CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells.

We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase-8 and -9 and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential DeltaPsi m and cytochrome c release), which are reduced by caspase-8 inhibitor, suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in all-trans-retinoic acid-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL.     

Effect of Coenzyme Q10 and green tea on plasma and liver lipids, platelet aggregation, TBARS production and erythrocyte Na leak in simvastatin treated hypercholesterolmic rats

This study was conducted to investigate the hypocholesterolemic effect of simvastatin (30 mg/kg BW) and antioxidant effect of coenzyme Q10 (CoQ10, 15 mg/kg BW) or green tea (5%) on erythrocyte Na leak, platelet aggregation and TBARS production in hypercholesterolemic rats treated with statin. Food efficiency ratio (FER, ADG/ADFI) was decreased in statin group and increased in green tea group, and the difference between these two groups was significant (p<0.05). Plasma total cholesterol was somewhat increased in all groups with statin compared with control. Plasma triglyceride was decreased in statin group and increased in groups of CoQ10 and green tea, and the difference between groups of statin and green tea was significant (p<0.05). Liver total cholesterol was not different between the control and statin group, but was significantly decreased in the group with green tea compared with other groups (p<0.05). Liver triglyceride was decreased in groups of statin and green tea compared with the control, and the difference between groups of the control and green tea was significant (p<0.05). Platelet aggregation of both the initial slope and the maximum was not significantly different, but the group with green tea tended to be higher in initial slope and lower in the maximum. Intracellular Na of group with green tea was significantly higher than the control or statin group (p<0.05). Na leak in intact cells was significantly decreased in the statin group compared with the control (p<0.05). Na leak in AAPH treated cells was also significantly reduced in the statin group compared with groups of the control and CoQ10 (p<0.05). TBARS production in platelet rich plasma was significantly decreased in the groups with CoQ10 and green tea compared with the control and statin groups (p<0.05). TBARS of liver was significantly decreased in the group with green tea compared with the statin group (p<0.05). In the present study, even a high dose of statin did not show a cholesterol lowering effect, therefore depletion of CoQ10 following statin treatment in rats is not clear. More clinical studies are needed for therapeutic use of CoQ10 as an antioxidant in prevention of degenerative diseases independent of statin therapy.     

A simple tool to evoke physicians' real training needs.

Commonly used methods for identifying the training needs of general practitioners do not enable the real needs felt during interviews with patients during office visits to be detected. In this study, the authors evaluate how physicians' use of a personal-office-visit diary affects the level of specificity of their expressed training needs. In 1999, the authors carried out a controlled intervention trial using a random sample of 1,038 general practitioners from a region of France, randomized to intervention and control groups. The practitioners in the intervention group were asked to identify their training needs using a personal-office-visit diary. The level of specificity for their expressed needs was compared with that of the expressed needs of the practitioners in the control group. The use of the diary was associated with a significantly higher level of specificity in the training needs identified by the general practitioners who participated. Independent of the intervention, practitioners under 40 years of age, those in urban practice, and those who were members of a continuing medical education (CME) association expressed their training needs with higher specificity. The personal-office-visit diary would seem to be a simple, inexpensive, and useful tool for more specifically identifying training needs, which could help establish more appropriate and better-targeted training programs. However, it should be assessed further by those involved in CME for general practitioners.     

Prevalence of latex sensitization and allergy in Portuguese children

The prevalence of latex allergy has been increasing not only in risk groups but also in the general population, where it is accepted to average 1%. In children, latex sensitization prevalence studies are scarce and involve different population sampling and allergy testing methods, which makes it difficult to compare across studies. Nevertheless, existing studies point towards a low prevalence of latex allergy in children, which still needs to be confirmed in the Portuguese population. Aiming at studying the prevalence of latex sensitization and allergy in a sample of Portuguese children, we studied 182 children from two different hospital outpatient clinics. A standardized questionnaire focusing on atopic background, previous history and allergic signs or symptoms on exposure to latex or fruits was given to all children and parents. Skin prick testing was performed with a battery of common aeroallergens as well as latex. Serum total IgE, Phadiatop, F x 5E and latex-specific IgE were determined in all children. Specific IgE to latex-crossreacting fruits was determined in latex-sensitized children. Based upon the questionnaire, the prevalence of latex allergy would be 0.5%. The prevalence of latex sensitization would be 3.8%, when based solely upon skin prick testing, and 12.1% (>/=0.35 IU/ml) or 6.6% (>/=0.70 IU/ml) when based singly upon determination of latex-specific IgE. When positive results for either test were considered, the prevalence of latex sensitization was 14.3%. All latex-sensitized children were atopic. Sensitivity to latex-crossreacting foodstuffs was demonstrated in 61.5% of latex-sensitized children (16/26). This study shows that the prevalence of latex allergy and sensitization in Portuguese atopic and non-atopic children, as analysed using various diagnostic methods, is similar to that observed in other countries. In addition, the assessment of latex allergy and sensitization should always include skin prick testing and determination of serum IgE.     

A double-blind, randomized, placebo-controlled trial of itopride (100 and 200 mg three times daily) on gastric motor and sensory function in healthy volunteers

Itopride, a dopamine D2 antagonist and acetylcholinesterase inhibitor, significantly improved symptoms in patients with functional dyspepsia in one phase II randomized trial. However, the mechanisms by which itopride may improve symptoms are unknown. We aimed to compare the effects of two doses of itopride and placebo on gastric volumes, gastric emptying, small bowel transit and satiation in female and male healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of itopride 100 mg (n = 16) or 200 mg (n = 15) or placebo (n = 15) t.i.d. Validated methods were used to study gastric accommodation (single photon emission computed tomography), gastric emptying and orocecal transit and satiation postnutrient challenge. The three arms were comparable with regard to age, gender and body mass index. There were no statistically significant effects of itopride on gastric emptying, orocecal transit, fasting gastric volume, maximum tolerated volume or aggregate symptom score with nutrient drink challenge. Postprandial (PP) change in gastric volume differed in the three groups (P = 0.019): 625[+/-28 (SEM)], 555(+/-26) and 512(+/-33) in placebo, itopride 100 and 200 mg groups, respectively. In healthy subjects, itopride reduced total PP gastric volume without accelerating gastric emptying or significantly altering gastric motor and sensory function in healthy individuals.     

Obstructive Uropathy Secondary to Ureteral Herniation in a Pediatric En Bloc Renal Graft

Ureteral herniation is a rare entity. We report the first case of extraperitoneal ureteral herniation in a pediatric en bloc renal graft causing obstructive uropathy. A 70-year-old, obese patient with an en bloc renal transplant was found to have ureterohydronephrosis in the right renal graft on magnetic resonance imaging. Nephrostomy with insertion of a double-J catheter confirmed the presence of a ureteral loop within the inguinal tract. Surgery confirmed herniation of the ureter through the internal inguinal ring, crossing over the spermatic cord. We performed release, resection, ureteral reimplantation and hernioplasty. Four months later, renal function was normal and urinary tract dilation had diminished. This case illustrates an unusual cause of obstructive uropathy in a transplanted kidney. Apart from obesity, two other factors may have contributed to its development: presence of a redundant ureter, and the fact that the ureter had been placed over, rather than under, the spermatic cord.     

Discussing options between patients and health care professionals in genetic diagnosis: ethical and legal criteria

The specific characteristics of genetic data lead to ethical-legal conflicts in the framework of genetic diagnosis. Several international organisations, including UNESCO and the Council of Europe, have enacted rules referring to the use of genetic information. This paper discusses possible legal and ethical criteria that could be used in genetic testing.