Dazoxiben in human sepsis and adult respiratory distress syndrome

Levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2, are elevated in human and experimental septic shock. The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia. A randomized prospective study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome (hypoxemia, radiologic evidence of the syndrome, and intrapulmonary shunt greater than 20%) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis. Five subjects received dazoxiben and five received placebo. Dazoxiben, 100 mg, or placebo was injected intravenously every 4 hours for a maximum of 72 hours. Plasma immunoreactive TxB2 (iTxB2) levels were determined by radioimmunoassay. Before dazoxiben, the plasma iTxB2 level was 752 +/- 261 pg/ml (n = 5) and was reduced within 1 hour to 333 +/- 137 pg/ml. The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 +/- 67 pg/ml (n = 4) 60 hours after dosing. In contrast, placebo had no significant effect on plasma iTxB2 levels (n = 5) throughout the entire period of observation. Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance, intrapulmonary shunting, clotting studies, or extravascular lung water. One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died. We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom, but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis.     

Does the consumption of green tea reduce the risk of lung cancer among smokers?

Experimental and epidemiological studies were reviewed to assess whether the consumption of green tea could reduce the risk of lung cancer in smokers. Articles published since 1990 were located by searching electronic databases PubMed, Ovid and Science Direct, using keywords 'lung cancer', 'tea' and 'smoking' without any restriction on language. After relevant articles had been located, further papers were obtained from their reference lists. Evidence from experimental studies (in vitro animal and human trials) suggested that regular intake of green tea may be protective against tobacco carcinogens. However, the mechanism behind the protective effect is only partly understood. In most of the epidemiological studies reviewed, the green tea exposure was within 5 years of the interview or follow-up, which would coincide with the induction period and latent period of lung cancer. Longer term studies are thus needed to further quantify the cancer risk. There is some evidence suggesting regular intake of green tea at high level (>3 cups per day) may reduce the risk of smokers developing lung cancer. Improvement in measuring green tea intake is required in order to confirm the evidence from epidemiological studies.     

The quality of spiritual care--developing a standard

Spiritual care is an important aspect of holistic care. However, it is seldom the subject of audit, or included in quality standards. This article reports on the work of the Trent Hospice Audit Group (THAG) into the development of a quality standard for the assessment, delivery and evaluation of spiritual care. The standard was drafted by a multidisciplinary team and circulated among the THAG user group and other interested specialists, and subsequently revised. Three levels of assessment are defined and the different levels of expertise needed for these assessments identified. Education has been highlighted as a key issue in enabling effective use of the standard package. Although acknowledging possible limitations and the importance of professional judgement, the standard should help provide a consistent approach to assessment, care planning and outcome review of spiritual care.     

Cell therapy for type 1 diabetes

ABSTRACT

Introduction

Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by the shortage of donors and need for chronic immune suppression. Novel strategies are needed to prevent β-cell loss and to rescue production of endogenous insulin.     

Lactate down-regulates cellular poly(ADP-ribose) formation in cultured human skin fibroblasts

BACKGROUND: Polyadenosine diphosphate-ribose (poly(ADP-ribose)) is a nuclear polymer which is derived from nicotinamide adenine dinucleotide (NAD(+)) catalysed by poly(ADP-ribose) polymerase 1 (PARP-1). Aside from the well known role of poly(ADP-ribosyl)ation (pADPR) in DNA repair, pADPR is also involved in other cellular processes such as apoptosis and gene expression. However, the factors that regulate the level of pADPR are not fully elucidated. In view of the fact that healing wounds contain high concentrations of lactate (10-15 mM) and exogenous lactate reduce the NAD(+) pool in cultured fibroblasts, we propose that high lactate lowers the level of nuclear pADPR. MATERIALS AND METHODS: Neonatal human dermal fibroblasts (NHDF) were plated to subconfluence and allowed to adhere. Cells were treated with 15 mM l-lactate and pADPR production was assessed by immunofluorescence analysis using 10H antibody. Difference in pADPR production was determined by calculation of positively stained cells compared to total cell numbers. Inhibition of PARP activity was tested by treatment with 100 microM 3-aminobenzamide (3-AB). Specificity of the lactate effect on pADPR synthesis was verified by using the analogue d-lactate. The contents of nicotinamide adenine dinucleotide (NAD(+)) and its reduced form (NADH) in lactated and non-lactated cell cultures were quantified by the enzymatic cyclic assay. RESULTS: We found that exogenous l-lactate (15 mM) can significantly depress pADPR content in cultured fibroblasts. PARP-1 activity was inhibited by 3-AB and analogue d-lactate showed no effect on pADPR synthesis. NAD(+)/NADH ratio was significantly lowered in lactated compared to non-lactated cell culture. CONCLUSIONS: Exogenous l-lactate (15 mM) can depress pADPR content in cultured fibroblasts. In view of the fact that healing wounds contain such high concentrations of lactate, we propose that down regulation of pADPR is associated with elevated tissue repair via pADPR dependent gene expression. This observation is important in understanding the stimulation of lactate-mediated protein expression during wound healing.     

Measuring Marrow Density and Area Using Peripheral Quantitative Computed Tomography at the Tibia: Precision in Young and Older Adults and Individuals With Spinal Cord Injury

The objective of this study was to compare the test-retest precision error for peripheral quantitative computed tomography (pQCT)-derived marrow density and marrow area segmentation at the tibia using 3 software packages. A secondary analysis of pQCT data in young adults (n?=?18, mean?±?standard deviation 25.4?±?3.2?yr), older adults (n?=?47, 71.8?±?8.2?yr), and individuals with spinal cord injury (C1–T12 American Spinal Injury Association Impairment Scale, classes A–C; n?=?19, 43.5?±?8.6?yr) was conducted. Repeat scans of the tibial shaft (66%) were performed using pQCT (Stratec XCT2000). Test-retest precision errors (root mean square standard deviation and root mean square coefficient of variation [RMSCV%]) for marrow density (mg/cm³) and marrow area (mm²) were reported for the watershed-guided manual segmentation method (SliceOmatic version 4.3 [Sliceo-WS]) and the 2 threshold-based edge detection methods (Stratec version 6.0 [Stratec-TB] and BoneJ version 1.3.14 [BoneJ-TB]). Bland-Altman plots and 95% limits of agreement were computed to evaluate test-retest discrepancies within and between methods of analysis and subgroups. RMSCV% for marrow density segmentation was >5% for all methods across subgroups (Stratec-TB: 12.2%–28.5%, BoneJ-TB: 14.5%–25.2%, and Sliceo-WS: 10.9%–23.0%). RMSCV% for marrow area segmentation was within 5% for all methods across subgroups (Stratec-TB: 1.9%–4.4%, BoneJ-TB: 2.6%–5.1%, and Sliceo-WS: 2.4%–4.5%), except using BoneJ-TB in older adults. Intermethod discrepancies in marrow density appeared to be present across the range of marrow density values and did not differ by subgroup. Intermethod discrepancies varied to a greater extent for marrow area and were found to be more frequently at mid- to higher-range values for those with spinal cord injury. Precision error for pQCT-derived marrow density segmentation exceeded 5% for all methods of analysis across a range of bone mineral densities and fat infiltration, whereas precision error for marrow area segmentation ranged from 2% to 5%. Further investigation is necessary to determine alternative acquisition and analysis methods for pQCT-derived marrow segmentation.     

Perfusion MR imaging of extracranial tumor angiogenesis

Dynamic contrast-enhanced MRI (DCE-MRI) using small molecular weight gadolinium chelates enables noninvasive imaging characterization of tissue vascularity. Depending on the technique used, data reflecting tissue perfusion (blood flow, blood volume, mean transit time), microvessel permeability surface area product, and extracellular leakage space can be obtained. Insights into these physiological processes can be obtained from inspection of kinetic enhancement curves or by the application of complex compartmental modeling techniques. Combining morphologic and kinetic features can increase the accuracy of clinical diagnoses. Potential clinical applications include screening for malignant disease, lesion characterization, monitoring lesion response to treatment, and assessment of residual disease. Newer applications include prognostication, pharmacodynamic assessments of antivascular anticancer drugs, and predicting efficacy of treatment. For dynamic MRI to enter into widespread clinical practice, it will be necessary to develop standardized approaches to measurement and robust analysis approaches.