Aplastic anemia: evidence for dysfunctional bone marrow progenitor cells and the corrective effect of granulocyte colony-stimulating factor in vitro

We investigated the effects of granulocyte-macrophage colony- stimulating factor, interleukin-3, stem cell factor, interleukin-6, and granulocyte colony-stimulating factor (G-CSF) alone, and in combination, on the clonogenic potential of normal and aplastic anemia (AA) bone marrow mononuclear cells (BMMC and CD34+ cells. AA BMMC consistently produced a significantly lower absolute number of colonies than normal, but, when account was taken of the reduced proportion of CD34+ cells in AA BM, there was no significant difference in terms of cloning efficiency (CE). However, when removed from the influence of accessory cells, the CE of AA CD34+ cells decreased significantly more than normal, indicating a defect in their function, either in terms of dependence on accessory cell-derived factors or susceptibility to cell damage when sorted. Of the factors studied, G-CSF had the most significant effect on the response of CD34+ cells from both groups when removed from their accessory cells. This was particularly true for AA CD34+ cells, whose response to cytokine stimuli containing G-CSF enabled them to match the response of normal CD34+ cells.     

Paroxysmal disorders in infancy and their risk factors in a population‐based cohort: the Generation R Study

Aim To examine the incidence of paroxysmal epileptic and non‐epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population‐based cohort. Method This study was embedded in the Generation R Study, a population‐based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth. Results Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non‐epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p<0.001) and low Apgar score at 1 minute (p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05). Interpretation Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations.     

A prospective trial of elective extubation in brain injured patients meeting extubation criteria for ventilatory support: a feasibility study

Introduction

To assess the safety and feasibility of recruiting mechanically ventilated patients with brain injury who are solely intubated for airway protection and randomising them into early or delayed extubation, and to obtain estimates to refine sample-size calculations for a larger study. The design is a single-blinded block randomised controlled trial. A single large academic medical centre is the setting.

Methods

Sixteen neurologically stable but severely brain injured patients with a Glasgow Coma Score (GCS) of 8 or less were randomised to early or delayed extubation until their neurological examination improved. Eligible patients met standard respiratory criteria for extubation and passed a modified Airway Care Score (ACS) to ensure adequate control of respiratory secretions. The primary outcome measured between groups was the functional status of the patient at hospital discharge as measured by a Modified Rankin Score (MRS) and Functional Independence Measure (FIM). Secondary measurements included the number of nosocomial pneumonias and re-intubations, and intensive care unit (ICU) and hospital length of stay. Standard statistical assessments were employed for analysis.

Results

Five female and eleven male patients ranging in age from 30 to 93 years were enrolled. Aetiologies responsible for the neurological injury included six head traumas, three brain tumours, two intracerebral haemorrhages, two subarachnoid haemorrhages and three ischaemic strokes. There were no demographic differences between the groups. There were no unexpected deaths and no significant differences in secondary measures. The difference in means between the MRS and FIM were small (0.25 and 5.62, respectively). These results suggest that between 64 and 110 patients are needed in each treatment arm to detect a treatment effect with 80% power.

Conclusions

Recruitment and randomisation of severely brain injured patients appears to be safe and feasible. A large multicentre trial will be needed to determine if stable, severely brain injured patients who meet respiratory and airway control criteria for extubation need to remain intubated.     

An evaluation of a Shockroom located CT scanner: a randomized study of early assessment by CT scanning in trauma patients in the bi-located trauma center North-West Netherlands (REACT trial)

Background

Trauma is a major source of morbidity and mortality, especially in people below the age of 50 years. For the evaluation of trauma patients CT scanning has gained wide acceptance in and provides detailed information on location and severity of injuries. However, CT scanning is frequently time consuming due to logistical (location of CT scanner elsewhere in the hospital) and technical issues. An innovative and unique infrastructural change has been made in the AMC in which the CT scanner is transported to the patient instead of the patient to the CT scanner. As a consequence, early shockroom CT scanning provides an all-inclusive multifocal diagnostic modality that can detect (potentially life-threatening) injuries in an earlier stage, so that therapy can be directed based on these findings.

Methods/design

The REACT-trial is a prospective, randomized trial, comparing two Dutch level-1 trauma centers, respectively the VUmc and AMC, with the only difference being the location of the CT scanner (respectively in the Radiology Department and in the shockroom). All trauma patients that are transported to the AMC or VUmc shockroom according to the current prehospital triage system are included. Patients younger than 16 years of age and patients who die during transport are excluded. Randomization will be performed prehospitally. Study parameters are the number of days outside the hospital during the first year following the trauma (primary outcome), general health at 6 and 12 months post trauma, mortality and morbidity, and various time intervals during initial evaluation. In addition a cost-effectiveness analysis of this shockroom concept will be performed. Regarding primary outcome it is estimated that the common standard deviation of days spent outside of the hospital during the first year following trauma is a total of 12 days. To detect an overall difference of 2 days within the first year between the two strategies, 562 patients per group are needed. (alpha 0.95 and beta 0.80).

Discussion

The REACT-trial will provide evidence on the effects of a strategy involving early shockroom CT scanning compared with a standard diagnostic imaging strategy in trauma patients on both patient outcome and operations research.

Trial registration

ISRCTN55332315     

Antiviral activity and safety of aplaviroc,a CCR5 antagonist,in combination with lopinavir/ritonavir in HIV‐infected,therapy‐naïve patients: results of the EPIC study (CCR100136)*

Background

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral‐naïve patients harbouring R5‐ or R5X4‐tropic virus.

Methods

A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed.

Results

This study was terminated prematurely because of APL‐associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent‐to‐treat (M‐ITT) population]; of these, 133 completed the 12‐week treatment phase. The proportion of subjects in the M‐ITT population with HIV‐1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4‐tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability.

Conclusions

While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.     

A supervised land cover classification of a western Kenya lowland endemic for human malaria: associations of land cover with larval Anopheles habitats

Background  

A supervised land cover classification was developed from very high resolution IKONOS satellite data and extensive ground truth sampling of a ca. 10 sq km malaria-endemic lowland in western Kenya. The classification was then applied to an investigation of distribution of larval Anopheles habitats. The hypothesis was that the distribution and abundance of aquatic habitats of larvae of various species of mosquitoes in the genus Anopheles is associated with identifiable landscape features.     

Latanoprost in the treatment of eyelash alopecia in alopecia areata universalis

Objectives The aim of this study was to test the efficacy of latanoprost in eyelash alopecia areata (AA). Design This study is a 2‐year prospective, non‐blinded, non‐randomized, bilateral eyelash alopecia controlled study. Setting The setting of this study was Trichology Unit, Virgen Macarena University Hospital, Seville, Spain. Patients We conducted a survey of 54 subjects with AA universalis treated with the protocol of the Trichology Unit of our Department. Control group comprised 10 subjects who received injections of 0.5 mg/cm² of triamcinolone acetonide (TAC) in their eyebrows and 1 mg/cm² of TAC injections in affected scalp. The treatment group included 44 subjects who received the same treatment as the control group in scalp and eyebrows but they also applied a drop of latanoprost 0.005% (50 μg/mL) ophthalmic solution in their eyelid margins every night. Subjects were reviewed every 3 months for 2 years. Results Forty subjects finished the study and four subjects were lost to follow‐up. In the treatment arm of this study, the course was well tolerated and uncomplicated. Both investigators and patients evaluated the regrowth. The results we obtained were: complete regrowth in 17.5%, moderate regrowth in 27.5%, slight regrowth in 30% and without response in 25%. Moderate and total regrowth constituted a cosmetically acceptable response. The therapy was continuous and the response remained without any side effects. No patients had cosmetically acceptable eyelash regrowth in the control group. Conclusions Latanoprost may be an effective drug in the treatment of eyelash AA because it induces acceptable responses (total and moderate) in 45% of the patients. A formal, blinded prospective unilateral controlled study will permit further understanding about this promising therapeutic agent for eyelash AA.     

Predictors of Apnea Test Failure During Brain Death Determination

Background  

In a recent publication (Wijdicks et al. in Neurology 71(16):1240, 2008), apnea test safety during brain death determination was evaluated at a single tertiary care center. One major conclusion was that apnea testing was safe in hemodynamically compromised patients in most circumstances and rarely aborted. Determinants of apnea test completion failure are unknown.