Pharmacokinetics of perfluorobutane following intravenous bolus injection and continuous infusion of sonazoid in healthy volunteers and in patients with reduced pulmonary diffusing capacity

The ultrasound contrast agent Sonazoidtrade mark was administered as an i.v. bolus injection of 0.6 microL microbubbles/kg body weight or as a continuous infusion over 30 min at a rate of 1.2 microL microbubbles/kg body weight to healthy volunteers and patients with reduced pulmonary diffusing capacity. Expired air and blood samples were collected from 32 subjects and perfluorobutane (PFB) gas was analyzed using validated gas chromatography mass spectrometry methods. Blood concentrations of PFB declined biphasicly with a distribution half-life (t(0.5 to 15)) of 2 to 3 min and an elimination half-life (t(15 to 120)) of 30 to 45 min. Area under the curve (AUC) values in patients with impaired gas diffusion were significantly larger than those in healthy volunteers. The exhalation kinetics were somewhat variable with a PFB elimination half-life (t(15 to 120)) of 28 to 111 min. Clearance of PFB was independent of study population and mode of administration. There were no deaths and no serious adverse events that resulted in the withdrawal of a subject from the study. With the exception that arthralgia predominated in healthy volunteers, healthy volunteers and diseased subjects did not show a different adverse event profile whether Sonazoid was administered as a bolus injection or as an infusion. Assessment of laboratory parameters (serum biochemistry, haematology and urinalysis), vital signs, oxygen saturation and electrocardiograms (ECGs) showed no changes which caused safety concern. (E-mail: Kristin.Landmark@ge.com).     

Comparison of HR MAS MR spectroscopic profiles of breast cancer tissue with clinical parameters

Breast cancer is the most frequent form of cancer in women and improved diagnostic methods are desirable. Malignant cells have altered metabolism and metabolic mapping might become a tool in cancer diagnostics. High-resolution magic angle spinning (HR MAS) MR spectroscopy of tissue biopsies provides detailed information on metabolic composition. The 600 MHz 1H HR MAS spectra were acquired of breast cancer tissue from 85 patients and adjacent non-involved tissue from 18 of these patients. Tissue specimens were investigated by microscopy after MR analysis. The resulting spectra were examined by three different approaches. Relative intensities of glycerophosphocholine (GPC), phosphocholine (PC) and choline were compared for cancerous and non-involved specimens. Eight metabolites, choline, creatine, beta-glucose, GPC, glycine, myo-inositol, PC and taurine, were quantified from the recorded spectra and compared with tumor histological type and size, patient's lymph node status and tissue composition of sample. The spectra were also compared with tumor histological type and size, lymph node status and tissue composition of samples using principal component analysis (PCA). Tumor samples could be distinguished from non-involved samples (82% sensitivity, 100% specificity) based on relative intensities of signals from GPC, PC and choline in 1H HR MAS spectra. Tissue concentrations of metabolites showed few differences between groups of samples, which can be caused by limitations in the quantification procedure. Choline and glycine concentrations were found to be significantly higher in tumors larger than 2 cm compared with smaller tumors. PCA of MAS spectra from patients with invasive ductal carcinomas indicated a possible prediction of spread to axillary lymph nodes. Metabolite estimates and PCA of MAS spectra were influenced by the percentage of tumor cells in the investigated specimens.     

Passage meditation reduces perceived stress in health professionals: a randomized, controlled trial

The authors evaluated an 8-week, 2-hr per week training for physicians, nurses, chaplains, and other health professionals using nonsectarian, spiritually based self-management tools based on passage meditation (E. Easwaran, 1978/1991). Participants were randomized to intervention (n = 27) or waiting list (n = 31). Pretest, posttest, and 8- and 19-week follow-up data were gathered on 8 measures, including perceived stress, burnout, mental health, and psychological well-being. Aggregated across examinations, beneficial treatment effects were observed on stress (p = .0013) and mental health (p = .03). Treatment effects on stress were mediated by adherence to practices (p = .05). Stress reductions remained large at 19 weeks (84% of the pretest standard deviation, p = .006). Evidence suggests this program reduces stress and may enhance mental health.     

Proposal on limits for chemical exposure in saturation divers' working atmosphere: the case of benzene

Saturation diving is performed under extreme environmental conditions. The divers are confined to a limited space for several weeks under high environmental pressure and elevated oxygen partial pressure. At present, divers are protected against chemical exposure by standard exposure limits only adjusted for the increased exposure length, i.e. from 8 to 24 hours a day and from 5 to 7 days a week. The objective of the present study was to indicate a procedure for derivation of occupational exposure limits for saturation diving, termed hyperbaric exposure limits (HEL). Using benzene as an example, a procedure is described that includes identification of the latest key documents, extensive literature search with defined exclusion criteria for the literature retrieved. Hematotoxicity and leukemia were defined as the critical effects, and exposure limits based upon concentration and cumulative exposure data and corresponding risks of leukemia were calculated. Possible interactions of high pressure, elevated pO?, and continuous exposure have been assessed, and incorporated in a final suggestion of a HEL for benzene. The procedure should be applicable for other relevant chemicals in the divers' breathing atmosphere. It is emphasized that the lack of interactions from pressure and oxygen indicated for benzene may be completely different for other chemicals.     

Patient characteristics associated with quality of life in European women seeking treatment for urinary incontinence: results from PURE

OBJECTIVE: To investigate the association between patient characteristics and disease-specific and generic quality of life (QOL) as well as the degree of bother in women seeking treatment for urinary incontinence (UI). METHODS: The Prospective Urinary Incontinence Research (PURE) was a 6-mo observational study with 1055 physicians from 15 European countries enrolling 9487 women. QOL was assessed at the enrolment visit using the urinary Incontinence Quality of Life questionnaire (I-QOL) and the generic EQ-5D. A single-item instrument was used to measure the degree of bother. UI severity was assessed using the Sandvik Index. UI was categorised into stress (SUI), mixed (MUI), and urge (UUI) urinary incontinence by a patient-administered instrument (Stress and Urge Incontinence Questionnaire [S/UIQ]). Multivariate linear (I-QOL, EQ-5D Visual Analogue Scale) and logistic (bother, EQ-5D health state index) regressions were performed. RESULTS: Mean total I-QOL scores were significantly and independently associated with UI severity, nocturia, age, UI subtype, number of selected concomitant medical conditions, length of suffering from UI before contacting a doctor, smoking status, ongoing use of UI medication, and country. After adjusting for all the covariates, the total I-QOL scores for SUI, MUI, and UUI were 62.7, 53.8 and 60.1, respectively. As with I-QOL, UI severity was also the most important predictor for bother. The number of concomitant medical conditions, together with UI severity, was the variable most strongly associated with EQ-5D. CONCLUSION: In addition to the UI subtypes, severity of UI should be given more importance in treatment algorithms and in treatment decision-making by both the patient and the physician.     

CD10+ stromal cells form B-lymphocyte maturation niches in the human bone marrow

In adult mammals, early B-lymphopoiesis takes place in the bone marrow in close association with stromal cells. Both the phenotype of the stromal cells and the molecules involved in this essential interaction are as yet inadequately described. In this study, all benign, differentiating B-cells (Pax-5+ lymphoid cells) are shown, by using two-colour immunohistochemistry on biopsies from human bone marrow, to be in close contact with scant dendritic CD10+ stromal cells until they leave via the sinusoids. This CD10+ stromal cell population does not fully overlap with the VCAM-1+ stromal cell population. Furthermore, using a set of B-cell differentiation markers (TdT, Pax-5, and CD20), B-cell development is shown to be spatially oriented, with maturation progressing towards bone marrow sinusoids. In conclusion, CD10+ stromal cells form distinct B-lymphocyte maturation niches in the human bone marrow.     

Recurrent high-grade cervical lesion after primary conization is associated with persistent human papillomavirus infection in Norway

Objective

This retrospective registry-based study aimed to assess the human papillomavirus (HPV)-type distribution in primary and recurrent high-grade cervical intraepithelial neoplasia (CIN2 +), and to discriminate pre-existing from newly-acquired infections.

Methods

Cervical specimens from 58 women (median age (Q1–Q3): 37.6 (31.7–44.9)) who underwent primary (1998–2003) and repeat conizations were confirmed as CIN2 + during expert pathology review. HPV testing was performed using PCR MP-TS123 Luminex for 16 HPV types. Molecular HPV16 E6 and HPV18 LCR DNA sequencing was performed on specimens with persistent HPV16/18.

Results

All 58 paired cones were HPV positive; 49 had CIN3 + in the primary cone. Forty-seven (95.9%) women with primary CIN3 + and recurrent CIN2 + had persistent high-risk (hr) HPV infection, of which 74.5% were HPV16/18. Two women had probable newly-acquired HPV16/52/56 and HPV39 infections. One woman with persistent HPV52 also had a probable new HPV16 E6 variant in the recurrent CIN2 +. Median time delay (Q1–Q3) between conizations was 2.0 years (1.1–4.0), being shorter for women older than 40 years: 2.6 years (1.1–3.7) than for women younger than 40 years: 6.0 years (2.0–8.7). Primary conization histology revealed CIN3, cervical adenocarcinoma in situ and microinvasive carcinomas in 43 (87.8%), 5 (10.2%) and 1 (2.0%) women, respectively. Primary HPV16- and HPV18-infected CIN3 + had a shorter delay between conizations: 1.8 years (1.2–4.4) and 2.2 years (0.4–NE), respectively, compared to HPV33-: 3.8 years (3.3–7.8) or other HPV type-infected: 8.2 years (6.0–NE) CIN3 +.

Conclusions

Routine post-conization hr-HPV DNA testing together with cervical cytology may provide a better prediction for potential recurrent disease. Further, primary prevention through adolescent vaccination may prevent CIN2 + and its recurrence.     

Brain-specific proteins in the cerebrospinal fluid of severely asphyxiated newborn infants

Upcoming trials of neuroprotective strategies in severely asphyxiated newborn infants emphasize the need for early and objective markers of both good and bad long-term prognosis. Traditional markers such as neurological depression and seizures are not specific. Aim : To study whether measurement in the cerebrospinal fluid of some proteins known to be specific to the central nervous system was in covariance with the clinical course and long-term prognosis. Methods : Twenty-two asphyxiated infants were included in the study and compared with a control group of 8 infants without signs of perinatal asphyxia. Cerebrospinal fluid (CSF) was collected during the first 4 d of life and analysed for neurofilament protein (NFp), glial fibrillary acidic protein (GFAp), protein S-100 and neuron-specific enolase (NSE). Results : The concentrations of all four proteins were significantly increased in the CSF of asphyxiated infants. The concentrations correlated significantly with other indicators of long-term prognosis and to neurological impairment at 1 y of age, or death before that time. Specifically, concentrations were excessively high in the five infants who died.

Conclusions : High concentrations of brain-specific proteins are released into the CSF of asphyxiated infants. It might therefore be useful to measure these concentrations when excluding patients with the gravest prognosis from neuroprotective trials.