NPY and NPY receptors in vascular remodeling

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that acts on multiple receptors (Y1-Y6) and exerts a variety of cardiovascular effects. Originally known as a vasoconstrictor acting on Y1 receptors, NPY is also a potent angiogenic factor as well as a powerful stimulator of vascular smooth muscle proliferation and atherogenesis in vitro and in vivo. These two types of vascular remodeling are predominantly mediated by Y2/Y5 and Y1 receptors respectively, but evidence suggests that all receptors are activated in both conditions. A strategy to inhibit neointima formation and atherosclerotic lesions without impairing ischemic angiogenesis and collateral vessel formation has been a major challenge to overcome. Studies in rodents show that Y1 receptor antagonist inhibits angioplasty-induced atherosclerotic-like vascular remodeling, without affecting ischemic revascularization. Conversely, Y2 receptor activation appears to be sufficient to stimulate angiogenesis in various animal models. Thus, the use of selective receptor agonists to promote angiogenesis through the Y2 receptor while antagonizing the pro-atherosclerotic and pro-stenotic effects with Y1 receptor-selective antagonists may help to successfully treat vascular remodeling in cardiovascular diseases.     

Effect of repeated co-treatment with imipramine and metyrapone on the behavioral reactivity of the central serotonin, dopamine and alpha 1-adrenergic systems in rats

The aim of present study was to examine the effect of repeated co-treatment with imipramine and metyrapone on the development of adaptive changes in the function of central serotonin 5-HT1A and 5-HT2A, dopamine D2/3 and alpha 1-adrenergic receptors in rats. The obtained results showed that repeated co-treatment with imipramine (5 or 10 mg/kg) and metyrapone (50 mg/kg) (twice daily for 14 days) either induced more potent inhibition of the behavioral syndrome evoked by 5-HT1A and 5-HT2A receptor agonists (8-OH-DPAT and (+/-)DOI, respectively), or did no change the action of amphetamine and wuinpirole (a dopamine D2/3 agonist) or phenylephrine (an alpha 1-adrenergic agonist) compared to treatment with either drug alone. The results described in the present paper support the hypothesis that repeated co-treatment with imipramine and metyrapone may possess more effective antidepressant activity than the treatment with imipramine alone, and that, among other mechanisms, 5-HT1A- and 5-HT2A (but not dopamine D2/3- or alpha 1-adrenergic) receptors may also play some role in this effect.     

Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression

The paper describes the effect of amantadine addition to imipramine therapy in patients suffering from treatment-resistant unipolar depression who fulfilled DSM IV criteria for major (unipolar) depression. Fifty patients were enrolled in the study on the basis of their histories of illness and therapy. After a 2-week drug-free period, 25 subjects belonging to the first group were treated only with imipramine twice daily (100 mg/day) for 12 weeks, and 25 subjects belonging to the second group were treated with imipramine twice daily (100 mg/day) for 6 weeks and then amantadine was introduced (150 mg/day, twice daily) and administered jointly with imipramine for the successive 6 weeks. Hamilton Depression Rating Scale (HDRS) was used to assess the efficacy of antidepressant therapy. Imipramine did not change the HDRS score after 3, 6 or 12 weeks of treatment when compared with the washout (before treatment). The addition of amantadine to the classic antidepressant reduced HDRS scores after 6-week joint treatment. Moreover, the obtained pharmacokinetic data indicated that amantadine did not significantly influence the plasma concentration of imipramine and its metabolite desipramine in patients treated jointly with imipramine and amantadine, which suggests lack of a pharmacokinetic interaction. The obtained results indicate that joint therapy with an antidepressant and amantadine may be effective in treatment-resistant unipolar depression.     

Antidepressant-like effect of combined treatment with selective sigma receptor agonists and a 5-HT1A receptor agonist in the forced swimming test in rats

The interaction between the selective sigma (sigma) receptor agonists and 8-OH-DPAT, a serotonin (5-HT)(1A) receptor agonist, was examined in the forced swimming test in rats. The results indicate that joint administration of DTG (5 mg/kg) or SA4503 (3 mg/kg), the selective sigma(1)/sigma(2)- or sigma(1)-receptor agonists, respectively, and 8-OH-DPAT (0.1 or 0.3 mg/kg) induces an antidepressant-like effect. The doses of sigma agonists and 8-OH-DPAT used in the study were inactive per se in this model. The effect of DTG and 8-OH-DPAT co-administration was partly counteracted by WAY 100635 (0.1 mg/kg) as well as by BD 1047 (3 mg/kg), a 5-HT(1A) and sigma(1) receptor antagonists, respectively, suggesting the involvement of both receptor types in the anti-immobility effect in rats.     

Cytomegalovirus Isolation from a Chimpanzee with Acute Demyelinating Disease After Inoculation of Multiple Sclerosis Brain Cells

A strain of cytomegalovirus (CMV) was isolated during the third subcultivation of explants from the left frontal lobe of a chimpanzee that developed paralysis more than 3 years after intracerebral inoculation at birth with brain cell cultures derived from a patient with multiple sclerosis. Another strain of CMV was also isolated from a lymph node culture taken from the same chimp. The isolates, designated MZM-13 and MZM-14, produced a cytopathic effect characteristic for CMV when inoculated into brain, ganglion, or fibroblast cultures of human or simian origin. Infected cells contained characteristic Cowdry A intranuclear as well as intracytoplasmic inclusion bodies, and 100-nm spherical herpes-like virus particles were detected by electron microscopy in the nucleus and cytoplasm of infected cells. Virus was further identified as CMV with convalescent human anti-CMV serum. Complement-fixing antibody to CMV was present at a titer of 1:32 when the acutely ill chimpanzee was sacrificed. No antibody was detected at birth or at 1 or 2 years of age. A newborn chimpanzee inoculated intracerebrally with MZM-13 developed clinically asymptomatic lesions in the central nervous system characterized by acute and chronic inflammation and degeneration of myelin in cranial and spinal nerve roots. Restriction endonuclease analysis of viral deoxyribonucleic acid isolated from these two viruses indicated that MZM-13 and MZM-14 are identical and are closely related to chimpanzee CMV. No similarity in restriction endonuclease fragment patterns was found between MZM virus and the Towne and Clegg strains of human CMV.     

Retinal Vessel Functionality Is Linked With ARMS2 A69S and CFH Y402H Polymorphisms and Choroidal Status in AMD Patients

PurposeWe aimed to investigate the reactivity of retinal vessels to a flickering stimulus in patients with age-related macular degeneration (AMD) and healthy participants. We also assessed whether the parameters of retinal vessels are dependent on genetic predisposition.MethodsA total of 354 patients with AMD and 121 controls were recruited for the study. All participants underwent thorough ophthalmologic examination and static and dynamic retinal vessel analysis. AMD risk polymorphisms were genotyped in the CFH and ARMS2 genes.ResultsWe found no differences between the AMD group and controls in central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), arteriovenous ratio (AVR), dynamic analysis of arteries (DAAs), or dynamic analysis of veins (DAVs). Eyes with early AMD presented with significantly higher AVR values than eyes with late AMD. In the AMD group, DAA correlated positively with both choroidal thickness (Rs = 0.14, P = 0.00096) and choroidal volume (Rs = 0.23, P < 0.0001), and no such associations were observed in the controls. We found significantly lower DAA (1.47 ± 1.50) in TT homozygotes for the ARMS2 A69S polymorphism in comparison with GG homozygotes (2.38 ± 1.79) and patients with GG + GT genotypes (2.28 ± 1.84). We also observed less prominent DAV (3.24 ± 1.71) in patients with TC + CC genotypes in the CFH Y402H polymorphism compared with TT homozygotes (3.83 ± 1.68).ConclusionsOur findings suggest that retinal microcirculation appears to be associated with the genetic background, choroidal parameters, and clinical features of the patients with AMD.     

Application of Color Doppler ultrasonography in the evaluation of the blood flow in the ocular vessels in patients with anterior ischemic optic neuropathy--the preliminary report

PURPOSE: Anterior ischemic optic neuropathy (AION) is one of the most common causes of acute loss vision in the middle-aged and elderly persons. It occurs due to hypoperfusion in the short posterior ciliary arteries supplying the optic nerve head. The aim of our study was evaluation of the usefulness of colour Doppler ultrasonography in diagnostics of AION. MATERIAL AND METHODS: Color Doppler imaging of the ophthalmic artery, central retinal artery and posterior ciliary arteries were performed in 10 patients with clinically evident AION. The peak-systolic velocity (PSV), end-systolic velocity (EDV) and resistance index (RI) were measured. RESULTS: No significant differences in the mean values of PSV, EDV and RI of ophthalmic arteries and posterior ciliary arteries between the affected and non-affected eyes were found. Reduction of mean flow velocities as well as significantly increased resistance index were observed in the central retinal artery in eyes with AION. CONCLUSIONS: The Color Doppler findings in the ciliary arteries do not reflect the ischemic changes in patients with AION. It is probably due to anatomical limitation of this method in evaluation of the blood flow in posterior ciliary arteries supplying the optic nerve head. Abnormal blood flow parameters in the central retinal artery are secondary changes due to optic disc oedema.     

Elastase deposits in the kidney and urinary elastase excretion in patients with glomerulonephritis--evidence for neutrophil involvement in renal injury

OBJECTIVE: Elastase is a key proteolytic enzyme released during polymorphonuclear leukocyte degranulation. There are abundant data of elastase involvement in the development of injury in experimental models of glomerulonephritis (GN), but scant direct evidence of its involvement in human primary GN. The aims of this study were to determine the immunolocalization of elastase deposits in kidney biopsy specimens from patients with primary idiopathic GN, to attempt to correlate the distribution and intensity of deposits with urinary elastase excretion, and to determine clinical markers of renal injury in several types of primary idiopathic GN. MATERIAL AND METHODS: The immunohistochemical localization and intensity of elastase deposits in kidney biopsies, the urinary excretion of leukocyte elastase, and proteinuria and serum creatinine levels were evaluated in 23 patients with primary GN and the associations between these factors were sought. RESULTS: Patients with crescentic proliferative GN had the highest intensity of elastase deposits. In this group of patients, elastase was present in the glomerular endothelium, as well as in the tubular epithelium and interstitium. Patients with a high intensity of elastase deposits within the glomerular endothelium and Bowman's capsule had significantly higher urinary excretion of elastase. Patients with interstitial, mesangial and perivascular elastase deposits had significantly higher serum creatinine than those without. Patients with elastase deposits in the glomerular endothelium and in the interstitium had insignificantly higher proteinuria than those without. CONCLUSION: Our data provide morphological evidence of leukocyte elastase involvement in renal injury occurring in the course of primary idiopathic GN, in particular in the proliferative types.     

Frequency of DRB1-DQB1 two-locus haplotypes in tuberculosis: preliminary report

Analysis of correlation between tuberculosis (TB) and human leukocyte antigen (HLA) in populations from Asia and Latin America has shown conflicting results. The aim of this study was to evaluate the frequency of HLA-DRB1-DQB1 two-locus haplotypes of 61 TB patients and 125 healthy volunteers in the same ethnic group in Poland. DRB1 and DQB1 alleles were determined by PCR-SSP "low-resolution" and "high-resolution" methods. Our study showed that DRB1*1601 and DQB1*0502 alleles were more frequent, whereas DQB1*0201 was rarer in TB than in controls. DRB1*16-DQB1*05, DRB1*04-DQB1*03 and DRB1*1601-DQB1*0502 haplotype were more common, and DRB1*11-DQB1*03 less frequent in TB in comparison to controls. Positive linkage disequilibrium (LD) for DRB1*01-DQB1*05, DRB1*03-DQB1*02, DRB1*11-DQB1*03, DRB1*13-DQB1*06 and DRB1*15-DQB1*06 was found in controls. A trend towards the positive LD for DRB1*01-DQB1*05, DRB1*03-DQB1*02, DRB1*11-DQB1*03, DRB1*15-DQB1*06 and DRB1*16-DQB1*05 was shown in TB. The trend towards the positive LD for DRB1*16-DQB1*05 haplotype in TB patients was not observed in the control group. It seems likely that the presence of DRB1*1601, DQB1*0502 alleles and DRB1*1601-DQB1*0502, DRB1*04-DQB1*03, DRB1*14-DQB1*05 haplotypes may be related to a higher risk of developing TB, whereas low frequency of DQB1*0201 and DRB1*11-DQB1*03 haplotype may be linked to the resistance to TB.     

Antiphospholipid syndrome--interdisciplinary problem

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder, where the essence of the matter is the existence of antiphospholipid antibodies. The typical symptoms of APS are: venous thrombo-embolic disease and artery thrombosis in a brain. The authors present 5 patients (2 females and 3 males) at the age of 36-54 with ischemic stroke and one 26-year-old women with thrombosis of central retinal vein caused by APS. In 4 cases in secondary prevention anticoagulant (acenocumarol) was used and in 2--antiplatelet drug (aspirin). In 2 cases congenital disturbances of coagulation were also discovered. We suggest that in ischemic stroke and visual disturbances of not-well-known origin it is useful to make examinations concerning APS, as well as congenital thrombophilias.