Behavioral characterization of GLT1 (+/-) mice as a model of mild glutamatergic hyperfunction

GLT1 is one of the major transporters responsible for maintenance of glutamate homeostasis in the brain. In the present study, glutamate transporter 1-deficient GLT1 homozygous (-/-) and heterozygous (+/-) mice were investigated with the intention that they may provide a model of hyperglutamatergic state resulting in various behavioral alterations. The GLT1 (-/-) mice had lower body and brain weight, mild neuronal loss in CA1 hippocampal region as well as focal gliosis and severe focal neuronal paucity in layer II of the neocortex. The short life-span of GLT1 (-/-) precluded us from systematic behavioral studies in these mice. In contrast, GLT1 (+/-) mice exhibiting a 59% decrease in GLT1 immunoreactivity in their brain tissue, showed no apparent morphological brain abnormalities, and their life-span was not markedly different from controls. Behaviorally, GLT1 (+/-) presented moderate behavioral alterations compared to their wildtype littermates, such as: mild sensorimotor impairment, hyperlocomotion (at 3 month of age only), lower anxiety (at 6 months), better learning of cue-based fear conditioning but worse context-based fear conditioning. Our results suggest that GLT1 (+/-) mice may serve as a potentially useful model to study neurodegenerative disease conditions with mild hyperglutamatergic activity.     

Primary pigmented nodular adrenocortical disease (PPNAD) as an underlying cause of symptoms in a patient presenting with hirsutism and secondary amenorrhea: case report and literature review

Abstract

Hypercortisolemia in females may lead to menstrual cycle disturbances, infertility, hirsutism and acne. Herewith, we present a 18-year-old patient, who was diagnosed due to weight gain, secondary amenorrhea, slowly progressing hirsutism, acne and hot flashes. Thorough diagnostics lead to a conclusion, that the symptoms was the first manifestation of primary pigmented nodular adrenocortical disease (PPNAD). All symptoms of Cushing syndrome including hirsutism and menstrual disturbances resolved after bilateral adrenalectomy. Our report indicates that oligo- or amenorrhea, hirsutism, acne in combination with weight gain, growth failure, hypertension and slightly expressed cushingoid features in a young woman requires diagnostics towards hypercortisolemia. Despite PPNAD is a very rare cause of ACTH-independent Cushing syndrome, it has to be taken into consideration, especially when adrenal glands appear to be normal on imaging and paradoxical rise in cortisol level in high-dose dexamethasone test is observed. Unlike in our patient, in vast majority of patients, PPNAD is associated with Carney complex (CC). Therefore, these patients and their first-degree relatives should be always carefully screened for symptoms of PPNAD, CC and genetic mutations of PRKAR1A, PDE11A, and PDE8B genes.     

Improved low molecular weight Myc-Max inhibitors

Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc-expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc-expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric c-Myc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient alpha-helical content.     

First case of Trichinella nativa infection in wild boar in Central Europe—molecular characterization of the parasite

The examination of wild boars gained in Poland shows for the first time occurrence of Trichinella nativa, freeze-resistant species of Trichinella in this host from the central Europe region. This finding is not only one of several cases of T. nativa invasion in wild boars all over the world but also one of the very few cases of T. nativa detected so far beyond the known boundary of occurrence of this species. The molecular characterization of discovered larvae based on analysis of partial genes: 5s rDNA-ISR and CO1 confirm the findings. Moreover, the analyzed DNA sequences of both genes present new haplotypes of T. nativa in comparison to that described previously.

     

Co-expression of CXCL8 and HIF-1α is associated with metastasis and poor prognosis in hepatocellular carcinoma

Hypoxia inducible factor-1α (HIF-1α), induces cytokines such as CXCL8 and tumor dissemination, chemo- and radio-resistance. We analyzed correlation between HIF-1α and CXCL8 levels, tumor characteristics and overall survival in 102 hepatocellular carcinoma (HCC) patients. Levels of HIF-1α and CXCL8 were increased in HCC tissues and cell lines. Patients with high levels of HIF-1α and CXCL8 had worse outcome and poorer prognosis than those with lower levels. Co-overexpression of HIF-1α and CXCL8 was an independent negative prognostic factor for overall and disease-free survival. HIF-1α silencing and CXCL8 siRNA decreased migration under hypoxic conditions in vitro. Hypoxia-induced activation of AKT/mTOR/STAT3 pathways was reversed by depletion of CXCL8. We conclude that HIF-1α and CXCL8 induce HCC progression and metastasis, associated with activation of AKT/mTOR/STAT3. Co-expression of HIF-1α and CXCL8 is a prognostic marker and a potential therapeutic target in HCC.     

Mucinous cystadenocarcinomas of the pancreas

BACKGROUND/AIMS: The purpose of this study was to evaluate the clinicopathologic characteristics, diagnosis and treatment of mucinous cystadenocarcinomas (MCACs) of the pancreas. METHODOLOGY: This is a retrospective review of 6 patients who underwent curative resection for MCACs of the pancreas in the Department of General Endocrine and Transplantation Surgery, Medical University of Gdańsk from 1994-2004. Clinical presentation, radiological evaluation and surgical procedures were analyzed. RESULTS: There were 4 women and 2 men. Median age was 59 years. Patients complained of abdominal pain, nausea, vomiting and weigh loss, 2 of them had jaundice and 1 gastrointestinal (GI) bleeding. Ultrasonography and computed tomography showed cystic lesions. Solid component was found in 3 cases. Three endoscopic retrograde cholangiopancreatographys (ERCPs) were unhelpful in differentiating between malignant tumor and benign lesion. All patients underwent resection. In 3 cases Whipple resection, in 1 case Traverso - Longmire resection and in 2 cases distal pancreatectomy was performed. Histopathologically, all tumors were mucinous cystadenocarcinomas. CONCLUSIONS: Diagnostic accuracy for cystic pancreatic neoplasm is still limited. Surgical resection is recommended in all cystic tumors that are not clearly defined.     

Regulation of Renal Ouabain-Resistant Na+-ATPase by Leptin,Nitric Oxide,Reactive Oxygen Species,and Cyclic Nucleotides: Implications for Obesity-Associated Hypertension

This study examined the effect of leptin on renal ouabain-resistant Na⁺-ATPase, which drives the reabsorption of about 10% of sodium transported in the proximal tubule. Chronic leptin administration (0.25 mg/kg s.c. twice daily for seven days) increased Na⁺-ATPase activity by 62.9%. This effect was prevented by the coadministration of superoxide dismutase mimetic, tempol, or the NADPH oxidase inhibitor, apocynin (2 mM in the drinking water). Acutely administered NO donors decreased Na⁺-ATPase activity. This effect was abolished by soluble guanylate cyclase inhibitor, ODQ, but not by protein kinase G inhibitors. Exogenous cGMP reduced Na⁺-ATPase activity, but its synthetic analogues, 8-bromo-cGMP and 8-pCPT-cGMP, were ineffective. The inhibitory effect of NO donors and cGMP was abolished by EHNA, an inhibitor of cGMP‐stimulated phosphodiesterase (PDE2). Exogenous cAMP analogue and dibutyryl-cAMP increased Na⁺-ATPase activity and abolished the inhibitory effect of cGMP. Finally, the administration of superoxide-generating mixture (xanthine oxidase+hypoxanthine) increased Na⁺-ATPase activity. The results suggest that nitric oxide decreases renal Na⁺-ATPase activity by stimulating cGMP, which in turn activates PDE2 and decreases cAMP concentration. Increased production of reactive oxygen species may lead to the elevation of Na⁺-ATPase activity by scavenging NO and limiting its inhibitory effect. Chronic hyperleptinemia is associated with increased Na⁺-ATPase activity due to excessive oxidative stress.