IL-4 influences the differentiation and the susceptibility to activation-induced cell death of human naive CD8+ T cells

It is now well established that the cytokine environment influences the activation, differentiation, proliferation and death of T lymphocytes during the primary response to antigen. Using an in vitro model, we investigated the influence of IL-4, added at the onset of TCR stimulation, on phenotypic and functional markers of naive CD8+ T cell activation including the up-regulation of activation markers, proliferation as well as the susceptibility to activation-induced cell death (AICD). We report that IL-4, unlike IL-2 added at the onset of repeated TCR stimulation of naive CD8+ T cells prevents AICD, in part due to its ability to maintain the level of the survival-related protein Bcl-2. Moreover, TCR-triggered activation of naive CD8+ T cells in the presence of IL-4 leads to the development of a CD8+ T cell subset that proliferates normally, but which fails to exhibit characteristic activation parameters such as the up-regulation of CD25 and Granzyme B. Taken together, these results demonstrate that exposure to IL-4 during primary activation influences CD8+ T cell differentiation by inducing the development of a sub-population of AICD-resistant, proliferation-competent cells that do not show some of the typical features of CD8+ T cell activation.     

Relationship Between Fear of Falling and Outcomes of an Inpatient Geriatric Rehabilitation Population—Fear of the Fear of Falling

OBJECTIVES: To examine the effects of various risk factors on three functional outcomes during rehabilitation. SETTING: Geriatric inpatient rehabilitation unit. DESIGN: Observational longitudinal study. PARTICIPANTS: One hundred sixty‐one geriatric rehabilitation inpatients (men, women), mean age 82, who were capable of walking at baseline. MEASUREMENTS: Functional status was assessed weekly between admission and discharge and at a follow‐up 4 months later at home using the function component of the Short Form—Late Life Function and Disability Instrument, the Barthel Index, and Habitual Gait Speed. Various risk factors, such as falls‐related self‐efficacy (Falls Efficacy Scale–International), were measured. Associations between predictors and functional status at discharge and follow‐up were analyzed using linear regression models and bivariate plots. RESULTS: Fear of falling predicted functioning across all outcomes except for habitual gait speed at discharge and follow‐up. Visual comparison of functional trajectories between subgroups confirmed these findings, with different levels of fear of falling across time in linear plots. Thus, superior ability of this measure to discriminate between functional status at baseline across all outcomes and to discriminate between functional change especially with regard to the performance‐based outcome was demonstrated. CONCLUSION: Falls‐related self‐efficacy is the only parameter that significantly predicts rehabilitation outcome at discharge and follow‐up across all outcomes. Therefore, it should be routinely assessed in future studies in (geriatric) rehabilitation and considered to be an important treatment goal.     

Spondylodiscitis of the lumbar spine in a non-immunocompromised host caused by Yersinia enterocolitica O:9

Here presented is an extremely rare case of a spinal osteomyelitis (L5–S1) with epidural empyema in a non-immunocompromised 62-year-old man caused by Yersinia enterocolitica O:9. The infection occurred acutely and required immediate surgical treatment. Y. enterocolitica was cultured from the empyema fluid, wound swabs of the intervertebral disc L5–S1 and stool cultures. Following the surgical decompression and antibiotic treatment, the patient recovered completely, without neurological deficits. A review of the literature revealed only sparse cases of spondylodiscitis due to other Y. enterocolitica serogroups. To our knowledge, we report here the first case of a spondylodiscitis of the lumbar spine caused by Y. enterocolitica serovar O:9 in a non-immunocompromised patient.     

Lateral osteoma--auditory exostosis or hamartoma?

An osteoma of the external meatus the size of a hazelnut was found in a 30-year-old man, arising from the bony edge of the external meatus near the tympanomastoid fissure. Histology showed epithelial cysts, trabeculae, blood-forming areas, fat cells, connective tissue and blood vessels. The site of origin and histological findings seem to indicate true hamartoma.     

Reliability of the patient's history in the diagnosis of urinary incontinence

The reliability of a patient's history has been challenged in the preoperative evaluation of stress urinary incontinence. In this study, 122 consecutive patients referred to our Gynecology/Urology clinic were evaluated and an additional 32 control patients (continent women with no urinary symptoms) were evaluated. All patients answered a detailed 64-item questionnaire, and all patients received a complete urodynamic evaluation. Our detailed questionnaire provided a mean positive predictive value of 80% for genuine stress incontinence and 25% for detrusor instability. The conditions leading to a false positive history suggestive of genuine stress incontinence were detrusor instability and urethral diverticulum. The conditions leading to a false positive history suggestive of detrusor instability were urethritis, unstable urethra, vaginitis and polyuria. History alone can be misleading in diagnosing urinary incontinence.     

Diffuse neonatal haemangiomatosis: Successful management with high dose corticosteroids

We report two cases of diffuse neonatal haemangiomatosis. The multiple cutaneous lesions were associated with massive hepatic involvement and congestive heart failure in one, while in the other laryngeal haemangiomas caused stridor and inspiratory distress. A significant regression in vascular lesions was achieved with high dose corticosteroid therapy.     

Permissive and suppressive effects of dexamethasone on enzyme induction in hepatocyte co-cultures

1. Steroids are known to act as permissive factors in hepatocytes. This study shows that dexamethasone (DEX) is a permissive factor for induction of CYP2B1/2, CYP3A1, CYP2A1 and probably also CYP2C11 in cultures with primary rat hepatocytes. 2. The induction factor of phenobarbital (PB)-induced formation of 16beta-hydroxytestosterone (OHT), a testosterone biotransformation product predominantly formed by CYP2B1, is increased 18-fold by the addition of 32 nM DEX to the culture medium. Interestingly, higher concentrations of DEX up to 1000 nM led to a concentration-dependent maximally 5-fold decrease (p = 0.002) of phenobarbital-induced 16beta-OHT formation compared with the effect observed with 32 nM DEX. Thus, DEX shows permissive and suppressive effects on enzyme induction depending on the concentration of the glucocorticoid. 3. Qualitatively similar but smaller permissive and suppressive effects of DEX were observed for PB-induced CYP3A1 activity as evidenced by formation of 2beta-, 6beta- and 15beta-OHT. 4. DEX is a permissive factor for induction of CYP2A1 activity by 3-methylcholanthrene (3MC), as evidenced by the formation of 7alpha-OHT. Without addition of DEX, 3MC did not induce formation of 7alpha-OHT, whereas an almost 3-fold induction occurred in the presence of DEX. In contrast to CYP2B and CYP3A, concentrations up to 1000 nM DEX were not suppressive for the induction of CYP2A1. 5. We described recently a technique that allows preparation of cultures from cryopreserved hepatocytes. An almost identical influence of dexamethasone on enzyme induction was observed here in cultures from cryopreserved compared with freshly isolated hepatocytes. 6. Cultures with primary hepatocyte cultures represent a well-established technique for the study of drug-drug interactions. However, a large interlaboratory variation is known. Our study provides evidence that differences in glucocorticoid concentration in the culture medium contribute to this variation.     

Bioequivalence evaluation of two brands of gliclazide 80 mg tablets (Glyzide & Diamicron)--in healthy human volunteers

A randomized, two-way, crossover, bioequivalence study in 24 fasting, healthy, male volunteers was conducted to compare two brands of gliclazide 80 mg tablets, Glyzide (Julphar, UAE) as test and Diamicron (Servier Industries, France) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in joint venture with Speciality Hospital, Amman, Jordan. The drug was administered with 240 ml of 20% glucose solution after a 10 h overnight fasting. After dosing, serial blood samples were collected for a period of 48 h. Plasma harvested from blood was analyzed for gliclazide by validated HPLC method. Various pharmacokinetic parameters including AUC(0-t), AUC(0- proportional, variant), C(max), T(max), T(1/2), and elimination rate constant were determined from plasma concentrations of both formulations. Statistical modules (ANOVA and 90% confidence intervals) were applied to AUC(0-t), AUC(0- proportional, variant), and C(max) for bioequivalence evaluation of the two brands which revealed no significant difference between them, and 90% CI fell within US FDA accepted bioequivalence range of 80-125%. Based on these statistical inferences, Glyzide was judged bioequivalent to Diamicron.     

Bioequivalence evaluation of two brands of metformin 500 mg tablets (Dialon & Glucophage)--in healthy human volunteers

A randomized, two-way, crossover study was conducted in 24 fasting, healthy, male volunteers to compare the bioavailability of two brands of metformin 500 mg tablets; Dialon (Julphar, UAE) as test and Glucophage (Lipha Pharmaceutical Industries, France) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in joint venture with Al-Mowasah Hospital, Amman, Jordan. The drug was administered with 240 ml of water after a 10-h overnight fasting on two treatment days separated by 1-week washout period. After dosing, serial blood samples were collected for a period of 30 h. Plasma harvested from blood was analyzed for metformin by validated HPLC method with UV-visible detector capable to detect metformin in the range of 0.05-5.0 microg/ml with limit of quantitation of 0.05 microg/ml. Various pharmacokinetic parameters including AUC(0-t), AUC(0-proportional to), C(max), T(max), T(1/2), and lambda(Z) were determined from plasma concentrations of both formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-proportional to) and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on ANOVA; 90% confidence interval (97.9-110.8% for AUC(0-t), 97.4-110.7% for AUC(0-proportional to); 95.3-110.5% for C(max)) of test/reference ratio for these parameters were found within bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Dialon is bioequivalent to Glucophage.