The role and regulation of apoptosis in sepsis

Today, sepsis continues to be a growing problem in the critically ill patient population. A number of laboratories have been interested in understanding how changes in immune cell apoptosis during sepsis appear to contribute to septic morbidity. Consistently, it has been found that immune cell apoptosis is altered in a variety of tissue sites and cell populations both in experimental animals and humans. While divergent mediators, such as steroids and TNF, contribute to some of these apoptotic changes, their effects are tissue and cell population selective. Inhibition of FasL-Fas signaling (by either FasL gene deficiency, in vivo gene silencing [siRNA] or with FasL binding protein) protects septic mice from the onset of marked apoptosis and the morbidity/mortality seen in sepsis. Further, this extrinsic apoptosis response appears to utilize aspects of the Bid-induced mitochondrial pathway. This is in keeping with the findings that pan-specific caspase inhibition or the overexpression of Bcl-2 also protect these animals from the sequellae of sepsis.     

Platelet activity, reactivity and platelet-leukocyte conjugate formation before and after exhaustive or moderate exercise in patients with IDDM

Diabetes mellitus alters blood coagulation and platelet function which supports the suggestion that diabetes mellitus is a hypercoagulable state. Firstly the aim of the study was to investigate if differences in platelet activity, reactivity and platelet-leukocyte conjugate (PLC) formation can be observed in subjects with IDDM; secondly, if differences can be seen between the diabetic and control group concerning exercise-induced changes in platelet activation and conjugate formation; and thirdly, if different types of exercise lead to different patterns in platelet activation. Sixteen subjects with IDDM and 16 controls underwent a maximal step test and an endurance test (90% IAT, 45 min). Blood samples were taken after 30 min rest, and immediately and 1 h after completion of exercise. CD62P expression and differentiated platelet-leukocyte conjugates (CD45, CD14, CD41) were detected flow-cytometrically with and without stimulation with TRAP-6. The rest values of the platelet-granulocyte (PGC) and platelet-lymphocyte conjugates (PLyC) were higher (P < 0.05) in the diabetics. After exercise, platelet reactivity (CD62P-TRAP; P < 0.05) but not the activity (CD62P-unstimulated), as well as all different conjugates with or without stimulation were increased (P < 0.05) independently from the group. Differences according to the type of exercise were barely observable. IDDM without vascular complications leads to higher PCG and PLyC at rest and to identical increases in differentiated platelet-leukocyte formation after exercise in comparison with matched controls.     

Subthalamic stimulation differentially modulates declarative and nondeclarative memory

Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.     

Still confused about rose bengal?

We have surveyed the ophthalmic literature of the last five years in an attempt to evaluate the use and usefulness of Rose Bengal staining as an aid to differential diagnosis in dry eyes. Included both as a criterion and as an adjunct measure of disease progression, Rose Bengal scores of patients with different dry eye conditions overlap, sometimes to a considerable extent. A mechanistic link between staining with this dye and disease etiology is unlikely; however, Rose Bengal could be a surrogate marker of changes in ocular surface physiology. The question whether the extent and pattern of staining with Rose Bengal provide the clinician with information not available from other tests, and in particular from fluorescein staining of the ocular surface, has to be answered positively, though the nature of this information is not clearly understood. A more widespread recognition that Rose Bengal is not a vital dye is necessary in order not to bias the interpretation of experimental results.     

Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus

OBJECTIVE: Inhibition of T cell DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo, suggesting that T cell DNA hypomethylation may contribute to autoimmunity. The hypomethylation effects are due, in part, to overexpression of lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18). Importantly, T cells from patients with active lupus have hypomethylated DNA and overexpress LFA-1 on an autoreactive subset, suggesting that the same mechanism could contribute to human lupus. The present study investigated the nature of the methylation change that affects LFA-1 expression in vitro and in human lupus. METHODS: Bisulfite sequencing was used to determine the methylation status of the ITGAL promoter and flanking regions in T cells from lupus patients and healthy subjects, and in T cells treated with DNA methylation inhibitors. "Patch" methylation of promoter sequences in reporter constructs was used to determine the functional significance of the methylation changes. RESULTS: Hypomethylation of specific sequences flanking the ITGAL promoter was seen in T cells from patients with active lupus and in T cells treated with 5-azacytidine and procainamide. Patch methylation of this region suppressed ITGAL promoter function. CONCLUSION: DNA methylation changes occur in specific sequences that regulate LFA-1 expression in lupus T cells and in the hypomethylation model, indicating that altered methylation of specific genes may play a role in the pathogenesis of lupus.     

Evaluation of mammographic and clinical follow-up after 755 stereotactic vacuum-assisted breast biopsies

PURPOSE: Stereotactic vacuum-assisted breast biopsy (VB) is a new method that promises high accuracy and reliability. In order to avoid surgery in cases with benign histology the examination must be quality assured and the accuracy should be well established. We present follow-up data of 755 VBs with benign results. METHODS: In all, 984 of 1268 consecutive VBs proved histopathologically benign (lobular carcinoma in situ and atypical ductal hyperplasia not included). Follow-up data are available for 755 of 984 (77%) lesions and constitute the basis of this evaluation. Follow-up mammograms were performed of 728 lesions at 6 to 67 months (mean 24, median 17.8) after VB. RESULTS: Seven technically unsuccessful cases underwent immediate rebiopsy; 3 unsuccessful cases were diagnosed otherwise. No false negative occurred among the 752 followed-up, eventually successful VBs. On follow-up mammography 444 of 728 (61%) benign lesions proved radiologically completely removed, 284 (39%) partially. In 6 cases (0.8%) a surgical biopsy was performed again during the follow-up time confirming the benign result. No scar was seen in 96%, a slight scar in 3.8%, and a small stellate scar with possible diagnostic interference in 0.3%. CONCLUSIONS: A benign diagnosis of quality assured VB is very reliable and leads to no or minimal scarring.     

Cost-effectiveness of sentinel lymph node biopsy in thin melanomas

BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for thin melanomas with poor prognostic features; however, few metastases are identified. The purpose of this study was to assess the cost effectiveness of SLNB in this population. METHODS: The prospective melanoma database was reviewed to identify patients with melanomas <1.2 mm thick who had undergone SLNB. Physician and hospital charges were collected from the appropriate billing department. RESULTS: A total of 138 patients were identified over an 8-year period (1994-2002). Two patients with positive SLNs were identified (1.4%), one with a melanoma <1 mm thick. Patient charges for SLNB ranged from $10,096 to $15,223 US dollars, compared with $1000 to $1740 US dollars for wide excision as an outpatient. Using these charges, the cost to identify a single positive SLN would be between $696,600 and $1,051,100 US dollars. The cost for wide excision would be between $69,000 and $120,100 US dollars. Assuming that all patients with a positive SLN would die of melanoma, the cost per life saved would be $627,000 to $931,000 US dollars. CONCLUSIONS: The cost of performing SLNB in this population is great and only a small number will have disease identified that will alter treatment. These data call into question the appropriateness of SLNB for thin melanomas.