Intercellular adhesion molecule-1 inhibition attenuates neurologic and hepatic damage after resuscitation in mice

BACKGROUND: Cardiac arrest and cardiopulmonary resuscitation may result in multiorgan damage after global hypoxia due to neutrophil recruitment. Patients display all signs of a systemic inflammatory response syndrome. Reducing neutrophil recruitment may thus preserve organ function. METHODS: Mice were subjected to cardiac arrest and resuscitation. CD18/CD11b expression on circulating neutrophils was assessed by flow cytometry. Intercellular adhesion molecule-1 expression was analyzed by Western blot and immunofluorescence. Neutrophil recruitment was quantified by immunohistochemistry. Neurologic function was assessed by a balance test. For liver and kidney function, plasma alanine aminotransferase activity and creatinine concentrations were determined. To reduce neutrophil recruitment, mice received 100 microg anti-intercellular adhesion molecule-1 antibody intraperitoneally. RESULTS: Resuscitation led to severe hypoxia, acidosis, and hypercarbia. Adhesion molecule expression and neutrophil recruitment were increased in the liver, kidney, and brain. Neurologic performance was impaired 24 h after cardiac arrest. Creatinine and alanine aminotransferase concentrations were significantly increased. Immunoneutralization of intercellular adhesion molecule-1 attenuated neutrophil influx in the liver along with alanine aminotransferase activity, whereas creatinine concentrations and neutrophil influx in the kidney remained unchanged. Neurologic function was improved in the treatment group. CONCLUSIONS: Global hypoxia induces activation of the endothelium in the brain, liver, and kidney. The resulting damage to the brain and liver are due to infiltration of neutrophils, whereas kidney damage is not, because reduction of neutrophil recruitment after cardiopulmonary resuscitation improves recovery of neurologic and hepatic but not renal function. Inhibition of intercellular adhesion molecule-1 after global hypoxia may be beneficial in patients experiencing cardiac arrest and resuscitation.     

PAX5/IGH rearrangement is a recurrent finding in a subset of aggressive B-NHL with complex chromosomal rearrangements

We present an extensive characterization of 10 B-cell lymphomas with a t(9;14)(p13;q32). The presence of the PAX5/IGH gene rearrangement was demonstrated by fluorescence in situ hybridization (FISH) using a validated probe set, whereas complex karyotypic changes were reassessed by multiplex-FISH (M-FISH). Pathologic and clinical review revealed the presence of this rearrangement in 4 histiocyte-rich, T-cell-rich B-cell lymphomas (HRTR-BCLs) and 2 posttransplantation diffuse large B-cell lymphomas (PTLD-DLBCLs). In contrast to initial observations describing this translocation in lymphoplasmacytic lymphoma (LPL) and LPL-derived large B-cell lymphoma, our data showed a wide morphologic and clinical spectrum associated with the PAX5/IGH rearrangement, pointing to an association between this aberration and a subset of de novo DLBCLs presenting with advanced disease and adverse prognosis. In addition, the recurrent incidence of this rearrangement in both HRTR-BCL (4 cases) and PTLD-DLBCL (2 cases) was previously unrecognized and is intriguing.     

Medication patterns for attention-deficit/hyperactivity disorder and comorbid psychiatric conditions in a low-income population

The aims of this study were two-fold: (1) to describe the patterns of comorbid psychiatric diagnosis and psychotropic drug therapy for children enrolled in a Medicaid-managed care program and diagnosed with attention-deficit/hyperactivity disorder (ADHD) in 2000 and (2) to examine child and provider characteristics associated with psychotropic medication patterns for this population. Multivariate logistic regression models were used to examine correlates of stimulant and seven nonstimulant psychotropic medication classes (alpha-agonists, mood stabilizer/anticonvulsant, antianxiety, standard antipsychotic, atypical antipsychotic, and tricyclic antidepressant (TCA)/other antidepressant and selective serotonin reuptake inhibitor (SSRI) antidepressant). With the exception of conduct disorders (odds ratio, 1.22; 95% confidence interval, 1.06-1.40), comorbid disorders had a significant protective effect (odds ratio less than 1) on dispensing stimulants. After adjusting for covariates, stimulant dispensing was strongly correlated with the interactions of geographic region with race/ethnicity and provider type. Children residing in the upstate New York region had an approximately ten-fold greater chance of being dispensed a stimulant compared to similar children in New York City. Utilizing a mental health provider increased the chance of being dispensed a stimulant by factor of two for children from New York City of any race/ethnicity group. Models predicting nonstimulant drug dispensing were distinct from the stimulant model. After adjusting for covariates, nonstimulant psychotropic medication dispensing was correlated with clinical factors, including comorbid disorder category and use of a mental health provider, as well as notable sociodemographic factors. Complex psychotropic medication and comorbid psychiatric disorder patterns were evident for this low-income population of children with ADHD. The roles of clinical, patient, and provider factors need to be better understood to explain these patterns of stimulant and nonstimulant psychotropic medications dispensed.     

Prenatal ultrasound and magnetic resonance imaging in fetal varicella syndrome: correlation with pathology findings

OBJECTIVES: To assess the diagnostic value of prenatal magnetic resonance imaging (MRI) in addition to prenatal ultrasound in a case of fetal varicella syndrome. METHODS: Comparison of prenatal ultrasound and MRI features obtained at 26 and 32 weeks, respectively, with neonatal imaging (ultrasound, MRI and CT) and macroscopic and microscopic pathology findings in a fatal case of varicella embryopathy. RESULTS: Prenatal ultrasound correlated fairly well with neonatal imaging and pathology findings. Most lesions of thoracic, abdominal and retroperitoneal viscera, limb involvement and even dermatologic features were apparent on ultrasonography. Involvement of the CNS, including cerebellar hypoplasia, was not apparent on ultrasound examination, but was clearly demonstrated by prenatal MRI. CONCLUSION: If maternal seroconversion for the varicella-zoster virus is suspected, combining prenatal ultrasound and magnetic resonance imaging may document the extent of tissue damage in fetal varicella syndrome to a larger extent than has been reported until now and therefore contribute to due counselling following maternal varicella exposure.     

Ischemic preconditioning reduces unloaded myocardial oxygen consumption in an in-vivo sheep model

OBJECTIVE: Ischemic preconditioning (IP) describes the adaptation of the myocardium to ischemic stress preceded by short periods of ischemia and reperfusion. However, its cardioprotective mechanisms are not completely understood. We assessed the effect of IP on ventricular energetics in an in-vivo sheep model. METHODS: IP was performed in six sheep by three 5 min aortic cross-clamping periods interspersed with 5 min of reperfusion during cardiopulmonary bypass and with six sheep as time-matched controls. Global myocardial ischemia was subsequently achieved by 30 min aortic cross-clamping with left ventricular unloading during normothermic cardiopulmonary bypass. Weaning from cardiopulmonary bypass was performed 40 min after reperfusion. At baseline, after treatment (IP or time-matched cardiopulmonary bypass), and up to 100 min after reperfusion, left ventricular pressure-volume loops were measured using a conductance catheter during a right heart bypass preparation. Contractility, diastolic function, and ventriculo-arterial coupling were evaluated. Ventricular energetics [the relation between myocardial oxygen consumption (MVO(2)) and systolic pressure-volume area (PVA)] was also evaluated. A right heart bypass was instituted to control the preload and to decompress the right ventricle completely, thereby eliminating parallel conductance variation and minimizing the contribution of the right ventricle to MVO(2). RESULTS: IP reduced unloaded MVO(2) (PVA-independent MVO(2)). Contractility, diastolic function, and ventriculo-arterial coupling in the IP group were better preserved than in the control group after ischemia-reperfusion. CONCLUSIONS: IP reduces unloaded MVO(2), and preserves contractility, diastolic function, and ventriculo-arterial coupling after 30 min global myocardial ischemia in an in-vivo sheep model.     

Strong general health care systems: a prerequisite to reach global tuberculosis control targets

We argue that tuberculosis control cannot reach its proposed global targets without investment in an adequate network of accessible, effective and comprehensive health services. Lessons from the past are reviewed. They underscore that passive case-detection and adequate case management is the central technical strategy for tuberculosis control. There is no compelling evidence to support active case-detection in the general population. We elaborate on why a strong health care system is a prerequisite in the framework of case-detection and treatment. The necessity to improve quality and accessibility of general health services for ensuring early detection and subsequent cure is demonstrated. It is argued why the need for strong public health care system becomes even more eminent in the light of the tuberculosis/HIV dual epidemics and of the rapid growth of unregulated private-for-profit services. We finally examine the financial gaps for tuberculosis control and discuss the need for allocating more resources to the strengthening of general health care systems.     

CHD5, a new member of the chromodomain gene family,is preferentially expressed in the nervous system

Chromatin remodeling is one of the mechanisms by which gene expression is regulated developmentally. Chromatin structure is controlled at least in part by post-translational modification of histones, as well as by chromodomain proteins. We have identified a novel gene encoding a protein with chromatin remodeling, helicase and DNA-binding motifs. This gene, called CHD5, is the fifth member of the CHD gene family identified in humans. This gene is most homologous to CHD3 and CHD4, which encode proteins that are part of the nucleosome remodeling and histone deacetylation (NuRD) complex. CHD5 is preferentially expressed in total brain, fetal brain, and cerebellum. It is also moderately expressed in the adrenal gland, but expression is undetectable in almost all other tissues examined. CHD5 maps within a small region of deletion on 1p36.3 in human neuroblastomas, a common pediatric tumor. We examined a panel of neuroblastoma cell lines for CHD5 expression, which was consistently low or undetectable in all these lines. Expression was also examined in a panel of 137 primary neuroblastomas, and low expression was highly correlated with 1p deletion, MYCN amplification, advanced stage, and unfavorable histology. These findings suggest that this gene may play a role in the development of the nervous system, and it may also play a role in the pathogenesis of neural tumors.