Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice

Excessive glutamate release followed by N-methyl-d-aspartate receptor (NMDAR) activation plays a crucial role in perinatal brain injury. We have previously shown that dextromethorphan, a low-affinity NMDAR antagonist with anti-inflammatory properties, is neuroprotective against neonatal excitotoxic brain injury. Of interest, dextromethorphan is also a sigma-1 receptor (σ1R) agonist. The pharmacologic class of σ1R agonists has yielded propitious results in various animal models of adult central nervous system pathology. In an established neonatal mouse model of excitotoxic brain injury, we evaluated the effect of the selective σ1R agonist 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE-084). A single intraperitoneal injection of 0.1μg/g (low dose) or 10μg/g (high dose) bodyweight (bw) PRE-084, given 1h after the excitotoxic insult, significantly reduced lesion size in cortical gray matter 24h and 120h after the insult. Repetitive injections of 0.1μg/g PRE-084 proved to be equally effective. PRE-084 treatment resulted in a decrease in cell death indicated by reduced TUNEL positivity and caspase-3 activation. Furthermore, it lowered the number of isolectin B4-positive, activated microglial cells. PRE-084 had no effect on developmental apoptosis in the undamaged brain. In vitro findings in primary hippocampal neurons suggest that PRE-084 treatment provides partial protection against glutamate induced morphological and functional changes. For excitotoxicity as playing a crucial role in the pathogenesis of perinatal brain injury, we demonstrate for the first time that systemic treatment with the highly selective σ1R agonist PRE-084 protects against NMDAR-mediated excitotoxic brain damage.     

Early exposure to latex products mediates latex sensitization in spina bifida but not in other diseases with comparable latex exposure rates

BACKGROUND: The high prevalence of latex sensitization in patients with spina bifida (SB) has been attributed to repeated and early exposure to latex products. Other diseases such as gastroschisis/omphalocoele and post-haemorrhagic/congenital hydrocephalus are also associated with repeated and early latex exposure. OBJECTIVE: The aim of the study was to evaluate whether the high prevalence of latex sensitization in patients with SB is rather related to the underlying disease itself than to disease-associated known risk factors. METHODS: We compared children with SB (n=35), children with gastroschisis/omphalocoele (G/O, n=20) and children with post-haemorrhagic/congenital hydrocephalus (PH, n=45). All children with SB and PH had a ventriculo-peritoneal shunt since a very young age. Patients who underwent three or less surgical procedures matched in terms of age, number of operations, atopy and gender distribution, and were analysed for IgE sensitization rates to latex. RESULTS: In the SB group, 16 of 35 patients (46%) showed elevated latex-specific IgE antibodies in contrast to one of 20 patients (5%) in the G/O group and four of 45 patients (8.9%) in the PH group (P<0.0005 and P<0.005, Fisher's exact test). Comparing matched control groups (相似文献   

Qualitätsvergleich von modifizierter Neurolept-, balancierter und intravenöser Anästhesie Teil 1. Studiendesign und Patientenanalyse der Krefelder Studie 1992*

The choice of appropriate anaesthesia in a more or less seriously ill patient requires detailed information on the risk and tolerance of each specific anaesthetic regimen. The objective of this prospective, randomised clinical trial was to test the hypothesis that three regimens of general anaesthesia – neurolept-(NLA), balanced (BAL), and intravenous propofol anaesthesia (IVA) - differ with regard to safety and comfort. The criteria for the intraoperative safety and postoperative comfort of the patients were the incidents, events and complications (IEC) that required medical treatment as well as the evaluation of postoperative complaints by the patients according to the IEC list and patient questionnaires of the German Society of Anaesthesia and Critical Care Medicine (DGAI). Methods. The study duration was about 4?months, from January to April 1992. During this period the patients of all nine operative departments of the hospital received strictly randomised NLA, BAL, or IVA. Patients who had regional anaesthesia or were not capable of understanding the German language, were nonco-operative, or were seriously ill (ASA class?IV to V) as well as children under 18?years of age did not participate in the study. All eligible patients provided their informed consent. Anaesthesia. For premedication 10?mg chlorazepate was administered the night before and on the day of surgery. Anaesthesia was conducted under normoventilation using a mixture of 70% nitrous oxide and 30% oxygen. NLA patients were induced intravenously with 0.2?mg/kg body weight etomidate and received 0.005?mg/kg fentanyl and 0.07?mg/kg droperidol before the start of surgery. The repetition dose was 0.2?mg fentanyl and 2.5?mg droperidol. In the BAL patients the dose of fentanyl and droperidol was reduced to 50% due to the addition of isoflurane up to 1?vol.?%. IVA patients received 2?mg/kg propofol over 3?min followed by an infusion of 3–5?mg/kg per hour together with 0.2?mg fentanyl/h. Neuromuscular blockade was accomplished with vecuronium 0.1?mg/kg. If the blood pressure and heart rate increased by more than 20% of preoperative values, analgesia was reinforced by an additional fentanyl dose. Anaesthesia was subsequently enhanced by increasing the neurolept/propofol/isoflurane dose by up to 50%. Data collection. The following parameters were registered: patients' personal data and physical condition according to ASA classification; the grade of risk according to the Munich risk checklist; the frequency of IEC during surgery; the patients' permanent medications; postanaesthetic vigilance and recovery; the acceptance of the assigned anaesthetic by the physician; the cost of the anaesthetic used; and pre- and postoperative complaints as well as the assessment of anaesthesia by the patient. The statistical evaluation was performed using the chi-square test. Results. A total of 1,346?patients were enrolled in the study; 28 (2%) were excluded because the treatment protocol was changed by the anaesthesiologist. Seventy per cent were recruited from general, gynaecologic, or otorhinolaryngologic surgery. The three anaesthetic regimens (NLA, BAL, and IVA) were used in other departments with the same frequency with the exception of ophthalmology and urology (P>0.1) (Fig.?1). Of the 1,318 eligible patients, 443 received NLA, 443 BAL, and 432 IVA (P=0.8). The distribution of the various parameters was surprisingly similar among the three groups: the average age was 50?years (P=0.91), body weight 71?kg (P=0.33), reference or initial blood pressure 130/80?mm?Hg (P=0.36), average time of anaesthesia 103?min (P=0.82), and all had the same risk score (P=0.42). Sixty per cent were female. An average of 85% of the 18- to 89-year-old patients were considered to be healthy according to the ASA risk classification (P=0.42). However, on applying the Munich risk checklist the average number of healthy individuals was 5% to 10% lower than that of the ASA risk classification. The average quantity of anaesthetics per patient in the NLA group was 7.1?mg droperidol and 0.54?mg fentanyl; in the BAL group the amount could be reduced to 50% by adding isoflurane, and in the IVA group propofol 493?mg/100?min was given with 0.3?mg fentanyl (Fig.?2). The costs of the three regimens were 27.43?DM for NLA, 31.68?DM for BAL, and 43.75?DM for IVA. Conclusion. The remarkably high degree of consistency of the patients' baseline characteristics as well as the equal distribution among the patient groups can be considered optimal randomisation. The present clinical trial compared the safety and tolerance of the three anaesthetic regimens under routine daily conditions. The results of the study should have great clinical significance for the choice of the appropriate anaesthetic regimen while considering safety, tolerance, and cost-benefit aspects.     

Study on the Prevention of Allergy in Children in Europe (SPACE): Allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. Our objective was to prevent sensitization to house-dust mite and food allergens, as well as the development of atopic symptoms during infancy, by the combination of an educational package and the use of mite allergen-impermeable mattress encasings. A multicentre European, population-based, randomized, controlled study of children at increased atopic risk [Study on the Prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, the UK, and Lithuania), and included three cohorts – schoolchildren, toddlers, and newborns. We report on the newborn cohort. A total of 696 newborns were included from Austria, the UK, and Germany. Inclusion criteria were: a positive history of parental allergy; and a positive skin-prick test or specific immunoglobulin E (IgE) (IgE ≥ 1.43 kU/L) against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age, the overall sensitization rate against the tested allergens [dust-mite allergens: Dermatophagoides pteronyssinus and Dermatophagoides farinae ( Der  p and Der  f)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der  p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we were able to demonstrate, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero- and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of easy-to-perform preventive measures.     

Risk factors for childhood asthma and recurrent wheezy bronchitis

Using cross-sectional data of an epidemiological study, risk factors for asthma and recurrent wheezy bronchitis were investigated in 1812 primary school children. Children with asthma (n=63) had a similar pattern but a higher frequency of chronic respiratory symptoms than those with recurrent wheezy bronchitis (n=136). Logistic regression analyses showed similar risk factors for both disorders, however, more pronounced for asthma. Prematurity was a significant risk factor for asthma and for recurrent wheezy bronchitis. Children with asthma more often had a family history of paternal or maternal asthma and their mothers tended to be younger. Effects of paternal asthma and prematurity were also found when the atopic status of the child (defined as skin test positivity to any of seven aero allergens) was taken into account. Next to genetic effects, adverse circumstances in early life seem to be important for the development of asthma. In school children recurrent wheezy bronchitis and asthma seem to be similar disorders which differ in quantitative but not qualitative aspects.     

Nephrotoxic potential of cis-diamminedichloroplatinum and four analogs in male Fischer 344 rats

Cis-diamminedichloroplatinum [cis-DDP; NSC-119875] and four analogs (NSC-241240, NSC-271674, NSC-263158, and NSC-268252) were evaluated for their acute nephrotoxic potential in male F344 rats following iv administration. Indices of nephrotoxicity included blood urea nitrogen, serum creatinine, kidney weights, and microscopic examination. Results indicated that renal function, organ weights, and histology are important criteria for assessing the nephrotoxic potential of cis-DDP analogs, although alterations in these parameters may have been influenced by severe body weight loss. cis-DDP appeared to be the most nephrotoxic compound studied, and NSC-241240 demonstrated minimal renal damage. Ranking of compounds in order of their nephrotoxic potential (most to least) was cis-DDP, NSC-263158, NSC-268252, NSC-271674, and NSC-241240.     

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair.     

Nuclear targeting of Akt enhances ventricular function and myocyte contractility

Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca2+-ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho-protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart.