restriction endonuclease

The SfiI endonuclease has to interact with two copies of its recognition sequence before it can cleave DNA. To demonstrate that the reaction of SfiI on a DNA with two sites involves the formation of a DNA loop, and to characterise the looping interactions on supercoiled and linear DNA, a series of plasmids was constructed with lengths of DNA between two SfiI sites varying from 104 to 211 bp. Both supercoiled and linear forms of each DNA were tested as substrates for SfiI. The reactions were monitored from the rates of DNA cleavage and from the generation of partially cleaved products, the latter indicating loop disruption before cleavage of both sites. On both supercoiled and linear DNA, the stabilities of the complexes spanning two SfiI sites varied in sinusoidal fashion with the distance between the sites, in the manner characteristic of a process governed by the helical periodicity of DNA. In all cases, the looping interaction was stabilised by DNA supercoiling. The sinusoidal variation from SfiI reactions on supercoiled DNA at 50 degreesC yielded a helical repeat of about 11.5 base-pairs per turn.     

A naturally occurring mutation in Fc gamma RIIA: a Q to K127 change confers unique IgG binding properties to the R131 allelic form of the receptor

Fc gamma RIIa is widely expressed on hematopoietic cells. There are two known allelic polymorphic forms of Fc gamma RIIa, Fc gamma RIIa-R131 and Fc gamma RIIa-H131, which differ in the amino acid at position 131 in the second lg-like domain. In contrast to Fc gamma RIIa-R131, Fc gamma RIIa-H131 binds hlgG2 but not mIgG1, and this differential binding has clinical implications for host defense, autoimmune disease, immunohematologic disease, and response to therapeutic monoclonal antibodies. We identified a novel Fc gamma RIIA genotype in a healthy individual homozygous for Fc gamma RIIA R/R131 in whom a C to A substitution at codon 127 changes glutamine (Q) to lysine (K) in one of the two Fc gamma RIIA genes. This individual's homozygosity for Fc gamma RIIA-R/R131 leads to the prediction that the receptors on her cells would not bind hIgG2. Monocyte and neutrophil phagocytosis of hIgG2-opsonized erythrocytes was significantly higher (P < .05) for cells from this K/Q127, R/R131 individual than for Q/Q127, R/R131 donors. Platelet aggregation stimulated by an mIgG1 anti-CD9 antibody in this individual was significantly different (P < .05) from Q/Q127, H/R131 and Q/Q127, H/H131 donors and similar to Q/Q127, R/R131. Our data show that the K127/R131 receptors have a unique phenotype, binding both hIgG2 and mIgG1. Further functionally significant mutations in human Fc gamma receptors and possible novel mechanisms for inherited differences in disease susceptibility should be sought with unbiased screening methods.     

Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability

The possibility of primitive hematopoietic cell ex vivo expansion is of interest for both gene therapy and transplantation applications. The engraftment of autologous rhesus peripheral blood (PB) progenitors expanded 10 to 14 days were tracked in vivo using genetic marking. Stem cell factor (SCF)/granulocyte colony-stimulating factor (G-CSF)-mobilized and CD34-enriched PB cells were divided into two equal aliquots and transduced with one of two retroviral vectors carrying the neomycin-resistance gene (neo) for 4 days in the presence of interleukin-3 (IL-3), IL-6, and SCF in the first 5 animals, IL-3/IL-6/SCF/Flt-3 ligand (FLT) in 2 subsequent animals, or IL-3/IL-6/SCF/FLT plus an autologous stromal monolayer (STR) in the final 2. At the end of transduction period, one aliquot (nonexpanded) from each animal was frozen, whereas the other was expanded under the same conditions but without vector for a total of 14 days before freezing. After total body irradiation, both the nonexpanded and expanded transduced cells were reinfused. Despite 5- to 13-fold higher cell and colony-forming unit (CFU) doses from the expanded fraction of marked cells, there was greater short- and long-term marking from the nonexpanded cells in all animals. In animals receiving cells transduced and expanded in the presence of IL-3/IL-6/SCF/FLT, engraftment by the marked expanded cells was further diminished. This discrepancy was even more pronounced in the animals who received cells transduced and expanded in the presence of FLT and autologous stroma, with no marking detectable from the expanded cells. Despite lack of evidence for expansion of engrafting cells, we found that the addition of FLT and especially STR during the initial brief transduction period increased engraftment with marked cells into a clinically relevant range. Levels of marked progeny cells originating from the nonexpanded aliqouts were significantly higher than that seen in previous 4 animals receiving cells transduced in the presence of IL-3/IL-6/SCF, with levels of 10% to 20% confirmed by Southern blotting from the nonexpanded IL-3/IL-6/SCF/FLT/STR graft compared with 0.01% in the original IL-3/IL-6/SCF cohort. These results suggest that, although expansion of PB progenitors is feasible ex vivo, their contribution towards both short- and long-term engraftment is markedly impaired. However, a brief transduction in the presence of specific cytokines and stromal support allows engraftment with an encouraging number of retrovirally modified cells.     

Target-promoted alkylation of DNA

For 13 years between 1980 and 1992, 23 patients needed pacemaker (PM) implantation because of bradyarrhythmia, 21 of atrial fibrillation and two of complete A-V block, after valve surgery. Five of 88 survivors (5.7%) after OMC, 11 of 227 (4.8%) after MVR, one of 169 (0.6%) after AVR, five of 67 (7.4%) after MVR + AVR and one of 15 (6.7%) after TVR underwent PM implantation in postoperative period. Two cases who had heart failure was implanted PM in early postoperative period. In late period, the mean duration between previous valve surgery and PM implantation was 6.4 years in 12 cases after initial valve surgery and 2.3 years in nine after second valve surgery. Postoperative course after PM implantation was almost good, but one case was died due to critical arrhythmia. And one case underwent re-MVR because of mitral bioprosthesis dysfunction and one, without anticoagulant after OMC, was complicated cerebral infarction.     

Effects of hypertension on the static mechanical properties and chemical composition of the rat aorta

The contributions of the relative radius, relative wall thickness, incremental strain, incremental elastic modulus, and medial scleroprotein content to the static elastic properties of the rat aortic wall have been examined in three groups of rats. Controls, rats made hypertensive at four weeks of age, and rats whose blood pressure was lowered after 6 weeks hypertension, were studied. The results show evidence of adaptive changes in the aorta of hypertensive animals, and that irreversible alterations in the mechanical properties of the wall may be induced by a brief period of hypertension. A direct relationship between aortic medial scleroprotein content and the elastic properties of the wall is demonstrated.     

Derepressed alloantigen in transplacentally induced lung tumor coded for by H-2 linked gene

A transplacentally induced lung tumor of strain C3Hf mice grows progressively when transplanted to (C3Hf X A)F1 hybrid mice but not when transplanted to C3Hf recipients. Progressive tumor growth occurs in [(C3Hf X A)F1 X C3Hf] backcross mice inheriting the H-2a haplotype from the F1 parent. Furthermore, radioresistant immunity to the lung tumor can be induced in C3Hf mice by immunization with normal tissue of B10.A and B10.A(2R) but not of B10 or B10.A(5R) strain mice.