Cocaine Modulation of Frontostriatal Expression of Zif268, D2, and 5-HT2c Receptors in High and Low Impulsive Rats

Impulsivity shares high comorbidity with substance abuse in humans, and high impulsivity (HI) in rats has been identified as a predictive factor for cocaine addiction-like behavior. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of HI within the corticostriatal circuitry and determined how they interact with a protracted history of cocaine self-administration. We used in situ hybridization to map brain expression of two major genes implicated in impulsivity, encoding the dopamine D2 receptor (DA D2R) and the 5-HT2c receptor (5-HT2cR), and an immediate early gene associated with neuronal plasticity, zif268, in groups of rats selected for HI and low impulsivity (LI) on a 5-choice serial reaction time task (5-CSRTT) immediately after 5-CSRTT training, and following 10 or 50 days of cocaine self-administration. HI rats exhibited decreased DA D2R mRNA in the mesolimbic pathway, and increased 5-HT2cR mRNA in the orbitofrontal cortex compared with LI rats. HI rats also showed decreased zif268 mRNA in the ventral and dorsomedial striatum. Cocaine exposure decreased striatal D2R mRNA in both HI and LI rats, decreased 5-HT2cR mRNA differentially in striatal and prefrontal areas between HI and LI rats, and selectively decreased zif268 mRNA in the orbitofrontal and infralimbic cortices of HI animals. These findings implicate novel markers underlying the vulnerability of impulsive rats to cocaine addiction that localize to the OFC, infralimbic cortex, and striatum.     

Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1

OBJECTIVE: To describe and correlate pulmonary function and high-resolution CT (HRCT) scan scores in individuals with a high risk for development of pulmonary fibrosis, ie, Hermansky-Pudlak syndrome (HPS) patients with mutations in the HPS-1 gene. DESIGN: Cross-sectional analysis of consecutive, eligible patients. PATIENTS: Thirty-eight HPS inpatients at the National Institutes of Health Clinical Center with HPS-1 mutations. RESULTS: Thirty-seven patients were Puerto Rican and exhibited the typical 16-base pair (bp) duplication in exon 15 of HPS-1. One non-Puerto Rican was homozygous for a different mutation (intervening sequence 17 -2 A-->C) previously reported in the HPS-1 gene; he died at age 35 of pulmonary insufficiency. For the 23 patients who had pulmonary symptoms, the mean age of onset was 35 years. For all 38 patients (mean age, 37 +/- 2 years), the mean FVC was 71% of predicted; the mean FEV(1), 76%; mean total lung capacity (TLC), 72%; mean vital capacity (VC), 68%; and mean diffusing capacity of the lung for carbon monoxide (DLCO), 72%. When patients were grouped according to the extent of their reduction in FVC, the other four pulmonary function parameters followed the FVC. Seventeen patients had abnormal chest radiographs, and 31 (82%) had abnormal HRCT scans of the chest, for which a scoring system of 0 (normal) to 3 (severe fibrosis) is presented. The mean +/- SEM HRCT score for 38 patients was 1.30 +/- 0.17. HRCT scores correlated inversely with FVC and DLCO. CONCLUSIONS: Mutations in the HPS-1 gene, whether or not they involve the typical 16-bp duplication seen in Puerto Rican patients, are associated with fatal pulmonary fibrosis. In affected patients, the FVC, FEV(1), TLC, VC, and DLCO fall in concert, and this functional deficit correlates with HRCT scan evidence of progression of interstitial lung disease.     

Down syndrome and congenital heart disease: why the regional difference as observed in the Libyan experience?

Background

Children with Down syndrome (DS) have about a 40 to 50% incidence of congenital heart disease (CHD). The objectives of this study were to evaluate the distribution and frequency of CHD patterns in Libyan children with DS.

Methods

All patients with DS who were referred to the cardiology clinic between January 1995 and December 2008 were reviewed.

Results

Of the 1 193 patients reviewed, 537 (45%) had an associated CHD. Overall there were 349 (65%) patients who had a single cardiac lesion, and 188 (35%) had multiple cardiac lesions. The most common isolated cardiac lesion was atrial septal defect (ASD), found in 125 (23%) patients, followed by atrioventricular septal defect (AVSD) in 103 (19%), and ventricular septal defect (VSD) in 76 (14%).

Conclusion

Atrial septal defect was the most common cardiac lesion. The distribution of CHDs in Libyan children with DS was similar to what has been reported internationally, but the frequency was not compared with international rates.     

Ileal Crohn's disease in a woman with Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction. A subset of patients also show ceroid deposition, which can result in pulmonary fibrosis or granulomatous colitis. Whether this colitis may be considered Crohn's disease is under debate. We report a case of a patient with HPS associated with inflammatory bowel disease which affected the distal small bowel but not the colon. Ileitis was severe, and recurred rapidly after surgery. Search for mutations in HPS1, ADTB3A, HPS3, HPS4 and for CARD15 were negative. Symptoms and ileal ulcerations which recurred after surgery were successfully treated with azathioprine and infliximab.     

The effect of experimental streptococcus infection in myocarditis on some biochemical and inflammatory markers in albino rats

Background

Myocarditis is an uncommon disease that presents with a wide range of symptoms in children and adults. It is histologically characterized by varying degrees of myocardialnecrosis, edema and cellular infiltration myocardial inflammation is a nonspecificresponse to many triggers such as bacterial infection, cardio toxic agents, ormechanical injury.

Objective

This study was carried out to investigate the experimental Streptococcus faecalis induction of myocarditis and its effect on some blood parameters, inflammatory markers and histopathological changes in male albino rats.

Methods

Rats were infected by intraperitoneal injection of 10 8 CFU/ml of Streptococcus faecalis and sacrificed after one, two and seven days post infection. Biochemical analyses of blood were carried out to investigate the serum biomarkers of inflammation, liver function tests, cardiac enzymes & kidney function tests.

Results

All biochemical analyses showed statistically significant increase in the measured parameters due to bacterial infections except for blood urea which appear to be normal. A significant positive correlation was observed between lactate dehydrogenase enzyme (LDH) with creatinine (r =0.778, P<0.01). In the 7 days group, there were significant positive correlations between aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (r=0.675, P<0.05), erythrocyte sedimentation rate (ESR) with Urea (r=0.659, P<0.05) and alkaline phosphatase (ALP) with C-reactive protein (CRP) (r=0.765, p<0.01).

Conclusion

Many of these biomarkers will provide important new insights into pathophysiology and aid in the diagnosis and management of cardiovascular patients.     

The Gne M712T mouse as a model for human glomerulopathy

Pathological glomerular hyposialylation has been implicated in certain unexplained glomerulopathies, including minimal change nephrosis, membranous glomerulonephritis, and IgA nephropathy. We studied our previously established mouse model carrying a homozygous mutation in the key enzyme of sialic acid biosynthesis, N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Mutant mice died before postnatal day 3 (P3) from severe glomerulopathy with podocyte effacement and segmental glomerular basement membrane splitting due to hyposialylation. Administration of the sialic acid precursor N-acetylmannosamine (ManNAc) led to improved sialylation and survival of mutant pups beyond P3. We determined the onset of the glomerulopathy in the embryonic stage. A lectin panel, distinguishing normally sialylated from hyposialylated glycans, used WGA, SNA, PNA, Jacalin, HPA, and VVA, indicating glomerular hyposialylation of predominantly O-linked glycoproteins in mutant mice. The glomerular glycoproteins nephrin and podocalyxin were hyposialylated in this unique murine model. ManNAc treatment appeared to ameliorate the hyposialylation status of mutant mice, indicated by a lectin histochemistry pattern similar to that of wild-type mice, with improved sialylation of both nephrin and podocalyxin, as well as reduced albuminuria compared with untreated mutant mice. These findings suggest application of our lectin panel for categorizing human kidney specimens based on glomerular sialylation status. Moreover, the partial restoration of glomerular architecture in ManNAc-treated mice highlights ManNAc as a potential treatment for humans affected with disorders of glomerular hyposialylation.