HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8(+) T cells producing both interferon-gamma and tumor necrosis factor-alpha

CD8(+) T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8(+) T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8(+) T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8(+) T cells secreting interferon-gamma but no tumor necrosis factor-alpha (TNF-alpha) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P =.57), a subset of CD8(+) T cells secreting both inter-feron-gamma and TNF-alpha was substantially more strongly associated with cytotoxicity (R = 0.67, P <.001). This subset of CD8(+) T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex vivo HIV-1-specific cytoxicity than CD8(+) T cells secreting solely interferon-gamma following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8(+) T cells is preferentially mediated by a subset of CD8(+) T cells secreting both interferon-gamma and TNF-alpha.     

Kinetics of thymidine incorporation into detergent-soluble DNA of mouse lymphocytes.

We reported recently that splenocytes from concanavalin A-stimulated mice rapidly incorporated [3H]thymidine into non-mitochondrial DNA that was detergent soluble and distributed in size classes between 200 and 5000 base pairs. In this report we show that small [3H]thymidine-labeled oligonucleotides (less than 100 base pairs long) appear by 15 min. Subsequently, [3H]thymidine in small oligonucleotides diminishes as incorporation into larger size classes of detergent-soluble DNA occurs in a pattern that is stable for at least 3 hr. Although incorporation of [3H]thymidine into the oligonucleotides is not sensitive to aphidicolin or hydroxyurea, the appearance of [3H]thymidine in larger species is blocked by both drugs. These results indicate that the enzymatic process involved in synthesis of oligonucleotides is somehow distinct from the process involved in synthesis of larger detergent-soluble size classes. Synthesis of the latter may be replication related.     

Developing an Older Adult Volunteer Program in a New York Chinese Community: An Evidence-Based Approach

This study reports the results of a pilot volunteer project for older Chinese immigrants and documents benefits for both volunteers and caregiver recipients. Using a social marketing approach, the volunteer project was designed as a social model to promote better health among older Chinese immigrants in New York City. The packaging of this health promotion project as a volunteer program was based on a strengths perspective. In the program, 18 older Chinese immigrants were trained to provide support and referral to family caregivers of ill relatives in the Chinese community. At 6 months, outcomes were evaluated for both volunteers and caregivers. The older volunteers perceived benefits associated with volunteering, specifically, a greater sense of well-being and satisfaction with life. In addition, the majority of volunteers felt empowered by training and volunteering (100 %), felt the skills they learned improved communication with their own families (90 %), and reported physical and emotional health benefits (61 %). At the same time, caregivers reported stress reduction following volunteer support. Findings suggest that a volunteer program model may be an effective health promotion intervention for older Chinese immigrants.     

Discussion on incidence of tuberculosis patients among nurses in Osaka City

PURPOSE: To analyze conditions of developing TB among nurses and to discuss preventive measures. METHODS: TB patient cards of nurses and other health workers registered in Osaka City from 1999 to 2003 were studied. RESULTS: Incidence rate of TB among female nurse/ assistant-nurse was 3.0 times higher than that of all female population. The route of case finding were as follows with descending order, visit to medical facilities with symptoms (55.8%), regular health check (35.8%), individual health check (5.8%), and contact examination (2.5%). Among risk factors related to the development of TB work in hospitals account for 55.0% in nurse patients of all ages, 72.5% in 20s, 47.4% in 30s, 37.5% in 40s, 36.4% in 50s and 0% in 60s. Individual risk factors were identified as follows in descending order, "TB patients diagnosed in the hospital." (10.0%), "examined at TB contact examination." (9.2%), "history of TB treatment at 18 years of age and over" (7.5%), "working experience in TB hospital/TB ward." (6.7%), "TB patients diagnosed among colleague." (5.0%), "increased reaction of tuberculin skin test after employment." (2.5%), "diagnosis of 'healed TB lesion" at regular health check." (1.7%), "default of chemoprophylaxis" (1.7%). Among various risk factors, "examined at TB contact examination" and "TB patients diagnosed in the hospital" are the two most common factors and occupied 38.8% in patients in 20s. DISCUSSION: Therefore it is important to promote further nosocomial TB infection control with a view to lower incidence rate of TB among nurses, which is 3 times higher than that of all female population.     

Total joint arthroplasty: When do fatal or near-fatal complications occur?

BACKGROUND: With the recent trend toward minimally invasive total joint arthroplasty and the increased emphasis on faster recovery and shorter hospital stays, it has become increasingly important to recognize the timing and severity of the various complications associated with elective total joint arthroplasty to ensure that early patient discharge is a safe practice. METHODS: We evaluated the systemic and local complications associated with primary unilateral lower-extremity arthroplasties performed during one year in 1636 patients. A total of 966 patients had a primary total hip arthroplasty, and 670 had a primary total knee arthroplasty. All complications that occurred in the hospital and for six weeks following the index surgery were recorded. The circumstances leading to the complications and the details of the therapeutic intervention for each complication were recorded. Analyses were performed to predict the factors that predispose patients to serious complications. RESULTS: One patient (0.06%) in the cohort died during the hospital stay. There were a total of 104 major (life-threatening) complications, including cardiac arrest (one), tachyarrhythmia (thirty-three), pulmonary edema or congestive heart failure (ten), myocardial infarction (six), hypotensive crisis (four), pulmonary embolus (twenty-five), acute renal failure (fourteen), stroke (six), bowel obstruction or perforation (three), and pneumothorax (one). There were seventeen major local complications. Ninety-four (90%) of the major complications occurred within four days after the index surgery. Although older age, increased body mass, and preexistent comorbidities were important predisposing factors for serious medical complications, 58% of the patients who had life-threatening complications develop had no identifiable predisposing factors. CONCLUSIONS: This study demonstrated that most of the complications of lower-extremity total joint replacement occur within the time-frame of the typical hospital stay. Given the serious nature of some of these complications and the inability to identify many of the patients who may be at risk, we caution against early discharge of patients from the hospital after elective total joint arthroplasty in the lower extremity.     

Effects of etanercept, a tumour necrosis factor-alpha antagonist, in an experimental model of periodontitis in rats

BACKGROUND AND PURPOSE: Etanercept is a tumour necrosis factor antagonist with anti-inflammatory effects. The aim of our study was to evaluate, for the first time, the therapeutic efficacy of in vivo inhibition of TNF-alpha in an experimental model of periodontitis. EXPERIMENTAL APPROACH: Periodontitis was induced in adult male Sprague-Dawley rats by placing a nylon thread ligature around the lower 1st molars. Etanercept was administered at a dose of 5 mg kg-1, s.c., after placement of the ligature. KEY RESULTS: Periodontitis in rats resulted in an inflammatory process characterized by oedema, neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells, production of a range of inflammatory mediators, tissue damage, apoptosis and disease. Treatment of the rats with etanercept (5 mg kg-1, s.c., after placement of the ligature) significantly reduced the degree of (1) periodontitis inflammation and tissue injury (histological score), (2) infiltration of neutrophils (MPO evaluation), (3) iNOS (the expression of nitrotyrosine and cytokines (eg TNF-alpha)) and (4) apoptosis (Bax and Bcl-2 expression). CONCLUSIONS AND IMPLICATIONS: Taken together, our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury, events associated with periodontitis.     

Episcleral brachytherapy for uveal melanoma: analysis of 136 cases

Purpose  

To assess the results of I-125 episcleral brachytherapy (EB) in uveal melanoma: tumour control, visual acuity (VA), eye preservation and survival.     

Comparing the effectiveness of polyethylene covers (Gladwrap) with lanolin (Duratears) eye ointment to prevent corneal abrasions in critically ill patients: a randomized controlled study

Background

In unconscious ventilated patients, various eye protective measures have been used to prevent corneal abrasions. Two randomized controlled studies in Australia had compared the effectiveness of polyethylene films and eye instillations to prevent corneal abrasions but results were inconsistent. The local acceptance of polyethylene films as a standard eye protective measure is still limited.

Objectives

Our study aims to compare the effectiveness of polyethylene covers (Gladwrap™) with lanolin (Duratears^®) eye ointment in the prevention of corneal abrasions in critically ill patients.

Design

A prospective randomized controlled study was conducted between April 2004 and December 2005.

Setting and participants

One hundred and twenty ventilated patients admitted to the intensive care unit (ICU) were randomly assigned to receive either polyethylene covers or lanolin eye ointment to prevent corneal abrasions.

Methods

All participants received a standard eye care regime together with the eye protective interventions. A fluorescein stain test was performed by the eye care team daily and then weekly to detect any corneal abrasions.

Results

Four participants were not included in the data analysis as they died soon after commencement of the study. A total of 116 patients were included in the final analysis. Of the seven patients (6.0%) that had a positive fluorescein test, four (6.8%) were in the polyethylene covers group (n = 59) and three (5.3%) were in the lanolin eye ointment group (n = 57). This was not statistically significant (p = 0.519). One patient in the lanolin eye ointment group had an eye infection. Upon follow-up of those patients with positive fluorescein test results, two patients spontaneously converted to stain negative within 24 h and two patients died before the ophthalmologist's assessment. The remaining three patients were diagnosed to have epithelial cell loss without corneal abrasions.

Conclusions

With the implementation of a standardized eye care protocol, polyethylene cover is found to be equally effective in preventing corneal abrasions when compared with lanolin eye ointment. The additional benefit of polyethylene cover as a physical barrier to protect patients’ eyes needed further evaluation.     

Effects of thalidomide in a mouse model of cerulein-induced acute pancreatitis

Current knowledge shows that pathophysiology of acute pancreatitis is characterized by intraacinar enzyme activation and subsequent dysregulation in immune response. Interactions between leukocytes, soluble mediators such as cytokines and vascular endothelium contribute to the systemic progression of the inflammatory response, whose entity may--in the end--determine disease severity and outcome. Recently, it has been shown that TNF-[alpha] may be a novel target for the treatment of acute pancreatitis; but the role of thalidomide, an immunomodulatory agent that inhibits TNF-(alpha) and angiogenesis, has not been investigated so far. The aim of the present study was to assess the effects of thalidomide in a murine model of necrotizing acute pancreatitis. Necrotizing acute pancreatitis was induced in mice by intraperitoneal injection of cerulein (hourly, x5, 50 microg/kg); in another group of animals, thalidomide was administered (200 mg/kg orally) at 1 h after first cerulein injection. After 24 h, biochemical, histological, and immunohistochemical evidences of acute pancreatitis developed in all cerulein-treated mice. On the contrary, pancreatitis histological features, amylase, lipase, TNF-alpha and IL-1beta levels, pancreas edema, and myeloperoxidase activity as well as immunohistochemical staining for inflammatory cytokines, leukocyte adhesion molecules, transforming growth factor [beta], vascular endothelial growth factor, and apoptosis-related proteins were found reduced in thalidomide-treated mice. Therefore, thalidomide treatment attenuates the development of acute pancreatitis caused by cerulein in mice. We propose that this evidence may help to clarify the role of anti-TNF-alpha and immunomodulatory agents in patients with acute pancreatitis.     

TNF-alpha blockage in a mouse model of SCI: evidence for improved outcome

The aim of our study was to evaluate in vivo the therapeutic efficacy of genetic inhibition of TNF-alpha using TNF-R1 knockout mice in an experimental model of spinal cord trauma. Spinal cord injury was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. To elucidate whether the observed anti-inflammatory status is related to the inhibition of TNF-alpha, we also investigated the effect of infliximab, a TNF-alpha-soluble receptor construct, on spinal cord damage. Pharmacological and genetic TNF-alpha inhibition significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (evaluated by myeloperoxidase activity), (3) cytokine expression (TNF-alpha), (4) and apoptosis (terminal deoxynucleotidyltransferase-mediated uridine triphosphate end labeling staining, Bax, Bcl-2, and Fas-L expression). In a separate set of experiments, we have also demonstrated that TNF-alpha inhibition significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results demonstrate that inhibition of TNF-alpha reduces the development of inflammation and tissue injury associated with spinal cord trauma, suggesting a possible role of TNF-alpha on the pathogenesis of spinal cord injury.