Ocular toxicology: the Draize eye test

PURPOSE OF REVIEW: Superficial ocular tissues are frequently exposed to damage produced by chemical compounds applied on or around the ocular surface for cosmetic, therapeutic or accidental reasons. An experimental test measuring objectively and in a reproducible way any potential damaging effect would certainly help in prospectively minimizing unwanted effects. The Draize eye test, although commonly employed to date, does not seem to be quite satisfactory in this respect. RECENT FINDINGS: The limits of the Draize eye test and the results of some modified versions of the test are analysed. In particular, the good predictivity of the so-called low-volume Draize eye test and the recent findings of studies on the in-vitro and ex-vivo alternatives to the Draize eye test are presented. SUMMARY: The Draize eye test, despite criticisms, has been used in the clinical setting for a long time and still remains the reference protocol. To date, only a combination of alternative methods, none of which is devoid of serious criticisms, seems to be able to exhaustively recognize potential irritants and avoiding for that purpose, in some cases, the use of living animals.     

Improving the Procedure for Detection of Intrahepatic Transplanted Islets by Magnetic Resonance Imaging

Islet transplantation is an effective therapy for restoring normoglycemia in type-1 diabetes, but long-term islet graft function is achieved only in a minority of cases. Noninvasive magnetic resonance imaging of pancreatic islets is an attractive option for "real-time" monitoring of graft evolution. So far, previous studies have been performed in the absence of a standardized labeling procedure and, besides a feasibility study in patients, the effectiveness and safety of various labeling approaches were tested only with high field magnets (4.7 T). In this study, we addressed: (a) standardization of a labeling procedure for human islets with clinically-approved contrast agent Endorem^®, (b) safety aspects of labeling related to inflammation and (c) quality of imaging both at 7 T and 1.5 T. We have highlighted that the ratio of Endorem^®/islet is crucial for reproducible labeling, with a ratio of 2.24 ug/IEQ, allowing successful in vivo imaging both with 1.5 T and 7.0 T magnets up to 143 days after intrahepatic transplant. With this standardized labeling procedure, labeled islets are neither inflamed nor more susceptible to inflammatory insults than unlabeled ones. This report represents an important contribution towards the development of a standardized and safe clinical protocol for the noninvasive imaging of transplanted islets in humans.     

Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells

Successful transplantation requires the prevention of allograft rejection and, in the case of transplantation to treat autoimmune disease, the suppression of autoimmune responses. The standard immunosuppressive treatment regimen given to patients with autoimmune type 1 diabetes who have received an islet transplant results in the loss of T cells. In many other situations, the immune system responds to T cell loss through cytokine-dependant homeostatic proliferation of any remaining T cells. Here we show that T cell loss after islet transplantation in patients with autoimmune type 1 diabetes was associated with both increased serum concentrations of IL-7 and IL-15 and in vivo proliferation of memory CD45RO(+) T cells, highly enriched in autoreactive glutamic acid decarboxylase 65-specific T cell clones. Immunosuppression with FK506 and rapamycin after transplantation resulted in a chronic homeostatic expansion of T cells, which acquired effector function after immunosuppression was removed. In contrast, the cytostatic drug mycophenolate mofetil efficiently blocked homeostatic T cell expansion. We propose that the increased production of cytokines that induce homeostatic expansion could contribute to recurrent autoimmunity in transplanted patients with autoimmune disease and that therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet transplantation.     

Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: the GISEA study

OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-alpha (TNF-alpha) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF-alpha blockers. All patients received one TNF-alpha blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-alpha blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA.     

Kapillarmikroskopie und rheumatische Erkrankungen: State of the art

Nailfold capillaroscopy (NVC) represents the best method for analyzing microvascular abnormalities in rheumatic diseases. Raynaud’s phenomenon (RP) represents the most frequent clinical aspect of microvascular involvement and is a key feature of several such diseases. Under normal conditions or in primary RP (exclusion by the cold-exposure test), the normal nailfold capillaroscopic pattern shows a regular disposition of the capillary loops within the nail bed. However, in subjects suffering from secondary RP, one or more alterations in the capillaroscopic findings should alert the physician to search for an underlying connective tissue disease. Architectural disorganization, giant capillaries, hemorrhages, loss of capillaries and avascular areas characterize more than 95% of patients with overt systemic sclerosis (sclerodema, SSc). Therefore, the term “scleroderma pattern”, includes all capillaroscopic changes typical of the microvascular involvement in SSc. The capillaroscopic aspects observed in dermatomyositis and in undifferentiated connective tissue disease are generally reported as “scleroderma-like patterns”. This peripheral microangiopathy can be effectively detected early in the course of the disease and studied in detail by nailfold capillaroscopy or, better, with NVC. In addition, early differential diagnosis between primary and secondary RP is the greatest advantage NVC has to offer. In addition, interesting capillaroscopic changes have been observed in systemic lupus erythematosus, antiphospholipid syndrome and Sjögren’s syndrome. However, further epidemiological and clinical studies are needed to better standardize NVC patterns.     

Delta-Aminolevulinic Acid Dehydratase Activity of Erythrocytes and Liver Tissue in Man

The delta-aminolevulinic acid dehydratase (ALAD) activity of erythrocytes and of liver tissue was studied in subjects not occupationally exposed to lead. A considerable heterogeneity in the levels of ALAD activity of erythrocytes and of blood lead was confirmed in this group of subjects, an expression of the varying degree of absorption of lead that occurs in each individual who is exposed through pollution of the atmosphere and food. In the group of subjects studied, there was a correlation between the values of erythrocyte ALAD activity and the values of ALAD activity of liver tissue.     

Surgical management of liver hydatidosis: a multicentre series of 1412 patients

Background: The management of hydatid liver disease (HLD) includes various nonsurgical and surgical treatment options. Methods: The purpose of the present longitudinal study was to report the changes in surgical management and the consequent outcome of HLD patients in 10 referral surgical centres in Argentina from 1975 to 2007. The study result analysis was divided into two study periods (1975–1990 and 1991–2007). Results: A total of 1412 patients underwent radical (Group 1: 396 patients), conservative (Group 2: 748 patients) or combined (Group 3: 536 interventions in 268 patients) surgical procedures. The overall mortality and complication rate (Clavien I–IV) was 1.8 and 39% respectively. The complication rate was significantly lower in Group 1 (26%) compared with Group 2 (45%) and Group 3 (42%) There was a significant decrease in mortality (2.3 vs. 1%), complication (42 vs. 34%) and early reoperation (12 vs. 6%) rates between the first study part (918 patients) and the second study part (494 patients). During a median follow‐up of 7 years, there was a significant decrease in the first part of this study in the late reoperation rate (8.4–3%) and in disease recurrence (9–1.6%). Conclusion: This large national observational multicentre series shows a significant improvement in surgical management of HLD in Argentina, with a decrease in mortality, morbidity, early and late reoperation and recurrence rates. A recent trend was observed in favour of an earlier diagnosis, less complicated clinical presentation and recent use of minimally invasive approaches.