Increased brain water content in pseudotumour cerebri measured by magnetic resonance imaging of brain water self diffusion

Brain water self diffusion was investigated by magnetic resonance scanning in 7 patients fulfilling conventional diagnostic criteria for pseudotumour cerebri. Quantitative diffusion measurements were obtained using single spin echo pulse sequences with pulsed magnetic field gradients of different magnitude. In all patients the diffusion images showed an increased diffusion in various brain regions when compared with the diffusion coefficients for corresponding regions in healthy subjects. In 3 pseudotumour patients the increased self diffusion was localized to the periventricular regions, while 4 patients had increased diffusion in the whole brain. The findings indicate the presence of increased brain water content both intra- and extracellularly suggesting that patients with pseudotumour have two defects of pathogenetical significance: intracellular water accumulation and increased resistance to cerebrospinal fluid (CSF) outflow leading to an interstitial oedema.     

Penicillin G Treatment in Infective Endocarditis Patients – Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Penicillin G is frequently used to treat infective endocarditis (IE) caused by streptococci, penicillin‐susceptible staphylococci and enterococci. Appropriate antibiotic exposure is essential for survival and reduces the risk of complications and drug resistance development. We determined penicillin G plasma concentration [p‐penicillin] once weekly in 46 IE patients. The aim was to evaluate whether penicillin G 3 g every 6 hr (q6 h) resulted in therapeutic concentrations and to analyse potential factors that influence inter‐ and intra‐individual variability, using linear regression and a random coefficient model. [P‐penicillin] at 3 hr and at 6 hr was compared with the minimal inhibitory concentration (MIC) of the bacteria isolated from blood cultures to evaluate the following PK/PD targets: 50% fT > MIC and 100% fT > MIC. [P‐penicillin] varied notably between patients and was associated with age, weight, p‐creatinine and estimated creatinine clearance (eCLcr). Additionally, an increase in [p‐penicillin] during the treatment period showed strong correlation with age, a low eCLcr, a low weight and a low p‐albumin. Of the 46 patients, 96% had [p‐penicillin] that resulted in 50% fT > MIC, while 71% had [p‐penicillin] resulting in 100% fT > MIC. The majority of patients not achieving the 100% fT > MIC target were infected with enterococci. Streptococci and staphylococci isolated from blood cultures were highly susceptible to penicillin G. Our results suggest that penicillin G 3 g q6 h is suitable to treat IE caused by streptococci and penicillin‐susceptible staphylococci, but caution must be taken when the infection is caused by enterococci. When treating enterococci, therapeutic drug monitoring should be applied to optimize penicillin G dosing and exposure.     

Systematic identification and stratification of help-seeking school-aged youth with mental health problems: a novel approach to stage-based stepped-care

We investigated whether a novel visitation model for school-aged youth with mental health problems based on a stage-based stepped-care approach facilitated a systematic identification and stratification process without problems with equity in access. The visitation model was developed within the context of evaluating a new transdiagnostic early treatment for youth with anxiety, depressive symptoms, and/or behavioural problems. The model aimed to identify youth with mental health problems requiring an intervention, and to stratify the youth into three groups with increasing severity of problems. This was accomplished using a two-phase stratification process involving a web-based assessment and a semi-structured psychopathological interview of the youth and parents. To assess problems with inequity in access, individual-level socioeconomic data were obtained from national registers with data on both the youth participating in the visitation and the background population. Altogether, 573 youth and their parents took part in the visitation process. Seventy-five (13%) youth had mental health problems below the intervention threshold, 396 (69%) were deemed eligible for the early treatment, and 52 (9%) had symptoms of severe mental health problems. Fifty (9%) youth were excluded for other reasons. Eighty percent of the 396 youth eligible for early treatment fulfilled criteria of a mental disorder. The severity of mental health problems highlights the urgent need for a systematic approach. Potential problems in reaching youth of less resourceful parents, and older youth were identified. These findings can help ensure that actions are taken to avoid equity problems in future mental health care implementations.

     

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

Background and Purpose: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter.Experimental Approach: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.Key Results: Sotalol attained C_max values 1–3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.Conclusions and Implications: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.     

In vivo release and turnover of secreted platelet antiheparin proteins in rhesus monkey (Macaca mulatta)

Human and rhesus monkey platelets secrete at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4). Neither of these proteins showed species-related antigenic differences. As determined by radioimmunoassay, the levels of PF4 and LA-PF4 antigen per 10(9) monkey platelets amounted to 10.7 and 20.3 microgram, respectively. One milliliter of monkey plasma prepared from blood collected into an anticoagulant composed of EDTA, prostaglandin E1, and theophylline solution contained 22.4 ng LA-PF4 and 8.0 ng PF4. Concentrations of these two platelet-specific proteins in monkeys closely resembled levels found in human platelets and plasma. Infusion of prostacyclin (PGI2) (100 or 300 ng/kg/min) into monkeys for 15 min resulted in a significant decrease of plasma levels of LA-PF4 antigen and of PF4 by 40%--60% (p < 0.0001). This decrease was related to the inhibitory effect of PGI2 on the secretion of platelets stimulated by a catheter or by venipuncture. Longer infusion of PGI2 did not produce further significant change. The supernate obtained after aggregation of human platelets stimulated by thrombin was injected into monkeys receiving PGI2 infusion. The disappearance of LA-PF4 antigen in monkey plasma followed a biphasic exponential curve with half-lives for the fast and slow components of 8.4 and 63 min. PF4 disappeared faster but followed the same pattern (half-lives for the fast and slow component of 2.1 and 70 min). Analysis of the experimental data suggests that the low levels of secreted platelet proteins in monkey plasma are related to their minimal in vivo release and to their rapid clearance.