Development of an MR-compatible, rotation-insensitive, annular pressure sensor

There is a growing interest in performing intravascular interventions guided by MR imaging--a technique which offers the possibility of flow measurements during the intervention. For a reliable assessment of the haemodynamic significance of a stenosis, the flow and the pressure decay within the stenosis should both be measured. We have developed an optical, MR-compatible, pressure sensor (Annupres) that uses a novel annular element. Existing optical pressure sensors measure pressures unilaterally, thus giving rise to artefacts because of the dependence of the measurement on the angular orientation of the aperture. The annular element, however, measures blood pressure on all sides, and we show that by using circularly polarized light this pressure measurement is intrinsically insensitive to rotation of the sensor around its long axis. The Annupres sensor has been tested in an experimental set-up, and was able to measure pressures from 50 mmHg to 180 mmHg reliably with an accuracy of 1.5%.     

Early to late sparing of radiation damage to the parotid gland by adrenergic and muscarinic receptor agonists

Damage to salivary glands after radiotherapeutic treatment of head and neck tumours can severely impair the quality of life of the patients. In the current study we have investigated the early-to-late pathogenesis of the parotid gland after radiation. Also the ability to ameliorate the damage using pretreatment with adrenergic or muscarinic receptor agonists is studied. Rats were locally irradiated with or without i.p. pretreatment with phenylephrine (alpha-adrenoceptor agonist, 5 mg kg(-1)), isoproterenol (beta-adrenoceptor agonist, 5 mg kg(-1)), pilocarpine (4 mg kg(-1)), methacholine (3.75 mg kg(-1)) (muscarinic receptor agonists) or methacholine plus phenylephrine. Parotid salivary flow rate, amylase secretion, the number of cells and gland histology were monitored sequentially up to 240 days postirradiation. The effects were described in 4 distinct phases. The first phase (0-10 days) was characterised by a rapid decline in flow rate without changes in amylase secretion or acinar cell number. The second phase (10-60 days) consists of a decrease in amylase secretion and is paralleled by acinar cell loss. Flow rate, amylase secretion and acinar cell numbers do not change in the third phase (60-120 days). The fourth phase (120-240 days) is determined by a further deterioration of gland function but an increase in acinar cell number, albeit with poor tissue morphology. All drug pretreatments used could reduce radiation effects in phase I and II. The protective effects were lost during phase IV, with the exception of methacholine plus phenylephrine pretreatment. The latter combination of drugs ameliorated radiation-damage throughout the entire follow-up time. The data show that combined pre-irradiation stimulation of muscarinic acetylcholine receptors with methacholine plus alpha-adrenoceptors with phenylephrine can reduce both early and late damage, possibly involving the PLC/PIP2 second messenger pathways. This opens perspectives for the development of clinical applicable methods for long-term sparing of parotid glands subjected to radiotherapy of head and neck cancer patients.     

Children and guns in a well child cohort

BACKGROUND: The purpose of this study was to estimate the extent of and to identify predictors of preadolescent gun use in a well child cohort with matched parent and child data. METHODS: We analyzed self-report questionnaires from children and their parents using conditional logistic regression models. Questionnaires were given to 3,145 ten- to twelve-year-old children and 3,145 parents enrolled by their pediatricians in a prevention cohort study. RESULTS: Thirty-two percent of the children lived in households with guns. Children and parents generally agreed about the presence of guns in their homes; 17% had access to unlocked guns in their homes; 22% had fired guns. In this preadolescent cohort, firing guns was associated with being male, having guns in the home, having friends who use guns, and initiation of alcohol use. CONCLUSIONS: In this well child cohort, significant numbers of preadolescent, healthy boys in white, middle-class U.S. homes have access to guns, are using guns, and have friends who use guns. These children are also early alcohol adopters. Safety interventions with parents of preadolescents about the risks for accidental injury, death, and suicide due to child gun use may prove beneficial.     

APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease

Apolipoprotein E (APOE) has been extensively demonstrated to be a genetic risk factor for Alzheimer's disease (AD). Associations of APOE genotype have been reported with age at AD onset, rate of decline, and responsiveness to therapy. This study aimed to test these hypotheses in a large study population of AD patients. APOE genotype was determined from 1,528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria as probable AD patients, enrolled in four international placebo-controlled clinical trials of 3--12 months duration, designed to evaluate efficacy of treatment with galantamine or sabeluzole. In addition to patient demographics and baseline scores for Mini Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were recorded at the start, during, and at the end of the study. APOE epsilon 4 homozygotes had a significantly lower age at disease onset compared to patients with other APOE genotypes. The epsilon 4 allele was significantly over-represented in females compared to males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 11 on the DAD scale. The epsilon 4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared to the placebo-treated group, nor in any subgroup stratified by epsilon 4 allele count. Galantamine produced cognitive and functional improvement that were not affected by epsilon 4 allele count. In conclusion, our data confirm a strong association between epsilon 4 homozygotes and age at onset of AD but do not support an effect of epsilon 4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.     

Thermal sensitivity of the murine CFU-S-12: role of environmental cells

The hyperthermic sensitivity of the CFU-S-12 in bone marrow from normal and anaemic mice was determined. The terminal slope of the survival curves, demonstrated by the T0 values, does not significantly differ in the resting and active cycling stem cells. In the active cycling stem cells the initial shoulder region was less dominant compared with the resting stem cells. The difference in heat sensitivity between resting and active proliferating CFU-S-12 might be explained by a difference in the accumulation of damage before lethality becomes manifest. The difference in heat sensitivity appears to be independent of the environmental accessory cells, demonstrated by a similar hyperthermic effect of the purified stem cells from bone marrow and spleen and the stem cells in the total cell suspensions. Therefore the heat sensitivity of the haemopoietic stem cell is not mediated by a release of injurious substances from environmental heat-damaged cells. The heat treatment does not result in a selection of macroscopic detectable colonies 12 days after inoculation, as is demonstrated by the same morphology of the spleen colonies from the stem cells before and after the hyperthermic treatment.     

Arginine pharmacokinetics in humans assessed with an enzymatic assay adapted to a centrifugal analyzer

Arginine is used in supra-physiological concentrations as an insulin secretagogue, in both in vitro and in vivo studies. To investigate the pharmacokinetics of arginine in humans, we have developed a rapid, automated assay of arginine in serum, based on our manual enzymatic method (Clin Chim Acta 1988, 176; 185-94). The limit of linearity of the automated assay was an arginine concentration of 3 mmol/L. Within-run CVs for Ortho control sera with added arginine were 5.5%, 0.8%, and 0.7% at concentrations of 0.16, 1.30, and 2.50 mmol/L, respectively. After 30 min of primed continuous infusions with arginine at infusion rates of 3, 9, 15, and 21 mg/kg per minute, mean (+/- SEM) arginine concentrations in serum from eight volunteers were 1.17 +/- 0.08, 3.44 +/- 0.21, 6.84 +/- 0.58, and 9.25 +/- 0.39 mmol/L, respectively, well within the range of arginine concentrations shown (in vitro) to stimulate insulin secretion. Metabolic clearance of arginine was approximately 11 mL/kg body wt per minute. For the lowest three infusion rates, the half-life (t1/2) of arginine was approximately 15 min and the volume of distribution (Vd) was approximately 290 mL/kg. At the highest infusion rate, t1/2 was significantly increased (27.3 +/- 3.1 min), owing to an increased Vd (446 +/- 83 mL/kg).     

Peripheral Blood Grafts for T Cell–Replete Haploidentical Transplantation Increase the Incidence and Severity of Cytokine Release Syndrome

T cell–replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34⁺ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade < 2) was not associated with differences in overall survival or nonrelapse mortality. Severe CRS was associated with a statistically nonsignificant trend toward higher incidences of grades III to IV acute GVHD, especially in the context of peripheral blood grafts. CRS is a common complication after T cell–replete peripheral blood haploHCT, but post-transplant survival outcomes may not be affected in those with severe CRS.     

Identification of a novel circulating recombinant form (CRF) 36_cpx in Cameroon that combines two CRFs (01_AE and 02_AG) with ancestral lineages of subtypes A and G

An array of CRFs have been identified in Cameroon, the most notable being CRF02_AG. HIV-1 in the East Province of Cameroon is particularly diverse: in a recent study, we found a high proportion of unique recombinant forms (URFs). Herein we describe the analysis of the full-length sequences of two of these URFs, which, after preliminary analysis of gag, pol, and env fragments, appeared to be a novel CRF. This novel strain, CRF36_cpx, contains fragments that can be assigned to the CRF01_AE, CRF02_AG, and subtype A and G radiations. Forty percent of the genome can be classified as CRF02_AG, including regions in gag, pol, env, and the accessory genes. Twenty-seven percent is CRF01_AE, comprising the majority of gag, the beginning of env, and the end of env into the 3' LTR. Twenty percent of the genome can be assigned to subtype A, with segments in pol and env. The remaining 13% of the sequence is classifiable as subtype G, in pol and vpu. The subtype A and G lineages formed by the CRF36_cpx sequences are unique and appear ancestral in nature. CRF36_cpx is both the first to combine more than one CRF and the first to include fragments of CRF02_AG. The ancestral sequences present in CRF36_cpx represent a link to extinct strains, and, potentially, insight into the evolution of HIV-1.     

Analysis of Gene Polymorphisms Associated with K+ Ion Circulation in the Inner Ear of Patients Susceptible and Resistant to Noise-induced Hearing Loss

Noise-induced hearing loss (NIHL) is one of the leading occupational health risks in industrialized countries. It results from an interaction between environmental and genetic factors, however the nature of the genetic factors contributing to NIHL has not yet been clarified. Here, we investigated whether genetic variations in 10 genes putatively involved in the potassium recycling pathway in the inner ear may influence susceptibility to noise. 99 SNPs were genotyped in Polish noise-exposed workers, categorized into susceptible and resistant subjects. The most interesting results were obtained for KCNE1 and KCNQ4 as we replicated associations that were previously reported in a Swedish sample set, hence confirming that they are NIHL susceptibility genes. Additionally we report significant associations in GJB1 , GJB2 , GJB4 , KCNJ10 and KCNQ1 , however due to the lack of replication in the Swedish sample set, these results should be seen as suggestive.