A change in the Dutch Directive on Medical Research Involving Human Subjects strongly increases the number of eligible intensive care patients: an observational study

Objectives To determine the effect of a change in the “Dutch Directive on Medical Research Involving Human Subjects” (DD) on the number of eligible intensive care unit (ICU) patients for medical research. In addition, we determined how family members experience their role as acting representative for giving informed consent, and in turn whether patients feel their representatives would do well representing them.Design and setting Prospective observational study in three Dutch ICUs.Participants 714 consecutive ICU patients. Analysis was restricted to 211 patients who were incapacitated for more than 24 h after ICU admission.Measurements and results The old DD left 45.5% of patients without a legal representative; with the new DD this figure declines to 8.1%. Older age was significantly associated with the impossibility of obtaining informed consent in the old DD; after the change there was no effect of age. The median grade of confidence that representatives had in giving informed consent for incapacitated patients was 8.0 (IQR 7.0–9.0) on a scale from 0 to 10. Patients gave an equal median grade to their representatives.Conclusion When patients' adult children are not legally allowed to give informed consent, older patients are excluded from medical research, causing selection bias. The change in the DD has increased the number of surrogates allowed to give informed consent. Representatives felt very confident in their ability to represent the patients. In turn patients were equally confident that their representatives were able to represent them.This article is discussed in the editorial available at:     

G protein-coupled receptor for asthma susceptibility associates with respiratory distress syndrome

BACKGROUND: Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma. AIM: To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD. METHODS: A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants. RESULTS: In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples. CONCLUSIONS: The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.     

Perception of matching and conflicting audiovisual speech in dyslexic and fluent readers: an fMRI study at 3 T

We presented phonetically matching and conflicting audiovisual vowels to 10 dyslexic and 10 fluent-reading young adults during "clustered volume acquisition" functional magnetic resonance imaging (fMRI) at 3 T. We further assessed co-variation between the dyslexic readers' phonological processing abilities, as indexed by neuropsychological test scores, and BOLD signal change within the visual cortex, auditory cortex, and Broca's area. Both dyslexic and fluent readers showed increased activation during observation of phonetically conflicting compared to matching vowels within the classical motor speech regions (Broca's area and the left premotor cortex), this activation difference being more extensive and bilateral in the dyslexic group. The between-group activation difference in conflicting > matching contrast reached significance in the motor speech regions and in the left inferior parietal lobule, with dyslexic readers exhibiting stronger activation than fluent readers. The dyslexic readers' BOLD signal change co-varied with their phonological processing abilities within the visual cortex and Broca's area, and to a lesser extent within the auditory cortex. We suggest these findings as reflecting dyslexic readers' greater use of motor-articulatory and visual strategies during phonetic processing of audiovisual speech, possibly to compensate for their difficulties in auditory speech perception.     

Influence of cyclooxygenase inhibitors on gut immune cell distribution and apoptosis rate in experimental sepsis

The aim of this study was to determine if cyclooxygenase (COX) inhibitors influence immune cell distribution in the small intestinal mucosa and mesenteric lymph nodes (MLNs), the grade of mucosal damage, and the rate of apoptosis in septic rats. The effects induced by a selective COX-2 inhibitor (SC-236) were compared with those of a nonselective COX-1 and -2 inhibitor (indomethacin). Cecal ligation and puncture (CLP), CLP + SC-236 p.o, and CLP + indomethacin p.o, were evaluated. Animals were harvested 6 and 24 h after CLP, respectively. The concentration of proinflammatory cytokines was higher in ascitic fluid than in blood. CLP + SC-236 attenuated IL-6 in plasma and in ascitic fluid and CLP + indomethacin augmented TNF-alpha in ascitic fluid compared with CLP at 6 h. CLP + SC-236 gave a lesser degree of mucosal damage compared with CLP alone or with indomethacin at 6 and 24 h (P < 0.05). Untreated CLP had significant reductions in the number of T lymphocytes in the villi and increases of macrophages in the mucosa and MLNs compared with controls (P < 0.05). CLP + indomethacin decreased T lymphocytes in the villi and MLNs. CLP caused an enhanced apoptosis in the mucosa compared with controls (P < 0.05), pretreatment with COX inhibitors did not significantly change this. Both COX inhibitors enhanced apoptosis in MLNs and attenuated the increase of macrophages in mucosa and MLNs (P < 0.05). It is proposed that the increased apoptosis and the decrease in T cells in the mucosa may be causally related. Apoptosis of lymphocytes may impair the immunologic defense in sepsis. Furthermore, loss of intestinal epithelial cells may compromise bowel wall integrity and facilitate translocation.     

The effect of open lung ventilation on right ventricular and left ventricular function in lung-lavaged pigs

Introduction  

Ventilation according to the open lung concept (OLC) consists of recruitment maneuvers, followed by low tidal volume and high positive end-expiratory pressure, aiming at minimizing atelectasis. The minimization of atelectasis reduces the right ventricular (RV) afterload, but the increased intrathoracic pressures used by OLC ventilation could increase the RV afterload. We hypothesize that when atelectasis is minimized by OLC ventilation, cardiac function is not affected despite the higher mean airway pressure.     

Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study

Background

The aim of the current study was to assess the antidepressant efficacy and safety of Hypericum perforatum (St. John's wort) extract WS^® 5570 at doses of 600 mg/day in a single dose and 1200 mg/day in two doses.

Methods

The participants in this double-blind, randomized, placebo-controlled, multi-center clinical trial were male and female adult out-patients with an episode of mild or moderate major depressive episode (single or recurrent episode, DSM-IV criteria). As specified by the relevant guideline, the study was preceded by a medication-free run-in phase. For the 6-week treatment, 332 patients were randomized: 123 to WS^® 5570 600 mg/day, 127 to WS^® 5570 1200 mg/day, and 82 to placebo. The primary outcome measure was the change in total score on the Hamilton Rating Scale for Depression (HAM-D, 17-item version) between baseline and endpoint. Additional measures included the number of responders, the number of patients in remission, and several other standard rating scales. Efficacy and safety were assessed after 2 and 6 weeks. The design included an interim analysis performed after randomization with the option of early termination.

Results

After 6 weeks of treatment, mean ± standard deviation decreases in HAM-D total scores of 11.6 ± 6.4, 10.8 ± 7.3, and 6.0 ± 8.1 points were observed for the WS^® 5570 600 mg/day, 1200 mg/day and placebo groups, respectively (endpoint analysis). Secondary measures of treatment efficacy also showed that both WS^® 5570 groups were statistically superior to placebo. Significantly more patients in the WS^® 5570 treatment groups than in the placebo group showed treatment response and remission. WS^® 5570 was consistently more effective than placebo in patients with either less severe or more severe baseline impairment. The number of patients who experienced remission was higher in the WS^® 5570 1200 mg/day group than the WS^® 5570 600 mg/day group. The incidence of adverse events was low in all groups. The adverse event profile was consistent with the known profile for Hypericum extract preparations.

Conclusion

Hypericum perforatum extract WS^® 5570 at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily) were found to be safe and more effective than placebo, with comparable efficacy of the WS^® 5570 groups for the treatment of mild to moderate major depression.     

Assessment of PINK1 (PARK6) polymorphisms in Finnish PD

Recent data has demonstrated that mutations in PINK1, encoding PTEN-induced kinase 1, are a cause of early onset recessive parkinsonism (PARK6 locus). Common variability in genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). We analyzed whether six different genetic variants within and surrounding PINK1 contribute to the risk of sporadic PD in a Finnish case-control series. Our results indicate that this gene does not play a major role in the genetic predisposition to PD in this population.     

Selective attention for negative information and depression in schizophrenia

OBJECTIVES: Depression is a frequent feature of schizophrenia but the cognitive processes involved in its development and maintenance are unclear. Recent studies have shown that clinical depression is associated with faulty inhibitory mechanisms of selective attention for negative information. The current study examined whether patients with schizophrenia also have an attentional bias towards negative stimuli. The inhibitory processes of interference control and task-shifting abilities were also examined to assess whether patients would show a selective impairment. METHOD: Forty-three patients with schizophrenia and 24 healthy controls completed the Affective Shifting Task. RESULTS: As a group, schizophrenia patients did not show an attentional bias for negative material. However, those patients with high levels of depression demonstrated faster latencies when negative words were the targets, and higher depression scores were found to be associated with an increasing number of false alarms for negative words when they were not the targets. The results also showed that patients had impaired interference control but intact task-shifting abilities.CONCLUSIONS: Faulty inhibitory mechanisms of selective attention for negative information are not a general feature of schizophrenia but appear to be selective to those with a depressed mood. The results highlight the need for further studies examining the exact nature of the affective dysfunction in schizophrenia and the cognitive processes supporting negative emotions.     

IgAs against acetaldehyde-modified red cell protein as a marker of ethanol consumption in male alcoholic subjects, moderate drinkers, and abstainers

BACKGROUND: Alcohol abuse has been shown to result in the production of antibodies against acetaldehyde-modified epitopes in proteins. However, as yet, only limited information has been available on the clinical usefulness of such responses as markers of hazardous drinking. METHODS: We developed an ELISA to measure specific IgAs against acetaldehyde-protein adducts. This method was evaluated in cross-sectional and follow-up studies on male heavy drinkers with a current ethanol consumption of 40 to 540 g/d (n=40), moderate drinkers consuming 1 to 40 g/d (n=25), and abstainers (n=16). The clinical assessments included detailed interviews on the amounts and patterns of ethanol consumption and various biochemical markers of alcohol abuse and liver function. RESULTS: The mean antiadduct IgAs (198+/-28 U/L) in the alcohol abusers were significantly higher than those in the moderate drinkers (58+/-11 U/L, p<0.001) or abstainers (28+/-8 U/L, p<0.001). The values of moderate drinkers were also higher than those in abstainers (p<0.05). The amount of ethanol consumed during the period of 1 month preceding blood sampling correlated strongly with antiadduct IgAs (r=0.67, p<0.001). The sensitivity (73%) and specificity (94%) of this marker were found to exceed those of the conventional laboratory markers of alcohol abuse in comparisons contrasting heavy drinkers with abstainers although not in comparisons contrasting heavy drinkers with moderate drinkers. During abstinence, antiadduct IgAs disappeared with a mean rate of 3% per day. In additional analyses of possible marker combinations, antiadduct IgAs, together with CDT, were found to provide the highest sensitivity and specificity. CONCLUSIONS: Measurements of antiadduct IgAs may provide a new clinically useful marker of alcohol abuse, providing a close relationship between marker levels and the actual amounts of recent ethanol ingestion.