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Background: The number of studies where non-malignant pulmonary diseases are evaluated after occupational arsenic exposure is very few. Aims: To investigate the effects of occupational arsenic exposure on the lung by high-resolution computed tomography and pulmonary function tests. Study Design: Retrospective cross-sectional study. Methods: In this study, 256 workers with suspected respiratory occupational arsenic exposure were included, with an average age of 32.9±7.8 years and an average of 3.5±2.7 working years. Hair and urinary arsenic levels were analysed. High-resolution computed tomography and pulmonary function tests were done. Results: In workers with occupational arsenic exposure, high-resolution computed tomography showed 18.8% pulmonary involvement. In pulmonary involvement, pulmonary nodule was the most frequently seen lesion (64.5%). The other findings of pulmonary involvement were 18.8% diffuse interstitial lung disease, 12.5% bronchiectasis, and 27.1% bullae-emphysema. The mean age of patients with pulmonary involvement was higher and as they smoked more. The pulmonary involvement was 5.2 times higher in patients with skin lesions because of arsenic. Diffusing capacity of lung for carbon monoxide was significantly lower in patients with pulmonary involvement. Conclusion: Besides lung cancer, chronic occupational inhalation of arsenic exposure may cause non-malignant pulmonary findings such as bronchiectasis, pulmonary nodules and diffuse interstitial lung disease. So, in order to detect pulmonary involvement in the early stages, workers who experience occupational arsenic exposure should be followed by diffusion test and high-resolution computed tomography.

To evaluate the long-term effect of oral isotretinoin therapy on macula ganglion cell complex (GCC) thickness by spectral domain optical coherence tomography (SD-OCT).Newly diagnosed cystic acne patients who received low dose for a long time systemic isotretinoin therapy were included in this study. Thorough ophthalmic evaluation and GCC thickness analysis by using SD-OCT were performed at baseline, and at 1, 3, 6, and 12 months of treatment.Forty-eight eyes of 24 patients (15 females, 9 males) were included in the study. The mean age of patients was 19.37 ± 2.74 years (range 14-25 years). The full ophthalmologic examination was normal in all eyes before treatment. During the treatment there were no change in visual acuity, refractive error, intraocular pressure and tear break-up time. The mean GCC thicknesses were 81.45 ± 4.91, 81.45 ± 5.12, 81.81 ± 4.68, 81.87 ± 4.91 and 81.64 ± 5.09 μm at pretreatment and at 1, 3, 6, and 12 months of treatment, respectively (p = 0.803).One-year systemic use of isotretinoin had no significant effect on the thickness of macula ganglion cell. Macular ganglion cell analysis is useful for determining and following the toxic effects of systemic drugs on the retina. However, it is more rational to consider it as an adjunct to electrophysiological testing rather than used alone.

It was recently reported that the hexapeptide Ac-RYYRIK-ol binds with high affinity nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors and competitively antagonizes N/OFQ actions in the mouse vas deferens assay. Here we further describe the in vitro and in vivo pharmacological features of this NOP receptor ligand. In mouse brain homogenate the degradation half life of Ac-RYYRIK-ol (2.48 min) was significantly higher than that of the parent compound Ac-RYYRIK-NH 2 (1.20 min). In the electrically stimulated mouse vas deferens, Ac-RYYRIK-ol (10–1000 nM) competitively antagonized the inhibitory effect of N/OFQ (pA 2 = 8.46), while in the isolated mouse colon the hexapeptide mimicked N/OFQ contractile effects thus behaving as a NOP receptor agonist (pEC 50 = 9.09). This latter effect was no longer evident in colon tissues taken from mice knock out for the NOP receptor gene (NOP −/− ). In vivo in mice, similarly to N/OFQ, Ac-RYYRIK-ol (dose range 0.001–1 nmol) produced: i) pronociceptive effects after intracerebroventricular (i.c.v.) administration and antinociceptive actions when given intrathecally (i.t.) in the tail withdrawal assay; ii) inhibition of locomotor activity and iii) stimulation of food intake after supraspinal administration. Finally, in the forced swimming test, Ac-RYYRIK-ol was inactive per se, but reversed the antidepressant-like effects elicited by the NOP receptor selective antagonist UFP-101 ([Nphe 1 ,Arg 14 ,Lys 15 ]N/OFQ-NH 2 ). Thus, in all these in vivo assays Ac-RYYRIK-ol mimicked the actions of N/OFQ showing however higher potency. In conclusion, Ac-RYYRIK-ol displayed a complex pharmacological profile which is likely due to the low efficacy agonist nature of this novel ligand of the NOP receptor. The high potency, selectivity of action, and in vivo effectiveness make Ac-RYYRIK-ol a useful pharmacological tool for future studies in the field of N/OFQ and its NOP receptor.

Following the discovery of nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) and its endogenous ligand, an extensive search has started to find selective agonists and antagonists targeting this novel receptor-ligand system due to their therapeutic potentials. By the help of the combinatorial chemistry a series of hexapeptides with a general formula of Ac-RYY-R/K-W/I-R/K-NH(2) having high NOP receptor affinity and selectivity were identified. On the basis of this information we developed a number of novel compounds. The detailed structure-activity studies on the partial agonist Ac-RYYRIK-NH(2) are reported in this communication. Besides the modifications on N- and C-terminal, Arg-Cit exchange was performed on the template structure. The novel hexapeptides were analyzed in radioligand binding, functional biochemical [(35)S]GTPgammaS binding assays by using membranes from rat brains and Chinese hamster ovary cells expressing human NOP receptor. The agonist/antagonist properties were also tested on in the mouse vas deferens bioassay. C-terminal modification yielded a high affinity, selective and potent NOP ligand (Ac-RYYRIK-ol) with a partial agonist property. Several analogs of this compound were synthesized. The presence of the positively charged arginine residue at the first position turned out to be crucial for the biological activity of the hexapeptide. The N-terminal modifications with various acyl groups (ClAc, pivaloyl, formyl, benzoyl, mesyl) decreased the affinity of the ligand towards the receptor and the intrinsic activity for stimulating the G-protein activation was also decreased. The structure-activity studies on the hexapeptide derivatives provided some basic information on the structural requirements for receptor binding and activation.

Excitotoxicity is a contributing factor to the pathogenesis of acute or chronic neurodegenerative disease states. Kainic acid (KA) is an excitotoxic substance and the administration of it to rodents induces seizure activity (status epilepticus, SE) and leads to neurodegeneration. In this study the effect of KA-induced excitotoxicity on the G-protein activations and the gene expression levels of the opioid/nociceptin system receptors as MOPr, KOPr, DOPr, ORL-1, and PNOC (N/OFQ) were investigated, and the regulator effect of naloxone (Nal) on the gene expressions of the opioid system receptors against KA-induced seizures in the rat hippocampus was tested. In addition, the expression levels of stress-toxicity genes were assessed in the hippocampus following KA-induced excitotoxicity in order to determine the potential genetic targets which can be helpful for neuroprotective interventions. Our results indicate that the KA-induced excitotoxicity increased the mRNA levels of MOPr, DOPr, KOPr, PNOC, and ORL-1. However, G-protein activations of MOPr, DOPr, and KOPr remained relatively unchanged while both the potency and efficacy of N/OFQ were significantly increased. The PCR array data showed that KA-induced excitotoxicity altered the expression levels of genes in the cellular stress or toxicity pathways. Our data suggests that the induction of the opioid/nociceptin system may be involved in the cellular stress response following a neurodegenerative insult and that the genes modulated by the KA-treatment in the stress-toxicity pathways may be evaluated as targets of potential neuroprotective interventions.

Pityriasis rosea (PR) is an acute, self-limiting papulosquamous disorder of unknown etiology. Published studies of childhood PR are scarce and most are reviews. The aim of this study was to determine the demographic and clinical features of childhood PR.

Nociceptin, a 17-amino acid peptide (FGGFTGARKSARKLANQ, N/OFQ), is the endogenous ligand of the nociceptin/orphanin FQ (NOP) receptor. This receptor-ligand system is involved in various physiological as well as pathophysiological mechanisms, but owing to the peptidic structure, it is rapidly degraded by enzymes. The enzymatic digestion of nociceptin involves mainly aminopeptidases and yields Noc(2-17)-OH and other smaller fragments. We aimed at increasing the enzymatic stability against aminopeptidases in the case of peptide Noc(1-13)-NH(2), which possesses the minimum sequence capable of interacting with the NOP receptor. Therefore we developed a new procedure for the synthesis of peptides with the carbamic acid residue [...-NH-CH(R)-CO-NH-CO-NH-CH(Q)-CO-.]. A set of four carbamic acid-nociceptin derivatives were produced. The carbamic acid residue was incorporated into the inner part of the peptides, building on solid phase, by using a suitable dipeptide fragment with carbamic acid residue produced by a simple and efficient three-step solution phase procedure. Enzymatic stability of carbamic acid peptides was studied in the presence of aminopeptidase M (AP-M) and in rat brain membrane homogenate. The receptor-binding properties were also studied by radioligand binding assay on crude rat brain membranes and the activity of the ligands were analyzed on isolated mouse vas deferens (MVD) tissues. We found that incorporation of the carbamic acid residue into the N-terminal part of nociceptin significantly increases the resistance against AP-M. We observed the decrease of binding affinities to the NOP receptor in case of the peptides modified in the N-terminal portion. Consequently, the incorporation of the carbamic acid residue into peptides can be proposed as a promising and reasonable tool for increasing enzymatic stability, where the native molecule is less sensitive for carbamic acid residue-related structural change.

Nociceptin is an endogenous anti-opiate heptadecapeptide primarily interacting with the nociceptin (NOP) receptor. This neuropeptide-receptor system is involved in pain regulation, tolerance to and dependence on opiates as well as many other physiological and pathophysiological events. The role and mechanisms of nociceptin in pathological conditions is not clearly known yet. In an attempt to have a radiopharmaceutical labeled either with 99mTc or (111)In, we incorporated diethylenetriaminepentaacetic acid (DTPA) as chelator into the structure of [Arg14,Lys15]nociceptin(1-17)-NH2 at the epsilon-amino group of Lys15. Such a radiopeptide may be useful in imaging for diagnostical purposes. Preparation of the peptide ligands was carried out by solid phase synthesis. Two peptides containing DTPA were obtained and purified. The products were [Arg14,Lys(DTPA)15]nociceptin(1-17)-NH2 and its cross-linked dimer on the basis of mass spectrometric analysis. In (115)In3+ binding experiments the conjugates exhibited preserved indium ion chelating properties, indicating the potential use of radiolabeled DTPA-nociceptin derivatives as radiopharmaceutical. Biological properties of these compounds were studied in rat brain membrane preparations by radioligand binding, functional biochemical [35S]GTPgammaS binding assays and mouse vas deferens (MVD) bioassay. Besides the similar in vitro binding characteristics to nociceptin receptor, both of the DTPA-chelated compounds were more potent and efficient than nociceptin in functional biochemical and mouse vas deferens bioassays. Our further aim is to radiolabel these compounds in order to get a radiopharmaceutical which can be used diagnostically.

Objective: A relationship between the pathogenesis of some cancers and growth hormone, insulin-like growth factor-1 and insulin-like growth factors binding protein-3 has been shown. Our aim was to evaluate the expression of growth hormone receptor, insulin-like growth factor-1 receptor and insulin-like growth factors binding protein-3 in actinic keratosis, basal cell carcinoma and squamous cell carcinoma, and to compare the expression patterns of tumoral areas with normal epidermis and skin appendages. Material and Method: Th e formalin-fixed, paraff in-embedded tissues of 40 patients which were diagnosed as 15 actinic keratosis, 15 basal cell carcinoma and 15 squamous cell carcinoma were analyzed for growth hormone receptor, insulin-like growth factor-1 receptor and insulin-like growth factors binding protein-3 with the immunohistochemical method using the streptavidin-biotin-peroxidase technique. Results: Th ere was no diff erence between tumoral areas of actinic keratosis, basal cell carcinoma and squamous cell carcinoma in expression of growth hormone receptor and insulin-like growth factors binding protein-3 (P>0.05). However, a significantly higher expression of insulin-like growth factor-1 receptor was observed in tumoral areas of squamous cell carcinoma (P