Focusing on the 5F-MDMB-PICA, 4F-MDMB-BICA synthetic cannabinoids and their primary metabolites in analytical and pharmacological aspects.

Nowadays, more and more new synthetic cannabinoids (SCs) appearing on the illicit market present challenges to analytical, forensic, and toxicology experts. For a better understanding of the physiological effect of SCs, the key issue is studying their metabolomic and psychoactive properties. In this study, our validated targeted reversed phase UHPLC-MS/MS method was used for determination of urinary concentration of 5F-MDMB-PICA, 4F-MDMB-BICA, and their primary metabolites. The liquid-liquid extraction procedure was applied for the enrichment of SCs. The pharmacological characterization of investigated SCs were studied by radioligand competition binding and ligand stimulated [35S]GTPγS binding assays. For 5F-MDMB-PICA and 4F-MDMB-BICA, the median urinary concentrations were 0.076 and 0.312 ng/mL. For primary metabolites, the concentration range was 0.029-881.02* ng/mL for 5F-MDMB-PICA-COOH, and 0.396-4579* ng/mL for 4F-MDMB-BICA-COOH. In the polydrug aspect, the 22 urine samples were verified to be abused with 6 illicit drugs. The affinity of the metabolites to CB1R significantly decreased compared to the parent ligands. In the GTPγS functional assay, both 5F-MDMB-PICA and 4F-MDMB-BICA were acting as full agonists, while the metabolites were found as weak inverse agonists. Additionally, the G-protein stimulatory effects of the full agonist 5F-MDMB-PICA and 4F-MDMB-BICA were reduced by metabolites. These results strongly indicate the dose-dependent CB1R-mediated weak inverse agonist effects of the two butanoic acid metabolites. The obtained high concentration of main urinary metabolites of 5F-MDMB-PICA and 4F-MDMB-BICA confirmed the relevance of their routine analysis in forensic and toxicological practices. Based on in vitro binding assays, the metabolites presumably might cause a lower psychoactive effect than parent compounds.

A novel target for the promotion of dermal wound healing: Ryanodine receptors.

Ryanodine receptors have an important role in the regulation of intracellular calcium levels in the nervous system and muscle. It has been described that ryanodine receptors influence keratinocyte differentiation and barrier homeostasis. Our goal was to examine the role of ryanodine receptors in the healing of full-thickness dermal wounds by means of in vitro and in vivo methods. The effect of ryanodine receptors on wound healing, microcirculation and inflammation was assessed in an in vivo mouse wound healing model, using skin fold chambers in the dorsal region, and in HaCaT cell scratch wound assay in vitro. SKH-1 mice were subjected to sterile saline (n = 36) or ryanodine receptor agonist 4-chloro-m-cresol (0.5 mM) (n = 42) or ryanodine receptor antagonist dantrolene (100 µM) (n = 42). Application of ryanodine receptor agonist 4-chloro-m-cresol did not influence the studied parameters significantly, whereas ryanodine receptor antagonist dantrolene accelerated the wound closure. Inhibition of the calcium channel also increased the vessel diameters in the wound edges during the process of healing and increased the blood flow in the capillaries at all times of measurement. Furthermore, application of dantrolene decreased xanthine-oxidoreductase activity during the inflammatory phase of wound healing. Inhibition of ryanodine receptor-mediated effects positively influence wound healing. Thus, dantrolene may be of therapeutic potential in the treatment of wounds.

Characteristics of urolithiasis in the dog population of Hungary from 2001 to 2012.

The objective of this study was to describe the epidemiology of canine urolithiasis in Hungary in order to determine the annual incidence of urolithiasis and to identify breeds at risk for different types of urolithiasis. Data of a total of 2,543 canine uroliths analysed in the laboratory of the Budapest Urolith Centre were evaluated retrospectively from 2001 to 2012. Logistic regression was used to assess odds ratios for the proportion of each affected breed compared to those of crossbreeds. The annual incidence of urolithiasis was evaluated by the number of submissions compared to the estimated number of dogs in the population from which the samples originated. Epidemiologic data revealed a relatively high and increasing proportion of struvite urolithiasis. Statistical analysis of breed predispositions resulted in the detection of breeds not having been reported at risk (e.g. Bernese Mountain dog - struvite, Bichon Frise, Bolognese, Tibetan Terrier - purine, French Bulldog - cystine). Conflicting results were revealed for some other breeds previously described as being affected by certain types of urolithiasis (Chihuahua, Pekingese, Shih Tzu, English Cocker Spaniel). Regardless of the type of urolithiasis, its average cumulative incidence in the dog population of Hungary was found to be 1.76/10,000/year.

Urolithiasis in a captive group of Tammar wallabies (Macropus eugenii).

Urolithiasis is a well-known disease of the urogenital system in domestic animals, and it has also been described in captive and free-ranging wildlife. This article reports 15 cases of urolithiasis in a captive group of Tammar wallabies (Macropus eugenii) between 2004 and 2011. The analyzed stones were composed of pure calcium carbonate (n = 5), calcium carbonate with traces of calcium phosphate (n = 6), carbonate apatite (n = 2), and carbonate apatite mixed with calcium oxalate (n = 2). In 12 out of 15 cases uroliths were situated only in the renal pelvis; in two cases they were found in the renal pelvis and the ureter; while in one case in the ureter only. No common infectious agents were identified either by microbiological or histopathological methods. Although the exact cause remains unknown, the repetitive occurrence of calcium carbonate urolithiasis suggests husbandry-related causes. To the best of the authors' knowledge, this is the first report on recurrent appearance of urolithiasis in a captive group of Tammar wallabies.

Effect of Inflammatory Microenvironment on the Regenerative Capacity of Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells are increasingly being used in regenerative medicine as cell therapy targets, including in the treatment of burns and ulcers. The regenerative potential of AD-MSCs and some of their immunological properties are known from in vitro studies; however, in clinical applications, cells are used in non-ideal conditions and can behave differently in inflammatory environments, affecting the efficacy and outcome of therapy. Our aim was to investigate and map the pathways that the inflammatory microenvironment can induce in these cells. High-throughput gene expression assays were performed on AD-MSCs activated with LPS and TNFα. Analysis of RNA-Seq data showed that control, LPS-treated and TNFα-treated samples exhibited distinct gene expression patterns. LPS treatment increased the expression of 926 genes and decreased the expression of 770 genes involved in cell division, DNA repair, the cell cycle, and several metabolic processes. TNFα treatment increased the expression of 174 genes and decreased the expression of 383 genes, which are related to cell division, the immune response, cell proliferation, and differentiation. We also map the biological pathways by further investigating the most altered genes using the Gene Ontology and KEGG databases. Secreted cytokines, which are important in the immunological response, were also examined at the protein level, and a functional assay was performed to assess wound healing. Activated AD-MSC increased the secretion of IL-6, IL-8 and CXCL-10, and also the closure of wounds. AD-MSCs presented accelerated wound healing under inflammation conditions, suggesting that we could use this cell in clinical application.

Challenges in the Complex Management of Neglected Cutaneous Melanomas in the Head and Neck Area: A Single Center Experience.

Familiar controversies in the management of head and neck melanomas are more remarkable in locally advanced cases, and they represent a treatment challenge both surgically and oncologically. In our retrospective study, patients with surgically treated primary malignant melanoma of the head and neck region larger than 3 cm in diameter were included. Five patients met our inclusion criteria. In all cases, wide excision and immediate reconstruction were performed without sentinel lymph node biopsy. The defect on the scalp was covered by a split skin graft, with local flaps chosen for reconstruction on the face on an individual basis. After a 2-6 year follow-up, a good oncological, functional, and esthetic result was achieved. Our results show that in the case of large, locally advanced melanomas, surgical treatment still plays a crucial role that can provide long-term local control and support the effect of systemic treatment.

Mouse barley awn (Hordeum murinum) migration induced cystolithiasis in 2 male dogs.

Two male dogs were presented with cystic uroliths composed of magnesium ammonium phosphate (struvite). Each had an atypical nidus, a mouse barley awn (Hordeum murinum). To our knowledge, this is the first report of grass awns located in the bladder lumen of dogs. The composition of uroliths and the pathophysiology of grass awn migration to the urinary bladder are discussed.

Reconstruction of Alar-Perialar Defects with a Combined Subcutaneous and Cutaneous Pedicled Rotation-Advancement Nasolabial Flap.

Aim of the Study: During the reconstruction of alar defects involving the upper lip, reconstructive surgeons face the need for various thicknesses of tissues crucial to preserving the facial sulcus which is important for a cosmetically acceptable result. Our aim was to reconstruct the deep perialar and thinner lateral nasal alar defect in a single step procedure with a suitable flap which is reliable, has appropriate blood supply and provides an esthetically good result. Materials and Methods: Extended alar defect was reconstructed with a combined flap in 10 cases. During the procedure, a subcutaneous pedicle was created and the proximal part of the flap was rotated into the defect as a rotational flap. The procedure and the follow-up have been photo-documented in all cases. Furthermore, the perfusion of the flaps was monitored by means of laser Doppler flowmetry. Postoperative complications were evaluated with a semi-quantitative score and the patients completed a patient satisfaction questionnaire, too. Results: An optimal esthetic result was obtained in all cases after the operation. The lateral nasal alar part of the defect was reconstructed with the thinner proximal part of the flap while the deeper perialar region involving the upper lip was covered with the thicker distal part. The flaps have shown sufficient blood flow after the operation. There was no significant pin cushioning or "trap-door" effect in any case. Mild erythema and edema was found in few cases. The patients were satisfied with the cosmetic result of the intervention. Conclusions: The flap is suitable for the reconstruction of alar defects involving the perialar region. It has the advantage of covering the deeper perialar and the thinner alar defects, whilst eliminating the pin cushioning effect of the conventional subcutaneous island pedicle flaps.

A Randomized Controlled Trial with a Medical Device Containing Sodium Hyaluronate and Nicotinic Acid to Increase the Efficacy of Ultraviolet Phototherapy in Psoriasis.

INTRODUCTION: The dry and scaly skin of psoriatic patients decreases the efficacy of ultraviolet B (UVB) phototherapy. Different agents are used to facilitate the transmission of light, but most of these preparations are cosmetically unfavorable. We have tested a novel preparation containing sodium hyaluronate and nicotinic acid (UV Fotogel®; Pernix Ltd.) with the double aim to improve the efficacy of UVB phototherapy and assess the cosmetic acceptability of the preparation. METHODS: Ninety patients with plaque psoriasis were enrolled in the study, of whom 44 received narrow-band UVB (NB-UVB) phototherapy. Prior to phototherapy, one side of the patient's body was treated with UV Fotogel while the other side served as a control. The other 46 patients used the preparation at their homes before regular sunbathing. The Local Psoriasis Severity Index (L-PSI), cosmetic acceptability and tolerability were recorded. The median values with the 25th and 75th percentiles (25p and 75p, respectively) were determined for the UV Fotogel-treated and control sites and then compared. RESULTS: The sides of the body to which UV Fotogel was applied prior to NB-UVB phototherapy had a significantly lower median L-PSI score than the non-treated control sides at the end of the treatment (1.0 [25p-75p: 0.0-2.0] vs. 2.0 [1.0-3.0], respectively). The application of UV Fotogel prior to sunbathing also led to a significant decrease in L-PSI score. There was a significant reduction in the median L-PSI score of patients at the final visit compared to baseline (2.5 [25p-75p: 1.5-3.5] vs. 6.0 [6.0-7.0], respectively). Use of the preparation was not accompanied by considerable adverse effects, and the patients found it cosmetically acceptable. Application of UV Fotogel prior to sunbathing was well tolerated by the patients, and the cosmetic acceptability was also good. CONCLUSION: UV Fotogel is potentially a useful device for enhancement of the efficacy of phototherapy in patients with psoriasis.

A Possible Technique for the Complex Reconstruction of Exposed Breast Implant: Applicability and Microcirculation of the Capsule Flap.

Aim of the Study: Immediate breast reconstruction is often applied after mastectomy. However, inappropriate surgical technique, postoperative radiotherapy and infection may lead to tissue necrosis and implant protrusion. Traditional therapies frequently fail. However, previous data suggested that capsule flaps may be appropriate for the salvage of implants. Our goal was to investigate the usefulness of capsuloplasty in patients with exposed breast implant and to monitor the blood supply of capsule flaps during the operation. Materials and Methods: Capsuloplasty was performed in 19 patients with exposed implant. After removal of necrotic tissue, capsulotomy was performed, the planned flap was dissected free, the implant was covered with the flap and the wound was then closed. During operation, the blood flow of the flap was determined by means of laser Doppler flowmetry. Moreover, tissue samples were taken for histology and immunostaining for CD34. Results: The postoperative follow-up showed that capsule flaps survived in each case: no complications were found. The blood flow of the flaps did not change significantly during the intervention as compared with the baseline values. The histology and the immunohistochemistry revealed considerable vascularization and angiogenesis in the flap. Conclusions: Capsule flaps seem to be appropriate for the salvage of exposed implants and for enhancement of implant cover in the case of thin and injured tissue.

Description of five dirofilariasis cases in South Hungary and review epidemiology of this disease for the country.

BACKGROUND: Dirofilariasis is an emerging zoonosis (supported by climate change) in Central Europe. Human infections are usually caused by Dirofilaria repens and Dirofilaria immitis with mediation of mosquito vectors. Aims of this publication were to report our dirofilariasis cases, and to summarize Hungarian epidemiological data by reviewing literature. METHODS AND RESULTS: We present five (four ophthalomological, one subcutaneous) cases observed within a 2-year period in Southern Hungary. Ages of infected patients were between 31 and 74 years. First case during pregnancy is also reported. There was no travel history in the anamnesis of patients which could explain acquisition of the infection. Moving, intact worms eliminated by surgical interventions were identified on the basis of morphological features as D. repens. Since the first report of human case, 115 further episodes (in addition to ours) were diagnosed in Hungary. Mean age of the patients was 47 years. Reviewing national reports, the ratio of subcutaneous infections was higher than that of the ocular ones (66 and 45, respectively). Evaluation of the territorial distribution of human episodes revealed that most infections occurred in patients living in the Danube-Tisza interfluvial region and eastern part of the country. However, sporadic cases were also found in western counties during 2014. CONCLUSION: Most of the Hungarian dirofilariasis cases were autochthonous infections. Occurrence in the western counties may suggest the spreading of this emerging zoonosis to these areas. Comprehensive monitoring and data analysis are desirable, therefore reporting the epidemiologic data in the case of human infections should be made mandatory.

Effects of the combined PDL/Nd:YAG laser on surgical scars: vascularity and collagen changes evaluated by in vivo confocal microscopy.

The aim of this study was to investigate the efficacy of the sequential combined 585 nm PDL and the 1064 nm neodymium:yttrium-aluminium-garnet laser (PDL/Nd:YAG) in the treatment of surgical scars and to evaluate the short-term effects by in vivo confocal microscopy (RCM) and the long-term effects by clinical assessment of the scars. Twenty-five patients were enrolled with 39 postoperative linear scars; each scar was divided into two fields. One half was treated with the combined PDL/Nd:YAG laser, whereas the other half remained untreated. Each scar was treated three times at monthly intervals. Scars were evaluated by an independent examiner, using the Vancouver Scar Scale. The combined PDL/Nd:YAG laser significantly improved the appearance of the scars. In order to study the short-term effects of combined laser treatment, six additional patients were enrolled with 7 postoperative linear scars. One half of scars was treated once with the combined PDL/Nd:YAG laser. One week after this laser treatment, both the treated and the nontreated parts of the scars were examined by dermoscopy and RCM. The dermoscopic pictures revealed improvements even in treated areas. In conclusion, the combined PDL/Nd:YAG laser was found to be effective in improving the quality and appearance of the surgical scars.