Immunoreactivity of various peptides in typical and atypical bronchopulmonary carcinoid tumours.

The presence of a number of regulatory peptides (bombesin, gastrin, glucagon, somatostatin, calcitonin and ACTH) was compared in 30 typical carcinoid tumours and 27 well differentiated neuroendocrine carcinomas (atypical carcinoids) using conventional immunocytochemistry. Strong immunostaining for one or more peptide was observed in 97% of the typical carcinoids (29/30) whereas only 67% of the neuroendocrine carcinomas showed immunoreactivity. The peptide most frequently detected in typical carcinoids was bombesin (67%), while gastrin was more common in neuroendocrine carcinomas (44%). Immunoreactivity for more than one peptide was present in 33 tumours and in three cases, six different peptides were detected. The study shows that immunoreactivity to various peptides is more common in typical carcinoids than well differentiated neuroendocrine carcinomas. The significance of these findings is discussed

An abnormally displaced scaphoid fracture: a case report

Scaphoid fractures are generally known to be difficult to diagnose and difficult to heal. In some reports, up to 40% of scaphoid fractures were reported to be missed at initial presentation. Clinical examinations and plain radiographs are generally poor at identifying scaphoid fractures immediately after injury. In this study we report a scaphoid fracture that has no difficulty in diagnosis because of a very strange and abnormal displacement

Melatonin Attenuates Upregulation of Duox1 and Duox2 and Protects against Lung Injury following Chest Irradiation in Rats

Objective: The Lung is one of the most radiosensitive organs of the body. The infiltration of macrophages and lymphocytes into the lung is mediated via the stimulation of T-helper 2 cytokines such as IL-4 and IL-13, which play a key role in the development of fibrosis. It is likely that these cytokines induce chronic oxidative damage and inflammation through the upregulation of Duox1 and Duox2, which can increase the risk of late effects of ionizing radiation (IR) such as fibrosis and carcinogenesis. In the present study, we aimed to evaluate the possible increase of IL-4 and IL-13 levels, as well as their downstream genes such as IL4ra1, IL13ra2, Duox1, and Duox2. Materials and Methods: In this experimental animal study, male rats were divided into 4 groups: i. Control, ii. Melatonin-treated, iii. Radiation, and iv. Melatonin (100 mg/kg) plus radiation. Rats were irradiated with 15 Gy 60Co gamma rays and then sacrificed after 67 days. The expressions of IL4ra1, IL13ra2, Duox1, and Duox2, as well as the levels of IL-4 and IL-13, were evaluated. The histopathological changes such as the infiltration of inflammatory cells, edema, and fibrosis were also examined. Moreover, the protective effect of melatonin on these parameters was also determined. Results: Results showed a 1.5-fold increase in the level of IL-4, a 5-fold increase in the expression of IL4ra1, and a 3-fold increase in the expressions of Duox1 and Duox2. However, results showed no change for IL-13 and no detectable expression of IL13ra2. This was associated with increased infiltration of macrophages, lymphocytes, and mast cells. Melatonin treatment before irradiation completely reversed these changes. Conclusion: This study has shown the upregulation of IL-4-IL4ra1-Duox2 signaling pathway following lung irradiation. It is possible that melatonin protects against IR-induced lung injury via the downregulation of this pathway and attenuation of inflammatory cells infiltration. © 2019 Royan Institute (ACECR). All rights reserved

Two Decades of Global Progress in Authorized Advanced Therapy Medicinal Products: An Emerging Revolution in Therapeutic Strategies

The introduction of advanced therapy medicinal products (ATMPs) to the global pharma market has been revolutionizing the pharmaceutical industry and has opened new routes for treating various types of cancers and incurable diseases. In the past two decades, a noticeable part of clinical practices has been devoting progressively to these products. The first step to develop such an ATMP product is to be familiar with other approved products to obtain a general view about this industry trend. The present paper depicts an overall perspective of approved ATMPs in different countries, while reflecting the degree of their success in a clinical point of view and highlighting their main safety issues and also related market size as a whole. In this regard, published articles regarding safety, efficacy, and market size of approved ATMPs were reviewed using the search engines PubMed, Scopus, and Google Scholar. For some products which the related papers were not available, data on the relevant company website were referenced. In this descriptive study, we have introduced and classified approved cell, gene, and tissue engineering-based products by different regulatory agencies, along with their characteristics, manufacturer, indication, approval date, related regulatory agency, dosage, product description, price and published data about their safety and efficacy. In addition, to gain insights about the commercial situation of each product, we have gathered accessible sale reports and market size information that pertain to some of these products

RGTA® or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to curing patients

The importance of extracellular matrix (ECM) integrity in maintaining normal tissue function is highlighted by numerous pathologies and situations of acute and chronic injury associated with dysregulation or destruction of ECM components. Heparan sulfate (HS) is a key component of the ECM, where it fulfils important functions associated with tissue homeostasis. Its degradation following tissue injury disrupts this delicate equilibrium and may impair the wound healing process. ReGeneraTing Agents (RGTA®s) are polysaccharides specifically designed to replace degraded HS in injured tissues. The unique properties of RGTA® (resistance to degradation, binding and protection of ECM structural and signaling proteins, like HS) permit the reconstruction of the ECM, restoring both structural and biochemical functions to this essential substrate, and facilitating the processes of tissue repair and regeneration. Here, we review 25 years of research surrounding this HS mimic, supporting the mode of action, pre-clinical studies and therapeutic efficacy of RGTA® in the clinic, and discuss the potential of RGTA® in new branches of regenerative medicine

Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy.

Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients

How do general practitioners experience providing care to refugees with mental health problems? A qualitative study from Denmark

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Metformin protects against radiation-induced heart injury and attenuates the upregulation of dual oxidase genes following Rat's chest irradiation

Radiation-induced heart toxicity is one of the serious side effects after a radiation disaster or radiotherapy for patients with chest cancers, leading to a reduction in the quality of life of the patients. Evidence has shown that infiltration of inflammatory cells plays a key role in the development of functional damages to the heart via chronic upregulation of some pro-fibrotic and pro-inflammatory cytokines. These changes are associated with continuous free radical production and increased stiffness of heart muscle. IL-4 and IL-13 are two important pro-fibrotic cytokines which contribute to the side effects of ionizing radiation exposure. Recent studies have proposed that IL-4 through upregulation of DUOX2, and IL-13 via stimulation of DUOX1 gene expression, are involved in the development of radiation late effects. In the present study, we aimed to detect changes in the expression of these pathways following irradiation of rat's heart. Furthermore, we evaluated the possible protective effect of metformin on the development of these abnormal changes. 20 male rats were divided into 4 groups (control, radiation, metformin treated, metformin + radiation). These rats were irradiated with 15 Gy 60 Co gamma rays, and sacrificed after 10 weeks for evaluation of the changes in the expression of IL4R1, IL-13R2a, DUOX1 and DUOX2. In addition, the levels of IL-4 and IL-13 cytokines, as well as infiltration of macrophages and lymphocytes were detected. Results showed an upregulation of both DUOX1 and DUOX2 pathways in the presence of metformin, while the level of IL-13 did not show any significant change. This was associated with infiltration of macrophages and lymphocytes. Also, treatment with metformin could significantly attenuate accumulation of inflammatory cells, and upregulate these pathways. Therefore, suppression of dual oxidase genes by metformin may be a contributory factor to its protective effect. © 2018, Babol University of Medical Sciences

Regulation of the High Affinity IgE Receptor (FcεRI) in Human Neutrophils: Role of Seasonal Allergen Exposure and Th-2 Cytokines

The high affinity IgE receptor, FcεRI, plays a key role in the immunological pathways involved in allergic asthma. Previously we have demonstrated that human neutrophils isolated from allergic asthmatics express a functional FcεRI, and therefore it was of importance to examine the factors regulating its expression. In this study, we found that neutrophils from allergic asthmatics showed increased expression of FcεRI-α chain surface protein, total protein and mRNA compared with those from allergic non asthmatics and healthy donors (p<0.001). Interestingly, in neutrophils isolated from allergic asthmatics, FcεRI-α chain surface protein and mRNA expression were significantly greater during the pollen season than outside the pollen season (n = 9, P = 0.001), an effect which was not observed either in the allergic non asthmatic group or the healthy donors (p>0.05). Allergen exposure did not affect other surface markers of neutrophils such as CD16/FcγRIII or IL-17R. In contrast to stimulation with IgE, neutrophils incubated with TH2 cytokines IL-9, GM-CSF, and IL-4, showed enhanced FcεRI-α chain surface expression. In conclusion, these results suggest that enhanced FcεRI expression in human neutrophils from allergic asthmatics during the pollen season can make them more susceptible to the biological effects of IgE, providing a possible new mechanism by which neutrophils contribute to allergic asthma

Hookah smoking is strongly associated with diabetes mellitus, metabolic syndrome and obesity: a population-based study

Objectives The adverse effects of cigarette smoking have been widely studied before, whilst the effects of hookah smoking has received less attention, although it is a common habit in the Middle East. Here we have investigated the effects of cigarette and hookah smoking on biochemical characteristics in a representative population sample derived from the Mashhad stroke and heart atherosclerotic disorder (MASHAD) cohort study, from Northeastern Iran. Study design A total of 9840 subjects from the MASHAD population study were allocated to five groups; non-smokers (6742), ex-smokers (976), cigarette smokers (864), hookah smokers (1067), concomitant cigarette and hookah smokers (41). Methods Baseline characteristics were recorded in a questionnaire. Biochemical characteristics were measured by routine methods. Data were analyzed using SPSS software and p < 0.05 was considered significant. Results After adjustment for age and sex; the presence of CVD, obesity, metabolic syndrome, DM and dyslipidemia were significantly (p < 0.001) related to smoking status. After multivariate analysis, HDL (p < 0.001), WBC (p < 0.001), MCV (p < 0.05), PLT (p < 0.01) and RDW (p < 0.001), and the presence of CVD (p < 0.01), obesity (p < 0.001), metabolic syndrome (p < 0.05) and DM (p < 0.01) remained significant between cigarette smokers and non-smokers. Between hookah smokers and non-smokers; uric acid (p < 0.001), PLT (p < 0.05) and RDW (p < 0.05), and the presence of obesity (p < 0.01), metabolic syndrome (p < 0.001), diabetes (p < 0.01) and dyslipidemia (p < 0.01) remained significant after logistic regression. Conclusion There was a positive association between hookah smoking and metabolic syndrome, diabetes, obesity and dyslipidemia which was not established in cigarette smoking