Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin

Background  

The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy.     

Functional treatment after surgical repair of acute Achilles tendon rupture: wrap vs walking cast

The aim of this study was to compare the clinical outcome for patients treated with walking cast immobilization and wrap early mobilization after surgical repair of acute Achilles tendon ruptures. A total of 39 consecutive patients with complete ruptures of the Achilles tendon were identified, treated, and functionally rehabilitated with either a walking cast or a wrap. Because the randomization was quasi-random, chi-square and t-tests were performed to compare the baseline characteristics. A statistically significant difference was present only for the injured side ( p<0.05). Therefore, groups were considered comparable for analysis of outcome. All patients were evaluated at an average follow-up of 6.7 years (range 5-8 years). Functional postoperative treatment with a wrap allowed a significantly shorter hospital stay ( p<0.05) as well as a shorter period to return to pre-injury sports level ( p<0.01) compared with treatment with a walking cast. According to the modified Rupp score, 91.3% of patients in the walking cast group had a good or excellent result, as did 93.8% in the wrap group ( p=0.9). Slight atrophy of the calf muscles was reported in 3 patients in the walking cast group (13.0%) and in 4 in the wrap group (25.0%). One re-rupture was reported in the walking cast group (4.3%). Functional treatment after surgical Achilles tendon repair is safe, and there is no increased risk of re-rupture or wound healing problems. Functional treatment with a wrap is preferable to treatment with a walking cast with respect to hospitalization time and return to sports.     

Acetylator phenotype and genotype in HIV-infected patients with and without sulfonamide hypersensitivity

Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow acetylator phenotype are predisposed to these reactions, whereas other studies suggest that the slow acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow acetylator phenotype, while 8 of 14 patients (57%) without such a history exhibited this same phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow acetylator phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between acetylator genotype and phenotype.     

Changes in UCP2, PPARgamma2, and c/EBPalpha gene expression induced by a neuropeptide Y (NPY) related receptor antagonist in overweight rats

Neuropeptide Y (NPY), a peptide released by nervous cells, appears to contribute to adiposity regulation by increasing food intake and inhibiting lipolysis. New NPY receptor related antagonists such as S.A.0204 are being developed as potential anti-obesity drugs affecting adipocyte lipid metabolism and thermogenesis. In this sense, those animals fed on a high-energy yielding (cafeteria) diet decreased body fat weight as compared to overweight controls, when they were administered with S.A.0204, and increased body temperature, which statistically correlated with high UCP2 mRNA expression levels in white adipose tissue. In addition, the in vivo NPY-antagonist administration was able to prevent white adipose tissue growth in animals fed the cafeteria (high-fat) diet by impairing PPARy and CIEBPalpha mRNA expression in white fat cells. In summary, this novel NPY related-antagonist S.A.0204 may regulate body fat deposition by affecting both energy dissipation and white adipose tissue deposition, representing a potential new pharmacological strategy for obesity management.     

Mediterranean diet and reduction in the risk of a first acute myocardial infarction: an operational healthy dietary score

Summary. Background: Although an important secondary prevention trial reported an impressive protection by a Mediterranean dietary pattern on reinfarction and cardiovascular death, scarce direct epidemiologic evidence is currently available regarding the role of the Mediterranean diet in the aetiology of coronary heart disease. Aims: The aim of the study was to quantify the risk reduction of incident myocardial infarction provided by a Mediterranean dietary pattern. Methods: We included 342 subjects (171 patients who suffered their first acute myocardial infarction and 171 matched controls) in a case-control study. A validated semi-quantitative food frequency questionnaire (136 items) was used. We defined an a priori Mediterranean dietary pattern. We assessed six food items that we considered protective: 1) olive oil, 2) fiber, 3) fruits, 4)vegetables, 5) fish and 6) alcohol. For each of these six dietary factors, we calculated the distribution according to quintiles within the study and assigned each participant a score of 1 to 5 corresponding to the quintile of intake, with 1 representing the lowest and 5 representing the highest quintile. We also estimated the quintiles of two other elements assumed to be associated with a higher risk: 7) meat/meat products and 8) some items with high glycaemic load (white bread, pasta and rice). For these two elements we inversely ranked the score, with 1 representing the highest and 5 representing the lowest quintile. Finally, we summed up the eight quintile values for each participant. A second score (post hoc pattern) was built using only a single cut-off point for these eight elements. The cut-off points for each element in this post hoc pattern were decided according to the dose-response relationships between the consumption of each food item and the risk of myocardial infarction observed in the analyses that used quintiles of each food item. Results: For both patterns, we found that the higher the score, the lower the odds ratio of myocardial infarction. A significant linear trend was apparent after adjustment for the main cardiovascular risk factors. For each additional point in the a priori Mediterranean pattern (observed range: 9–38) the odds ratio (95 % confidence intervals) was 0.92 (0.86–0.98). This estimate was 0.55 (0.42–0.73) when we used the post hoc pattern (range: 0–8). Conclusions: Our data support the hypothesis that a Mediterranean diet (that emphasizes olive oil, fiber, fruits, vegetables, fish and alcohol and reduces meat/meat products) can be an effective measure for reducing the risk of myocardial infarction. However, our results support the exclusion of refined cereals with a high glycaemic load as healthy elements of this pattern. Received: 24 January 2002, Accepted: 13 May 2002     

Beta(2)-adrenergic receptor mutation and abdominal obesity risk: effect modification by gender and HDL-cholesterol

Summary Objective and design A case-control study was conducted to examine the association between the 27Glu polymorphism of the β₂-adrenergic receptor gene (ADRB2) and the risk of abdominal obesity (defined by a waist/hip ratio: WHR higher than 0.85). Methods The case series encompassed 112 obese subjects with body mass index (BMI) > 30 kg/m² and WHR > 0.85 and no other major disease except for type 2 diabetes, while the controls were 127 healthy subjects, BMI < 25 kg/m² and WHR < 0.85. Results The association between the risk of abdominal obesity and the 27Glu polymorphism was estimated using multivariate logistic regression. A higher crude odds ratio (OR) of 4.08 (95 % confidence interval: 0.98–16.3) for the 27Glu allele was found among men, while no increased risk was apparent among female participants. Moreover, when the model was adjusted for age, male subjects carriers of the 27Glu allele had a significant ten-fold higher risk of abdominal obesity (OR = 10.31; 95 % CI: 1.4–76.8) and the product-term for the interaction (effect modification) between gender and the ADRB2 mutation was near to the limits of statistical significance (Likelihood ratio test p = 0.056). Interestingly, we also found an effect modification with higher OR among individuals with low HDL-cholesterol (< 1.5 mmol/l) after adjustment for age and gender (OR = 2.87 95 % CI 1.09–7.50) and the product-term for interaction between the 27Glu allele and HDL-cholesterol was statistically significant (Likelihood ratio test p = 0.003). Conclusions. Our results showed that the 27Glu allele of the ADRB2 gene appears to be a risk factor for abdominal obesity among male subjects, specially among those with lower HDL-cholesterol levels. Received: 26 November 2001, Accepted: 2 March 2002     

Direct and indirect inhibition by nociceptin/orphanin FQ on noradrenaline release from rodent cerebral cortex in vitro

1 The modulation exerted by nociceptin/orphanin FQ (NC) on noradrenaline (NE) release in rodent cerebral cortex slices and synaptosomes was studied. 2 Rat, mouse and guinea-pig cortical slices and synaptosomes were preincubated with 0.1 micro M [(3)H]-NE and superfused. NE release was evoked by 2 min of electrical (3 Hz) stimulation in slices and by 1 min pulse of 10 mM KCl in synaptosomes. 3 In rat cortical slices, 0.01-3 micro M NC reduced the evoked [(3)H]-NE efflux (E(max)-54%), with a bell-shaped concentration-response curve, which regained its monotonic nature in the presence of either 0.1 micro M naloxone (NX) or 30 micro M bicuculline. In synaptosomes, the NC effect curve was sygmoidal in shape and reached a plateau at 1 micro M concentration. 4 In the rat, both 1 micro M [Phe(1)psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) and 10 micro M [Nphe(1)]NC(1-13)NH(2) (NPhe) antagonised NC-induced inhibition, without per se modifying [(3)H]-NE efflux. The effects of 0.3-1 micro M NC concentrations were partially prevented by 1 micro M NX; 1 micro M D-Phe-Cys-Thr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) was also an effective antagonist, but 0.1 micro M norbinaltorphimine was not. 5 In the mouse cerebral cortex, NC-induced inhibition of NE release (pEC(50) 6.87, E(max)-61%, in the slices) was prevented by Nphe but was NX-insensitive. In guinea-pig cortical slices, NC effect (pEC(50) 6.22, E(max)-38%) was prevented by Nphe, but was NX-insensitive. 6 These findings demonstrate that NC inhibits NE release from rodent cerebral cortex via presynaptically located ORL(1) receptors. In the rat, micro opioid and GABA(A) receptors are involved as well.     

Endometriosis--a missed malady

Endometriosis is a disease that affects approximately 5.5 million girls and women in their reproductive years in the United States and Canada. During the menstrual cycle, the endometrial lining of the uterus thickens in preparation to receive a fertilized egg. If fertilization does not occur, this lining sloughs off during menstruation. Endometrial tissue can migrate out of the fallopian tubes and grow outside of the uterus as endometrial implants. This can result in severe pain. Endometriosis is very difficult to detect because most women become accustomed to painful menstrual cycles at an early age. The disease often will go undiagnosed because even with extensive endometriosis it is possible to have minimal symptoms or none at all. Physicians have few diagnostic tools to detect the scars and growths of endometriosis. The only way to confirm the diagnosis and stage of endometriosis is by laparoscopy. Treatment options include hormone therapy and surgery. In the past, the most successful treatment was open laparotomy with excision of the endometrial implants. This article discusses the use of the ultrasonic scalpel to resect endometrial implants. through the laparoscope. The patient's perioperative course also is discussed. AORN J 77 (Feb 2003) 298-313.