Thromboangitis obliterans agyi manifesztációja

Thromboangiits obliterans (Buerger's disease) is a non-atherosclerotic, segmental inflammatory and obliterative disease affecting small and medium sized arteries and veins. The etiology is still unknown, but it is in close relationship with tobacco use. Symptoms begin under the age of 45 years and the undulating course is typical. Patients usually present with acute and chronic ischemic or infectious acral lesions. Diagnosis is usually based on clinical and angiographic criteria and it is important to exclude autoimmune disease, thrombophilia, diabetes, and proximal embolic sources. Even though Buerger's disease most commonly involves the arteries of the extremities, the pathologic findings sometimes affect the cerebral, coronary and internal thoracic, renal and mesenteric arteries as well. The authors present the history of a patient with known Buerger's disease and acute ischemic stroke. Brain imaging detected acute and chronic ischemic lesions caused by middle cerebral non-atherosclerotic arteriopathy on the symptomatic side. Other etiology was excluded by detailed investigations. Orv. Hetil., 2016, 157(30), 1207-1211

UBIQUITIN CYTOCHEMICAL CHANGES DURING AZASERINE-INITIATED PANCREATIC CARCINOGENESIS

The ubiquitin (Ub)- proteasome proteolytic system is highly selective, and the specific proteins involved in cell division, growth, activation, signaling and transcription are degraded at different rate depending on the physio-pathological state of the cell. Ubiquitination serves first of all as a signal for protein degra- dation of short-lived and abnormal proteins under several stressful conditions. The immunocytochemical localization of Ub in some malignant tumours has recently been presented and differences in Ub expres- sion has been observed during malignant transformation. Change in the level of Ub and Ub-conjugated proteins might reflect a higher metabolic-catabolic ratio in neoplastic cells. Most studies have been focused on the malignant stage of tumour progression, and only a few papers have dealt with the change in Ub and Ub-protein conjugates level during the whole progression. To address this problem, we applied an azaserine-induced pancreatic carcinogenesis model, in which premalignant and malignant stages were investigated throughout the progression. The level of Ub immunoreactivity was measured in nucleus and cytoplasm by electron microscopic immunocytochemical and morphometrical methods. We found a sig- nificant increase of Ub level in the nucleus and the cytoplasmic area in premalignant atypical acinar cell nodule (AACN) cells and in malignant adenocarcinoma in situ (CIS) cells at month 20 after initiation

Molecular and functional interactions between glutamate and dopamine receptors in striatum

Molecular and functional interactions between glutamate and dopamine (DA) receptors regulate a large variety of brain functions and, when abnormal, they may contribute to and underlie numerous central nervous system (CNS) diseases. Here we show that D1 receptor activation at corticostriatal level induces a molecular and functional modification of the glutamatergic synapse. Treatment with D1 receptor agonist SKF38393 leads to a significant reduction of NR2A versus NR2B-containing NMDA receptors at synaptic sites and to a concomitant increase of GluR1-containing AMPA receptors insertion in the postsynaptic membrane. In addition, in vivo treatment with D1 receptor agonist induces a significant increase of dendritic spine head width of striatal medium spiny neurons. Notably, treatment of corticostriatal slices with NR2A antagonist NVP-AAM077 or with TAT2A (a cell-permeable peptide able to reduce NR2A-containing NMDA receptors) was sufficient to induce a similar significant morphological modification of dendritic spine head width. Conversely, NR2B antagonist ifenprodil blocked any morphological effect induced by D1 activation. Overall, we show that, in striatal spiny neurons, dopamine D1 receptor activation leads to a molecular, functional and morphological re-arrangement of the glutamatergic striatal synapse correlated to NR2A/NR2B subunits ratio in the postsynaptic compartment

Functional and molecular cross-talk between Dopamine and NMDA receptors in striatum

Molecular and functional interactions between glutamate and dopamine (DA) receptors regulate a large variety of brain functions and, when abnormal, they may contribute to and underlie numerous central nervous system (CNS) diseases. Here we show that modulation of D1 receptor activation at corticostriatal level induces a significant molecular and functional modification of the glutamatergic synapse. In particular, treatment with D1 receptor agonist SKF38393 leads to a significant reduction of NR2A vs NR2B-containing NMDA receptors at synaptic sites. This event is associated with a concomitant increase of GluR1-containing AMPA receptors in the postsynaptic membrane. In addition, morphological analysis of dendritic spines after D1 receptor activation showed a significant increase of dendritic spine head width of medium spiny neurons. Notably, treatment of corticostriatal slices with NR2A antagonist NVP-AAM077 or with TAT2A (a cell-permeable peptide able to reduce NR2A-containing NMDA receptors) was sufficient to induce a similar significant increase of dendritic spine head width. Conversely, NR2B antagonist ifenprodil blocked any morphological effect induced by D1 activation. Overall, we show that, in striatal spiny neurons, dopamine D1 receptor activation leads to a molecular, functional and morphological re-arrangement of the glutamatergic striatal synapse correlated to NR2A/NR2B subunits ratio in the postsynaptic compartment

D1 and NMDA receptor interplay in physiological and pathological conditions : focus on Parkinson's disease

Functional and structural interactions between D1 receptor (D1R) and NMDA receptor (NMDAR) have been shown to play a critical role in many functions of the brain. Interestingly, when these subtle interactions become abnormal, they might contribute to several diseases.Here we show that prolonged activation of D1R by SKF 38393 is able, in vitro as well as in vivo, to significantly reduce the quantity of NR2A subunit at the postsynaptic site. Interestingly, this molecular effect was in agreement with the reduction in the NMDA-AMPA ratio and specifically in NMDA(NR2A)-AMPA ratio as demonstrated by electrophysiological recordings. Considering the effect of this pharmacological approach on the NMDA subunit composition, we used SKF38393 in a model of \u201cearly\u201d Parkinson's Disease (PD), the so called \u201cpartial lesion\u201d model. In this condition, mild motor impairments were observed, compared to the more severe alterations occurring in the full lesion model. In addition, in corticostriatal slices recorded from partial lesioned animals (PL) a lack of Long Term Potentiation (LTP) was found, as well as a strong increase in the NR2A subunit abundance at the postsynaptic site. In the attempt to restore synaptic plasticity in PL, SKF38393 was administered in vivo. Surprisingly, the treatment successfully restored LTP in striatal neurons, by reducing the NR2A subunit levels at the postsynaptic site and it improved the motor performances. Finally, in order to avoid the typical side effects deriving from the dopaminergic treatment in PD, we used an alternative tool able to mimic the effect of the D1 agonist on the NMDAR subunit composition. To this end, we directly targeted NMDAR via a cell permeable peptide, TAT2A, acting towards the interruption of the NR2A subunit delivery to the NMDAR complex. Notably, TAT2A determined a significant improvement in motor behaviour and it rescued LTP thus representing a new therapeutic strategy in P

Supplementary Material for: Differential Gene Expression in Gonadotropin-Releasing Hormone Neurons of Male and Metestrous Female Mice

<p><b><i>Background:</i></b> Gonadotropin-releasing hormone (GnRH) neurons play a pivotal role in the regulation of the hypothalamic-pituitary gonadal axis in a sex-specific manner. We hypothesized that the differences seen in reproductive functions of males and females are associated with a sexually dimorphic gene expression profile of GnRH neurons. <b><i>Methods and Results:</i></b> We compared the transcriptome of GnRH neurons obtained from intact metestrous female and male GnRH-green fluorescent protein transgenic mice. About 1,500 individual GnRH neurons from each sex were sampled with laser capture microdissection followed by whole-transcriptome amplification for gene expression profiling. Under stringent selection criteria (fold change >1.6, adjusted p value 0.01), Affymetrix Mouse Genome 430 PM array analysis identified 543 differentially expressed genes. Sexual dimorphism was most apparent in gene clusters associated with synaptic communication, signal transduction, cell adhesion, vesicular transport and cell metabolism. To validate microarray results, 57 genes were selected, and 91% of their differential expression was confirmed by real-time PCR. Similarly, 88% of microarray results were confirmed with PCR from independent samples obtained by patch pipette harvesting and pooling of 30 GnRH neurons from each sex. We found significant differences in the expression of genes involved in vesicle priming and docking <i>(Syt1, Cplx1)</i>, GABAergic <i>(Gabra3, Gabrb3, Gabrg2)</i> and glutamatergic <i>(Gria1, Grin1, Slc17a6)</i> neurotransmission, peptide signaling <i>(Sstr3, Npr2, Cxcr4)</i> and the regulation of intracellular ion homeostasis <i>(Cacna1, Cacnb1, Cacng5, Kcnq2, Kcnc1)</i>. <b><i>Conclusion: </i></b>The striking sexual dimorphism of the GnRH neuron transcriptome we report here contributes to a better understanding of the differences in cellular mechanisms of GnRH neurons in the two sexes.</p

Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease

We describe here an innovative, non-transgenic animal model of Alzheimer's disease. This model mimics early stages of sporadic disease, which represents the vast majority of cases. The model was obtained by interfering with the complex between a disintegrin and metalloproteinase domain containing protein 10 (ADAM10), the main \u3b1-secretase candidate, and its partner, synapse-associated protein 97, a protein of the postsynaptic density-membrane associated guanylate kinase family. Association of ADAM10 with synapse-associated protein 97 governs enzyme trafficking and activity at synapses. Interfering with the ADAM10/synapse-associated protein 97 complex for 2 weeks by means of a cell-permeable peptide strategy is sufficient to shift the metabolism of the amyloid precursor protein towards amyloidogenesis and allows the reproduction of initial phases of sporadic Alzheimer's disease. After 2 weeks of treatment, we detected progressive Alzheimer's disease-like neuropathology, with an increase of \u3b2-amyloid aggregate production and of tau hyperphosphorylation, and a selective alteration of N-methyl-d-aspartic acid receptor subunit composition in the postsynaptic compartment of mouse brain. Behavioural and electrophysiological deficits were also induced by peptide treatmen