Efficacy of phthalocyanine tetrasulfonate against mouse-adapted human prion strains

In vitro and in vivo studies have shown that phthalocyanine tetrasulfonate (PcTS), a cyclic tetrapyrrole compound, is an efficient antiscrapie drug. To investigate the spectrum of PcTS against prion diseases, we tested the effect of PcTS on two mouse-adapted human strains. We also tested PcTS in rodents infected with two scrapie strains (139A and 263K). PcTS treatment significantly prolonged mean survival times of all infected animals. These results show that PcTS is effective on different prion strains, confirming its potential use for prion therapy. H. Abdel-Haq and M. Lu contributed equally to this work.     

Need to improve clinical trials in rare neurodegenerative disorders

Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.     

Increased brain levels of F2-isoprostane are an early marker of behavioral sequels in a rat model of global perinatal asphyxia

Perinatal asphyxia is a major cause of immediate and postponed brain damage in the newborn. It may be responsible for several delayed neurologic disorders and, in this respect, early markers of brain injury would be relevant for therapeutic intervention as well as for identification of infants at high risk for developmental disabilities. Biochemical measurements (brain F2-isoprostane levels) and behavioral tests (ultrasonic vocalization pattern on postnatal days (pnd) 5, 8, and 11, spontaneous motor behaviors on pnd 7 and 12, and homing response on pnd 10) were performed in a rat model of global perinatal asphyxia in the immature neonate. Caesarean section was performed in rats and the pups, still in uterus horns, were placed into a water bath at 37 degrees C for either 10 or 20 min. Caesarean delivered pups were used as controls. Pups experiencing severe (20 min), in contrast to those undergoing the 10 min, asphyctic insult presented with detectable abnormalities including early (two hours after the insult) increase in brain F2-isoprostane (a direct marker of oxidative injury) without detectable changes in PGE2, COX-2 and iNOS levels, and delayed physical (reduced weight gain on pnd 5 and thereafter) and behavioral disturbances (alterations in ultrasound emission on pnd 11 and spontaneous motricity levels mainly). These findings suggest that increased brain F2-isoprostane levels shortly after the asphyctic insult are predictive of delayed behavioral disturbances in the newborn rat. The present 20-min asphyxia model might serve for the assessment of preventive and curative strategies to treat neurologic/behavioral disturbances associated with perinatal asphyxia.     

Impairment of verb processing in frontal variant-frontotemporal dementia: a dysexecutive symptom

Object and action naming and comprehension were tested in frontotemporal dementia (frontal variant, FTD), in Alzheimer's disease (AD) and in controls. Although lower scores were obtained by all groups, we can confirm that actions were proportionally more impaired in FTD. The correlation between action naming deficit and severity of dementia was stronger in this group than in AD. The correlation analysis also suggested that the naming disorder was different in nature in FTD (mostly a dysexecutive deficit) and in AD (mostly a linguistic disorder). Our explanation is that since verbs are supposed to be more demanding of executive resources than nouns, a higher sensitivity to verbs should be expected in any brain pathology, but mostly in FTD in which executive resources are typically reduced.     

Prenatal stress affects 3,4-methylenedioxymethamphetamine pharmacokinetics and drug-induced motor alterations in adolescent female rats

We examined the influence of prenatal stress on 3,4-methylenedioxymethamphetamine (MDMA, 5 mg/kg p.o.) pharmacokinetics in adolescent female SD rats (30 days). Our results indicate that the metabolic rate of MDMA was higher in the prenatal stress group than in the control group. Moreover, MDMA-induced motor alterations were increased in prenatally stressed rats. These findings provide evidence that (i) prenatal stress increases sensitivity to MDMA, (ii) these effects are already detectable at the adolescent stage and (iii) early differences in metabolism may play a role in the behavioural changes associated with this drug of abuse.     

Biostatistical approaches to reducing the number of animals used in biomedical research

For ethical reasons, the least number of animals possible should be used in biomedical research, though not so few as to fail to detect biologically important effects or to necessitate the repetition of experiments. We describe biostatistical approaches that can contribute to either reducing the number of animals in single experiments or to increasing the quality of studies so that fewer subsequent studies (and thus animals) will be needed. The described approaches regard different phases of experimentation, specifically: planning the experimental design and calculating the sample size, controlling variability, choosing the response variable, postulating the statistical hypothesis to be tested, choosing the procedure for analysing data, and interpreting and suitably presenting the results.     

Results of a clinical trial on care improvement for the critically ill

OBJECTIVE: To develop, deploy, and evaluate an intervention designed to identify and mitigate conflict in decision making in the intensive care unit. DESIGN: Nonrandomized, controlled trial. SETTING: Seven intensive care units at four Boston teaching hospitals. PATIENTS: A total of 1,752 critically ill patients, including 873 study cases analyzed here. INTERVENTION: Social workers interviewed families of patients deemed at high risk for decisional conflict and provided feedback to the clinical team, who then implemented measures to address the problems identified. MEASUREMENTS AND MAIN RESULTS: Patient or surrogate satisfaction with intensive care unit care and the probability of choosing a specific plan for treatment in the intensive care unit was studied. Inclusion criteria identified 873 patients at risk for decisional conflict. Thirty-nine percent of the patients in the intervention phase of the study (172 patients) received the intervention. In multivariate analyses, receiving the intervention significantly increased the likelihood of deciding to forgo resuscitation (odds ratio [OR] = 1.81, p =.017), the likelihood of choosing a treatment plan for comfort-care only (OR = 1.94, p =.018), and the likelihood of choosing an aggressive-care treatment plan (OR = 2.30, p =.002). Receiving the intervention did not significantly affect overall satisfaction with the care provided (OR = 0.68, p =.14), satisfaction with the amount of information provided (OR = 0.86, p =.44), or satisfaction with the degree of involvement in decision making (OR = 0.84, p =.54). CONCLUSIONS: Although there was no impact on patient or surrogate satisfaction with care provided in the intensive care unit, the intervention did facilitate deliberative decision making in cases deemed at high risk for conflict. The lessons learned from the experience with this intervention should be helpful in ongoing efforts to improve care and to achieve outcomes desired by critically ill patients, their families, and critical care clinicians.     

Is growth-discordance in twins a substantial risk factor in adverse neonatal outcomes?

To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004-December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15-20% in 7 infants, 21-30% in 16 infants, 31-40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.     

A novel role of CXCR4 and SDF‐1 during migration of cloacal muscle precursors

The cloaca acts as a common chamber into which gastrointestinal and urogenital tracts converge in lower vertebrates. The distal end of the cloaca is guarded by a ring of cloacal muscles or sphincters, the equivalent of perineal muscles in mammals. It has recently been shown that the development of the cloacal musculature depends on hindlimb muscle formation. The signaling molecules responsible for the outward migration of hindlimb myogenic precursors are not known. Based on the expression studies for CXCR4 and SDF‐1, we hypothesized a role of this signaling pair during cloacal muscle precursor migration. The aim of our study was to investigate the role of SDF‐1/CXCR4 during cloacal muscle precursor migration in the chicken embryos. We show that SDF‐1 is expressed in the cloacal region, and by experimentally manipulating the SDF‐1/CXCR4 signaling, we can show that SDF‐1 guides the migration of CXCR4‐expressing cloacal muscle precursors. Developmental Dynamics 239:1622–1631, 2010. © 2010 Wiley‐Liss, Inc.