Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.     

Aicardi syndrome,an unsolved mystery: Review of diagnostic features,previous attempts,and future opportunities for genetic examination

Aicardi syndrome is a rare, severe neurodevelopmental disorder classically characterized by the triad of infantile spasms, central chorioretinal lacunae, and agenesis of the corpus callosum. Aicardi syndrome only affects females, with the exception of a few males with a 47, XXY chromosome constitution. All cases are de novo and the only cases of definitive recurrence in families are in identical twins. It is now recognized that individuals with Aicardi syndrome commonly exhibit a variety of other neuronal migration defects, eye anomalies, and other somatic features, including skin, skeletal, and craniofacial systems. The etiology of Aicardi syndrome remains unknown despite an international effort exploring different genetic mechanisms. Although various technologies examining candidate genes, copy number variation, skewing of X-chromosome inactivation, and whole-exome sequences have been explored, no strong genetic candidates have been identified to date. New technologies that can detect low-level mosaicism and balanced rearrangements, as well as platforms examining changes at the DNA and chromatin level affecting regulatory regions are all potential avenues for future studies that may one day solve the mystery of the etiology of Aicardi syndrome.     

Reduction of G protein-coupled receptor kinase 2 expression in U-937 cells attenuates H2 histamine receptor desensitization and induces cell maturation

Histamine and H2 agonists transiently induce an important cAMP response in promonocytic U-937 cells but fail to induce monocytic differentiation because of a rapid receptor desensitization mediated by G protein-coupled receptor kinases (GRKs). The aims of the present study were to investigate the participation of GRK2 in the desensitization mechanism of the H2 receptor in U-937 cells by reducing GRK2 levels through antisense technology and to evaluate the differentiating capacity of cells expressing lower GRK2 level, stimulated by H2 agonists. By stable U-937 cell transfection with a GRK2-antisense cDNA, we obtained D5 and A2 cell clones exhibiting a reduction in GRK2 expression and an H3 clone with no significant difference in GRK2 expression from control cells. The cAMP response induced by the H2 agonist in D5 and A2 but not in H3 cells was higher than in U-937 and persisted for a longer period of time, although the number of H2 receptors in D5 and A2 cells was lower than in U-937. Furthermore, D5 and A2 cells treated with H2 agonist showed patterns of c-Fos and CD88 expression consistent with monocytic differentiated cells. Overall, these results indicate a direct correlation between the expression of GRK2 and the desensitization of natively expressed H2 receptors in U-937 cells, suggesting that GRK2 plays a major role in the regulation of these receptors' response. In turn, desensitization process is a key component of H2 receptor signaling, determining the differentiation capability of promonocytic cells.     

Home care before and after hospitalization for acute myocardial infarction in Alberta, Canada

Home care services are provided to about 10% of those admitted to hospital for acute myocardial infarction and about 20% of those discharged from hospital. The use of home care in patients with an acute myocardial infarction is growing in Alberta over the brief time span of this four year study. Those that received home care prior to a hospitalization for acute myocardial infarction were "old and frail" with a high mortality rate during and after hospitalization. The provision of home care after hospitalization selected those patients that stay in hospital longer and required more hospital care. BACKGROUND: The use of home care before and after hospitalization for acute myocardial infarction is described. METHODS: Hospital discharge abstracts were used to identify patients hospitalized in alberta, canada for acute myocardial infarction which were then linked to home care administrative data. RESULTS: There were 12,648 patients with acute myocardial infarction from April 1, 1995 until March 31, 1999. Home care within 60 days prior to hospitalization was provided for 8.7% of patients with acute myocardial infarctions (n = 1097) which significantly (p = 0.023) increased from 7.6% in the fiscal year 1995/6 to 9.5% in the fiscal year 1998/9. Home care within 60 days after hospitalization was provided to 16.4% of patients with acute myocardial infarctions (n = 2076) which significantly (p < 0.000) increased from 14.1% in the fiscal year 1995/6 to 18.1% in fiscal year 1998/9. Recipients of home care were significantly older, had more comorbidities, and greater severity of illness, but were less likely to undergo coronary artery revascularization during hospitalization. After multivariate adjustment, length of hospital stay, 60 day re-admissions, and mortality were higher in those receiving home care post hospitalization. Nearly half of those receiving home care prior to hospitalization died within one year. 80% of those receiving home care prior to admission also received home care services after hospitalization. CONCLUSION: Those patients who received home care prior to a hospitalization for acute myocardial infarction were "old and frail" with a high mortality rate during and after hospitalization. The provision of home care after hospitalization selected those patients that stay in hospital longer and required more hospital care.     

Standardized evaluation and documentation of findings in patients with craniosynostosis

Surgical correction of craniosynostosis is usually performed according to standard procedures. However, a standard for clinical examination and report of findings for patients with craniosynostosis does not exist as yet. To compare findings from different hospitals, a documentation system was developed by a national craniosynostosis group. This system comprises a two-page document, clinical photographs, radiographs, CT scans, anthropometric measurements and molecular genetic findings. Data from craniosynostosis patients collected from participating hospitals are stored in a database, which facilitates online access.The documentation system was developed in cooperation with the group during 3 years since 1996. It was evaluated as being practicable and reliable and enables a comparability of findings reported in different hospitals. Molecular genetic analysis was found to support the investigation of patients with craniosynostosis and should therefore be integrated in the clinical evaluation. Copyright 2001 European Association for Cranio-Maxillofacial Surgery.     

Pesticide contamination of water alters the metabolism of juvenile silver catfish, Rhamdia quelen

We investigated how pesticide contamination of water affects the metabolism of the silver catfish, Rhamdia quelen, by studying fish maintained at two sites with low and high anthropic activity (Lino Creek, southern Brazil). Several pesticides were found at both stream sites. After 30 days plasma glucose levels were higher in fish exposed to water in the low anthropic activity site than those exposed to water in the high anthropic activity site. Plasma K⁺ levels, however, were lower after exposure to low anthropic water than after exposure to high anthropic water. Moreover, values of hepatic glycogen, muscle lactate and protein were higher, but glycogen and protein of the kidney were lower in fish exposed to water at the high anthropic activity site. Our results show that these fish can be used as pesticide toxicity indicators in streams near agricultural fields.     

Toxicological responses of Cyprinus carpio exposed to the herbicide penoxsulam in rice field conditions

Cyprinus carpio fish were exposed to penoxsulam (Ricer) in field conditions. The experiment in the rice field was carried out for 7, 21 and 72 days. Oxidative stress parameters and antioxidant profile were studied. The acetylcholinesterase (AChE) enzyme activity in the brain was increased after 7 days and reduced after 21 and 72 days of the experiment in the rice field. The AChE activity in muscle was reduced only after 72 days of exposure. Thiobarbituric acid-reactive species were increased in the liver, brain and muscle at 7 days of the trial, reduced at 21 days in the brain and unaltered after 72 days of exposure in muscle. However, an increase in this parameter in the brain and liver was observed. Liver glutathione S-transferase was reduced at 7 days, unchanged at 21 days and increased after 72 days of exposure. Catalase of the liver changed only in the second experimental period, when it was reduced. Liver protein carbonyl was reduced at 7 days and increased at 21 and 72 days of exposure. This study shows long-term effects of rice herbicide at environmentally relevant concentrations on toxicological parameters in different tissues (brain, muscle and liver) of Cyprinus carpio.     

Role of inducible nitric oxide synthase in the pathogenesis of experimental leptospirosis

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is a radical effector molecule of the innate immune system that can directly inhibit pathogen replication. In order to study subsequent iNOS kidney expression in experimental leptospirosis, Golden Syrian hamsters and C3H/HeJ mice were infected intraperitoneally with 10² or 10⁷ virulent Leptospira interrogans serovar Copenhageni (LIC) strain Fiocruz L1-130. Results showed increased levels of iNOS mRNA and protein in kidneys of infected animals when compared to that in mock-infected animals. To get a deeper insight into the role of iNOS in experimental leptospirosis, both subject species were treated or not treated with 4-aminopyridine (4-AP, 0.3 mg/kg), an iNOS inhibitor. Treatment of infected hamsters with 4-AP accelerated the mortality rate to 100% by one day and increased the mortality rate from 20 to 60% in mice at 14 days post-infection. In kidney tissues, 4-AP treatment increased the bacterial burden, as demonstrated through leptospiral DNA quantification by real-time PCR, and aggravated tubulointerstitial nephritis. In addition, iNOS inhibition reduced the specific humoral response against LIC when compared to that in untreated infected animals. According to these results, iNOS expression and the resulting NO have an important role in leptospirosis.