Use of linezolid in neonatal and pediatric inpatient facilities-results of a retrospective multicenter survey

The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8 years (interquartile range 0.6-15.5 years; range 0.1-21.2 years; ten patients were older than 18 years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14 days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12 years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved.

Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model

The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions.

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Improved serodiagnosis of alveolar echinococcosis of humans using an in vitro-produced Echinococcus multilocularis antigen

Serology is an important tool for the diagnosis of alveolar echinococcosis (AE) in humans. In order to improve serodiagnostic performance, we have developed an in vitro-produced Echinococcus mulilocularis metacestode vesicle fluid (EmVF) antigen for application in an immunoblot assay. Immunoblot analysis of EmVF revealed an abundant immunoreactive band triplet of 20-22 kDa, achieving a sensitivity of 100% based on the testing of sera from 62 pre-operative and pre-treatment cases of active and inactive AE. Thus, the EmVF-immunoblotting allowed the specific detection of cases seronegative by the Em2- and/or EmII/3-10-ELISA, usually attributable to abortive, inactive cases of AE. The specificity of the EmVF-immunoblotting did not allow discrimination between AE and cystic echinococcosis (CE) but was 100% with respect to non-Echinococcus parasitic infections or cancer malignancies. Based on the findings of this study, it is recommended that the current ELISA test combination (Em2- and II/3-10-ELISA) be complemented with EmVF-immunoblotting, allowing an improved diagnosis of both clinical and subclinical forms of AE, including those associated with E. multilocularis-specific antibody reactivities not detectable by ELISA.

Dose selection for radioiodine therapy of borderline hyperthyroid patients according to thyroid uptake of 99mTc-pertechnetate: applicability to unifocal thyroid autonomy?

PURPOSE: The aim of this study was to evaluate the feasibility of applying a previously described dose strategy based on (99m)Tc-pertechnetate thyroid uptake under thyrotropin suppression (TcTU(s)) to radioiodine therapy for unifocal thyroid autonomy. METHODS: A total of 425 consecutive patients (302 females, 123 males; age 63.1+/-10.3 years) with unifocal thyroid autonomy were treated at three different centres with (131)I, using Marinelli's formula for calculation of three different absorbed dose schedules: 100-300 Gy to the total thyroid volume according to the pre-treatment TcTU(s) (n=146), 300 Gy to the nodule volume (n=137) and 400 Gy to the nodule volume (n=142). RESULTS: Successful elimination of functional thyroid autonomy with either euthyroidism or hypothyroidism occurred at a mean of 12 months after radioiodine therapy in 94.5% of patients receiving 100-300 Gy to the thyroid volume, in 89.8% of patients receiving 300 Gy to the nodule volume and in 94.4% receiving 400 Gy to the nodule volume. Reduction in thyroid volume was highest for the 100-300 Gy per thyroid and 400 Gy per nodule strategies (36+/-19% and 38+/-20%, respectively) and significantly lower for the 300 Gy per nodule strategy (28+/-16%; p<0.01). CONCLUSION: A dose strategy based on the TcTU(s) can be used independently of the scintigraphic pattern of functional autonomous tissue in the thyroid.

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.

Sensitivity of osteoblasts, fibroblasts, bone marrow cells, and dendritic cells to 5-aminolevulinic acid based photodynamic therapy

INTRODUCTION: Photodynamic therapy with 5-aminolevulinic acid (5-ALA-PDT) exerts cell type specific effects on target cells. Since chondrocytes were found to be more resistant than osteoblasts to 5-ALA-PDT, the pre-treatment of osteochondral grafts with 5-ALA-PDT may represent a means to devitalize the osseous portion while maintaining functional cartilage. The present study was designed to determine the effects of 5-ALA-PDT in vitro on cell populations residing in skeletal tissues. METHODS: Osteoblasts, fibroblasts, bone marrow cells, and dendritic cells were incubated with 0.5 mM 5-ALA for 4 h. Protoporphyrin IX (PpIX) accumulation and after exposure to light cellular functions were assessed for up to 6 days. RESULTS: Accumulation of PpIX reached a plateau at 0.5 mM in osteoblasts, fibroblasts, and dendritic cells, and at 2.0 mM in bone marrow cells. At 0.5 mM 5-ALA, similar responses to illumination were observed in all cells with a survival rate of less than 12% at a light dose of 20 J/cm(2). The function of osteoblasts (proliferation, levels of mRNA encoding collagen type I, alkaline phosphatase activity) and fibroblasts (proliferation, levels of mRNAs encoding collagens type I and III) was not affected, when the cells were treated with 5-ALA and light doses of < or =10 J/cm(2). Paralleling the reduction of viable cells after 5-ALA-PDT, the capacity of dendritic cells to stimulate T cells in a mixed leukocyte reaction decreased to 4+/-2% at 20 J/cm(2). CONCLUSION: The investigated cell types were sensitive to 5-ALA-PDT and the residual cell debris did not elicit an allogenic response. These findings, together with the resistance of chondrocytes to 5-ALA-PDT, encourage the further investigation of this protocol in the pretreatment of osteochondral allografts.

Assessment of vertical facial and dentoalveolar changes using panoramic radiography

The purpose of the study was to analyse longitudinal vertical facial and dentoalveolar changes using panoramic radiographs (PRs) and to compare the results with measurements on lateral cephalometric radiographs (LCRs) in order to determine whether, under certain circumstances, the radiation dose for a patient may be reduced by taking only a PR instead of a PR and a LCR. Pre- and post-treatment PRs and LCRs of 30 (15 females and 15 males) orthodontically treated adolescents (mean age pre-treatment 10.9 years, post-treatment 13.4 years) were analysed using Pearson's correlation coefficients and gender differences using Fisher's z-transformation. The results revealed that most variables exhibited larger absolute values on PRs than on LCRs. Comparison of dentoskeletal morphology between the LCRs and the PRs revealed moderate to high, mostly statistically significant, interrelations both before and after orthodontic treatment. The lowest correlations were found for the maxillary jaw base angle (NL/H; r= 0.35***) and the highest for the gonial angle (ML/RL; r = 0.90***). However, when assessing the combined growth and treatment changes from before to after treatment, only weak to moderate, not statistically significant, interrelations were found between LCRs and PRs. Anterior face height (AFH; r = 0.43***), the mandibular plane angle (ML/H; r = 0.06*), and the distance of the incisal tip of the most extruded mandibular incisor to the ML-line (ii-ML; r = -0.21*) were the only statistically significant parameters. The average group differences for growth and treatment changes, however, were small for most parameters. Analysis of vertical facial and dentoalveolar parameters on PRs delivers a moderate approximation to the situation depicted on LCRs. However, PRs cannot be recommended for the analysis of individual longitudinal changes in vertical facial and dentoalveolar parameters.

Acute and late toxicity in prostate cancer patients treated by dose escalated intensity modulated radiation therapy and organ tracking

BACKGROUND: To report acute and late toxicity in prostate cancer patients treated by dose escalated intensity-modulated radiation therapy (IMRT) and organ tracking. METHODS: From 06/2004 to 12/2005 39 men were treated by 80 Gy IMRT along with organ tracking. Median age was 69 years, risk of recurrence was low 18%, intermediate 21% and high in 61% patients. Hormone therapy (HT) was received by 74% of patients. Toxicity was scored according to the CTC scale version 3.0. Median follow-up (FU) was 29 months. RESULTS: Acute and maximal late grade 2 gastrointestinal (GI) toxicity was 3% and 8%, late grade 2 GI toxicity dropped to 0% at the end of FU. No acute or late grade 3 GI toxicity was observed. Grade 2 and 3 pre-treatment genitourinary (GU) morbidity (PGUM) was 20% and 5%. Acute and maximal late grade 2 GU toxicity was 56% and 28% and late grade 2 GU toxicity decreased to 15% of patients at the end of FU. Acute and maximal late grade 3 GU toxicity was 8% and 3%, respectively. Decreased late > or = grade 2 GU toxicity free survival was associated with higher age (P = .025), absence of HT (P = .016) and higher PGUM (P < .001). DISCUSSION: GI toxicity rates after IMRT and organ tracking are excellent, GU toxicity rates are strongly related to PGUM.

Acute alcohol ingestion and sympathetic neural responses during orthostatic stress in humans

Acute alcohol consumption has been reported to decrease mean arterial pressure (MAP) during orthostatic challenge, a response that may contribute to alcohol-mediated hypotension and eventually syncope. Muscle sympathetic nerve activity (MSNA) increases during orthostatic stress to help maintain MAP, yet the influence of alcohol on MSNA during orthostatic stress has not been determined. We hypothesized that alcohol ingestion would blunt arterial blood pressure and MSNA responses to progressive lower body negative pressure (LBNP). MAP, MSNA, and heart rate (HR) were recorded during progressive LBNP (-5, -10, -15, -20, -30, and -40 mmHg; 3 min/stage) in 30 subjects(age 24 ± 1 yrs). After an initial progressive LBNP protocol (pre-treatment), subjects were randomly assigned to consume alcohol (0.8g ethanol/kg body mass; n=15) or placebo (n=15) and then repeated the progressive LBNP protocol (post-treatment). Alcohol increased (drug × treatment, P ≤ 0.05) resting HR (59 ± 2 to 65 ± 2 beats/min) and MSNA (13 ± 3 to 19 ± 4 bursts/min) when compared to placebo. While alcohol increased MAP (83 ± 2 to 87 ± 2 mmHg), these increases were also observed with placebo (82 ± 2 to 88 ± 1 mmHg; treatment, P < 0.05; drug × treatment, P > 0.05). During progressive LBNP, a prominent decrease in MAP was observed after alcohol (drug × time × treatment, P < 0.05), but not placebo. There was also a significant attenuated response in forearm vascular resistance (FVR) during progressive LBNP (drug × time × treatment, P < 0.05). MSNA and HR increased during all LBNP protocols, but there were no differences between treatments or groups (drugs). In summary, acute alcohol ingestion induces an attenuation in blood pressure response during an orthostatic challenge, possibly due to the effect that alcohol has on impairing peripheral blood vessel constriction.

Gingival recession following apical surgery in the esthetic zone: a clinical study with 70 cases

The present study evaluated gingival recession 1 year following apical surgery of 70 maxillary anterior teeth (central and lateral incisors, canines, and first premolars). A visual assessment of the mid-facial aspect of the gingival level and of papillary heights of treated teeth was carried out using photographs taken at pre-treatment and 1-year follow-up appointments. In addition, changes in the gingival margin (GM) and clinical attachment levels (CAL) were calculated with the use of clinical measurements, that is, pre-treatment and 1-year follow-up pocket probing depth and level of gingival margin. Changes in GM and CAL were then correlated with patient-, tooth-, and surgery-related parameters. The following parameters were found to significantly influence changes in GM and CAL over time: gingival biotype (P < 0.05), with thin biotype exhibiting more gingival recession than thick biotype; pre-treatment pocket probing depth (PPD) (P < 0.03), with cases of pre-treatment PPD < 2.5 mm demonstrating more attachment loss than cases of PPD > or = 2.5 mm; and type of incision (P < 0.01), with the submarginal incision showing considerably less gingival recession compared with the intrasulcular incision, papilla-base incision or papilla-saving incision. The visual assessment using pre-treatment and 1-year follow-up photographs did not demonstrate significant changes in gingival level or papillary height after apical surgery. In conclusion, gingival biotype, pre-treatment PPD, and type of incision may significantly influence changes in GM and CAL following apical surgery in maxillary anterior teeth.

Untersuchung der Materialalterung bei pulverbasierten Schichtbauverfahren

Additive, pulverbasierte Schichtbauverfahren, wie das Selektive Masken- oder La-sersintern, ermöglichen die Fertigung von komplexen Bauteilen ohne Werkzeug und Form. Aufgrund der hohen, verarbeitungsbedingten Bauraumtemperaturen kommt es während der Verarbeitung zu physikalischem und thermisch-oxidativem Abbau der eingesetzten Kunststoffpulver. Das im Bauraum nicht aufgeschmolzene Material, der so genannte Partcake, kann nach dem Bauprozess vom fertigen Bauteil entfernt und für weitere Bauprozesse verwendet werden. Zur Realisierung reproduzierbarer Bau-teileigenschaften ist jedoch eine Aufbereitung („Refreshen“) des Partcake-Pulvers notwendig. Im Rahmen des Beitrags werden Erkenntnisse zum Alterungsverhalten von Kunst-stoffpulvern vorgestellt. In einem Modellversuch wurde der Verarbeitungsprozess für PA12-Pulver nachgestellt und somit verschiedene Alterungsstufen generiert. Beson-deres Augenmerk wurde auf den Einfluss einer Materialvorbehandlung gelegt. Die gealterten Pulver wurden physikalisch und thermoanalytisch hinsichtlich ihrer verar-beitungsrelevanten Materialeigenschaften untersucht.

The effect of monoalkyl phosphates and fluoride on dissolution of hydroxyapatite, and interactions with saliva

The aims were to investigate the effect of monoalkyl phosphates (MAPs) and fluoride on dissolution rate of native and saliva-coated hydroxyapatite (HA). Fluoride at 300 mg/l (as NaF) inhibited dissolution of native HA by 12%, while potassium and sodium dodecyl phosphates (PDP, SDP), at 0.1% or higher, inhibited dissolution by 26-34%. MAPs, but not fluoride, also showed persistence of action. MAPs at 0.5% and fluoride at 300 mg/l were then tested separately against HA pre-treated with human saliva for 2 or 18 h. Agents were applied with brushing to half the specimens, and without brushing to the other half. In control (water-treated) specimens, pre-treatment of HA with human saliva reduced dissolution rate on average by 41% (2 h) and 63% (18 h). Brushing did not have a statistically significant effect on dissolution rate of saliva-coated specimens. In brushed specimens, fluoride significantly increased the inhibition due to 2- or 18-hour saliva pre-treatment. It is hypothesised that brushing partially removes the salivary film and allows KOH-soluble calcium fluoride formation at the surfaces of HA particles. Inhibition was reduced by PDP in 2-hour/non-brushed specimens and in 18-hour/brushed specimens. PDP did not affect dissolution rates in the remaining groups and SDP did not affect dissolution rate in any group. Possible reasons for these variable results are discussed. The experiments show that pre-treatment with saliva can significantly modify results of tests on potential anti-erosive agents and it is recommended that saliva pre-treatment should be a routine part of testing such agents.

Who stays, who benefits? Predicting dropout and change in cognitive behaviour therapy for psychosis

This study investigates predictors of outcome in a secondary analysis of dropout and completer data from a randomized controlled effectiveness trial comparing CBTp to a wait-list group (Lincoln et al., 2012). Eighty patients with DSM-IV psychotic disorders seeking outpatient treatment were included. Predictors were assessed at baseline. Symptom outcome was assessed at post-treatment and at one-year follow-up. The predictor x group interactions indicate that a longer duration of disorder predicted less improvement in negative symptoms in the CBTp but not in the wait-list group whereas jumping-to-conclusions was associated with poorer outcome only in the wait-list group. There were no CBTp specific predictors of improvement in positive symptoms. However, in the combined sample (immediate CBTp+the delayed CBTp group) baseline variables predicted significant amounts of positive and negative symptom variance at post-therapy and one-year follow-up after controlling for pre-treatment symptoms. Lack of insight and low social functioning were the main predictors of drop-out, contributing to a prediction accuracy of 87%. The findings indicate that higher baseline symptom severity, poorer functioning, neurocognitive deficits, reasoning biases and comorbidity pose no barrier to improvement during CBTp. However, in line with previous predictor-research, the findings imply that patients need to receive treatment earlier.

Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death

Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells. Pre-treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23(v2J/v2J) and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity.