Search

Aluminum (Al) is present on earth surface has different chemical forms. It is a toxic metal and it may cause different disorders such as osteomalacia, microcytic anemia, Alzheimer and Parkinson's disease. Thus, it is very important to understand the effects of Al on different organs. In order to examine its accumulation, rats (male Wistar) were exposed to 5 mg/kg/day AlCl3 through gavage method for 30 days. At the end of the process, heart, brain, kidney and skin were removed and dried under sunlight. The samples were analyzed on a sequential Wavelength Dispersive X-ray Fluorescence (WDXRF) spectrometer. The results indicate that Al accumulates significantly in the brain. These results can be associated with neurotoxin effects. Although this study focused on the accumulation of Al, the concentration changes of detected elements from Beryllium (Be) to Uranium (U) accumulations were analyzed. The current study has proved that the WDXRF method is a quick, inexpensive and effective method in toxicological studies. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to evaluate P-wave dispersion (PWD) in obese women, and to investigate the relationship between P-wave measurements, high sensitive C-reactive protein (hsCRP), carotid intima-media thickness (CIMT) and echocardiographic findings. Methods: Forty-four patients with obese premenopausal women and 30 females with normal weight were enrolled this cross sectional, observational study. Results of anthropometric measurements, laboratory assays, electrocardiographic and echocardiographic findings were recorded for each participant. Student t, Mann-Whitney U and Pearson Chi-square tests, and Spearman correlation analysis were used for statistical analysis. Multiple regression analysis was used to identify independent factors associated with PWD development. Results: The obese group had significantly higher values for PWD (41.8 ± 11.8 ms vs. 28.5 ± 9.3ms; p<0.001) as well as for P max (105.2 ± 14.3 ms vs. 89.0 ± 13.3 ms; p<0.001). Correlation analyses revealed the presence of a positive correlation between PWD and each of insulin, systolic blood pressure, diastolic blood pressure, hsCRP, CIMT, left atrial diameter (LAD), waist circumference, waist to hip ratio and body mass index in obese participants. The only significant association that was observed on multiple linear regression analysis, after adjustments for confounding risk factors, was between LAD and PWD (β=4.290, 95% CI:1.870-9.720, p=0.032). Conclusion: We found that increased PWD values in obese patients are correlated positively with hsCRP, CIMT and abdominal obesity. However, independent and significant association was found only between LAD and PWD. [ABSTRACT FROM AUTHOR]

Objective. Thyroid diseases coexisting with primary hyperparathyroidism (PHPT) may individually change the diagnosis, treatment and follow-up of the patients. In our study, we aimed to investigate the thyroid diseases coexisting with PHPT and the relation between these two clinical situations. Methods. We retrospectively investigated 255 patients who were diagnosed as PHPT between 2004-2009 in our clinic. The general characteristics of the patients, laboratory tests, which were performed preoperatively, neck ultrasonography, thyroid and parathyroid scintigraphy and fine needle aspiration biopsy (FNAB) results were assessed. Cytological results of the nodules with preoperative FNAB were compared with the postoperative histological results. Results. Of the patients, 49 were male (19.2%) and 206 were female (80.8%). Mean age was 54.5±12.8. Bilateral neck exploration (BNE) was performed on 69 cases (27%), minimal invasive parathyroidectomy (MIP) on 78 cases (30.5%) and BNE plus thyroidectomy on 108 cases (42.5%). When all thyroid diseases were taken into account, prevalence of the coexisting thyroid disease was 65%, prevalence of nodular thyroid disease 52.1%, thyroid cancer 16.7% and thyroid dysfunction 11.8%. The mean age of the patients with a nodular goitre was significantly higher than of the patients who did not have nodules (p<0.001). General demographic data, calcium and PTH levels did not show any difference. Number of nodules was correlated with age (p<0.001, r=0.227). Conclusion. The relation between PHPT and nodular thyroid diseases is coincidental and this can be explained by the fact that both diseases occur in advanced age. [ABSTRACT FROM AUTHOR]

AIM: The aim of this study was to evaluate the relationship between sublinical inflammation and glycemic status in patients with gestational diabetes mellitus (GDM). METHODS: Sixty-one patients with GDM and 40 healthy pregnant women were included in the study. Fasting blood glucose (FBG), insulin, high sensitivity C-reactive protein (hsCRP), lipid parameters and carotid artery intima-media thickness (CIMT) were measured. Fifty-five of the patients with GDM returned for a follow-up visit scheduled at 1-year post-partum. These patients were subjected to 75g oral glucose tolerance test (OGTT) followed by an evaluation of metabolic and subclinical inflammatory parameters were evaluated. RESULTS: The mean FBG, insulin, homeostasis model assessment insulin resistance (HOMA-IR), triglyceride (TG), hsCRP levels and CIMT in the women with GDM were significantly higher than those in the control group. C-reactive protein and CIMT were positively correlated with insulin, HOMA-IR, glucose value at the time of the OGTT 50, prepregnancy body mass index, TG and FBG. Multivariate logistic regression analysis on patients with sustained hyperglycemia one-year postpartum revealed elevated hsCRP levels to be independent risk factors for the development of dysglycemia. CONCLUSIONS: Elevated hsCRP levels could be predictors of progression to T2DM later in life in patients with GDM. [ABSTRACT FROM AUTHOR]

Purpose: Despite several factors that may have been associated with poor disease-free survival (DFS) in patients with medullary thyroid carcinoma (MTC), only a few studies have evaluated the prognostic factors affecting DFS in MTC patients. Therefore, this study evaluated the prognostic factors affecting DFS, in a large number of patients with MTC., Methods: Patients treated for MTC were retrospectively analyzed. Patients were stratified as having persistent/recurrent disease and no evidence of disease (NOD) at the last follow-up. The factors affecting DFS after the initial therapy and during the follow-up period were investigated., Results: This study comprised 257 patients [females 160 (62.3%), hereditary disease 48 (18.7%), with a mean follow-up time of 66.8 ± 48.5 months]. Persistent/recurrent disease and NOD were observed in 131 (51%) and 126 (49%) patients, respectively. In multivariate analysis, age > 55 (HR: 1.65, p = 0.033), distant metastasis (HR: 2.41, p = 0.035), CTN doubling time (HR: 2.7, p = 0.031), and stage III vs. stage II disease (HR 3.02, p = 0.048) were independent predictors of persistent/recurrent disease. Although 9 (8%) patients with an excellent response after the initial therapy experienced a structural recurrence, the absence of an excellent response was the strongest predictor of persistent/recurrent disease (HR: 5.74, p < 0.001)., Conclusions: The absence of an excellent response after initial therapy is the strongest predictor of a worse DFS. However, a significant proportion of patients who achieve an excellent response could experience a structural recurrence. Therefore, careful follow-up of patients, including those achieving an excellent response is essential., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize 99m Tc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with 99m Tc, the optimum radiolabeling condition was determined as 200 ppm SnCl 2 and 0.5 mg ascorbic acid, and both 99m Tc-MS/TOFA-9 and 99m Tc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

Toxoplasma gondii is an obligate intracellular parasite that can infect a variety of mammals including humans and causes toxoplasmosis. Unfortunately, a protective and safe vaccine against toxoplasmosis hasn't been developed yet. In this study, we developed a DNA vaccine encoding the SRS13 protein and immunized BALB/c mice thrice with pVAX1-SRS13 through the intramuscular route (IM) or intradermally using an electroporation device (ID + EP). The immunogenicity of pVAX1-SRS13 was analyzed by ELISA, Western blot, cytokine ELISA, and flow cytometry. The protective efficacy of the pVAX1-SRS13 was investigated by challenging mice orally with T. gondii PRU strain tissue cysts. The results revealed that pVAX1-SRS13 administered through IM or ID + EP routes induced high level of anti-SRS13 IgG antibody responses (P = 0.0037 and P < 0.0001). The IFN-γ level elicited by the pVAX1-SRS13 (ID + EP) was significantly higher compared to the control group (P = 0.00159). In mice administered with pVAX1-SRS13 (ID + EP), CD8 + cells secreting IFN-γ was significantly higher compared to pVAX1-SRS13 (IM) (P = 0.0035) and the control group (P = 0.0068). Mice vaccinated with the SRS13 DNA vaccine did not induce significant IL-4 level. Moreover, a significant reduction in the number of tissue cysts and the load of T. gondii DNA was detected in brains of mice administered with pVAX1-SRS13 through ID + EP and IM routes compared to controls. In conclusion, the SRS13 DNA vaccine was found to be highly immunogenic and confers strong protection against chronic toxoplasmosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 had devastating consequences for human health. Despite the introduction of several vaccines, COVID-19 continues to pose a serious health risk due to emerging variants of concern. DNA vaccines gained importance during the pandemic due to their advantages such as induction of both arms of immune response, rapid development, stability, and safety profiles. Here, we report the immunogenicity and protective efficacy of a DNA vaccine encoding spike protein with D614G mutation (named pcoSpikeD614G) and define a large-scale production process. According to the in vitro studies, pcoSpikeD614G expressed abundant spike protein in HEK293T cells. After the administration of pcoSpikeD614G to BALB/c mice through intramuscular (IM) route and intradermal route using an electroporation device (ID + EP), it induced high level of anti-S1 IgG and neutralizing antibodies (P < 0.0001), strong Th1-biased immune response as shown by IgG2a polarization (P < 0.01), increase in IFN-γ levels (P < 0.01), and increment in the ratio of IFN-γ secreting CD4 + (3.78-10.19%) and CD8 + (5.24-12.51%) T cells. Challenging K18-hACE2 transgenic mice showed that pcoSpikeD614G administered through IM and ID + EP routes conferred 90-100% protection and there was no sign of pneumonia. Subsequently, pcoSpikeD614G was evaluated as a promising DNA vaccine candidate and scale-up studies were performed. Accordingly, a large-scale production process was described, including a 36 h fermentation process of E. coli DH5α cells containing pcoSpikeD614G resulting in a wet cell weight of 242 g/L and a three-step chromatography for purification of the pcoSpikeD614G DNA vaccine., (© 2024. The Author(s).)

Objectives: Malassezia species are common, clinically relevant, and lipid-dependent yeasts of humans. They are also the leading causes of the dandruff problem of humans, and the azoles are used primarily in their topical and systemic treatment. Resistance to azoles is an emerging problem among Malassezia sp., which indicates the need of new drug assessments that will be effective against dandruff and limit the use of azoles and other agents in treatment. Among them, the efficacy of various combinations of piroctone olamine and climbazole against Malassezia sp. is highly important. Here, we assessed the efficacies of various piroctone olamine and climbazole formulations against Malassezia sp. in comparison with ketoconazole., Methods: A total of nine formulations were included in the study, where each formulation was prepared from different concentrations of piroctone olamine and climbazole and both. All formulations contained the same ingredients as water, surfactants, hair conditioning agents, and preservatives. Malassezia furfur CBS1878, Malassezia globosa CBS7874, and Malassezia sympodialis CBS9570 were tested for antifungal susceptibility of each formulation by agar diffusion method. Sizes of the inhibition zones were compared with standard medical shampoo containing 2% ketoconazole, and the data were analyzed by Dunnett's multiple-comparison test., Results: For all Malassezia sp. strains, climbazole 0.5% and piroctone olamine/climbazole (0.1%/0.1% and 0.1%/0.5%) combinations were found to have the same effect as the medical shampoo containing 2% ketoconazole. Piroctone olamine/climbazole 1.0%/0.1% formulation showed the same efficacy as 2% ketoconazole on M. furfur and M. sympodialis, while 0.1%/0.5% formulation to only M. furfur. For M. globosa, none of the formulations tested were as effective as ketoconazole., Conclusion: The species distribution of Malassezia sp. varies depending on the anatomical location on the host. According to the results of this study, climbazole and piroctone olamine combinations seem to be promising options against the dandruff problem with their high antifungal/anti dandruff efficacy., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Objectives: Despite the presumed overdiagnosis of papillary thyroid microcarcinoma (PTMC) which has resulted in a new trend toward less-extensive surgery and a preference for active surveillance, the impact of microscopic extrathyroidal extension (mETE) on the clinical outcomes of PTMC is still controversial. This study assessed the impact of mETE on the clinical outcomes of patients with classic subtype PTMC., Methods: The data of consecutive patients who underwent thyroidectomy and were histopathologically diagnosed as classic subtype PTMC were analyzed. Cox's proportional hazards model was used to assess the impact of contributing variables on persistent/recurrent disease. Disease-free survival was estimated using the Kaplan-Meier method., Results: This study included 1013 patients (84% females), with a mean follow-up period of 62.5 ± 35.3 months. Patients with mETE had a significantly higher rate of locoregional persistent/recurrent disease than patients without mETE (9.8% vs 2.1%, p < 0.001). The disease-free survival rate was significantly lower in patients with mETE than in those without (90.2% vs 97%, Log-Rank p < 0.001). Furthermore, mETE and neck lymph node involvement were independent predictors of persistent/recurrent disease in multivariate analysis (HR: 2.43, 95% CI:1.02-5.81, p = 0.043; HR: 4.38, 95% CI: 1.7-11.2, p = 0.002, respectively)., Conclusions: In patients with the classic subtype of PTMC, mETE is an independent predictor of persistent/recurrent disease and is associated with a lower DFS rate. However, neck lymph node involvement is the strongest predictor of persistent/recurrent disease. Therefore, PTMCs with mETE and neck lymph node involvement are at a higher risk of persistent/recurrent disease than individuals lacking both characteristics., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The enzyme steroid type II 5-alpha-reductase (SRD5α2) is responsible for the conversion of testosterone to dihydrotestosterone (DHT), which is involved in prostate cancer, benign prostatic hyperplasia, and androgenic alopecia. Inhibition of SRD5α2 activity has been explored and presented as a potential treatment for these conditions, but current drugs have side effects and alternative treatment approaches are needed. The CRISPR/Cas9 system, an innovative gene-editing tool, shows potential for targeting the SRD5α2 gene knockout as a therapeutic approach. Liposomes have been used for the immobilization and delivery of different proteins, and studies have shown that liposomes can enhance the stability and activity of enzymes. In this study, we provided the immobilization of Cas9 protein by encapsulating it in a novel cationic liposome formulation that carries sgRNA on its outer surface for gene delivery approaches. This novel delivery system has shown promising results in terms of physicochemical properties, stability, cytotoxicity, in vitro cellular uptake, and gene knockout efficiency, together with providing flexibility in sgRNA selection. The optimized final formulations showed an average diameter of 229.1 ± 3.66 nm, a polydispersity index of 0.089 ± 0.013, and a zeta potential value of 25.7 ± 0.87 mV. The encapsulation efficiency of the developed formulations has been revealed as 80.60%. The cellular uptake efficiency was evaluated and measured as 45.6% for the final formulation. Furthermore, the Lipo/Cas9:sgRNA (1.5:1) formulation decreased the relative SRD5α2 mRNA expression by 29.7% compared to the control group. The results of this study reveal that the liposomal formulation based on enzyme immobilization of Cas9 protein using CRISPR technology, an innovative gene-editing tool for SRD5α2 suppression, might be an alternative treatment option for prostate cancer or BPH treatment without current drug side effects., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Histologically aggressive micropapillary thyroid carcinomas (PTMC) subtypes are thought to be associated with an aggressive clinical course. However, evidence for unfavorable clinical outcomes in patients with aggressive PTMC subtypes is not clear. In this study, we intended to determine the difference in clinical outcomes between patients with aggressive and non-aggressive PTMC subtypes. In this multicenter cohort study, the computer-recorded clinical and histopathological data of patients who underwent thyroid surgery between January 2000 - January 2021 in 9 referral centers and were diagnosed as PTMC were analyzed. A total of 1585 patients [female 1340 (84.5%), male 245 (15.5%), mean age 47.9±11.63 years), with a mean follow-up time of 66.55±37.16 months], were included in the study. Ninety-eight cases were diagnosed as aggressive and 1487 as non-aggressive subtypes. Persistent/recurrent disease was observed in 33 (33.7% )and 41 (2.8%) patients with aggressive and non-aggressive subtypes (p<0.001). Diseases-free survival rates were markedly lower in patients with aggressive than in those with non-aggressive PTMC subtypes (66.3 vs. 94.8%, log-rank p<0.001). Moreover, in multivariate analysis, aggressive histology was an independent predictor of persistent/recurrent disease, after controlling for other contributing factors (HR 5.78, 95% CI 3.32-10, p<0.001). Patients with aggressive PTMC subtypes had higher rates of incomplete biochemical and structural response than patients with non-aggressive subtypes as well (p<0.001). Aggressive PTMC subtypes share many characteristics with histologically identical tumors>1 cm in size. Therefore, the histopathological subtype of PTMC should be taken into consideration to tailor a personalized management plan., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Infectious diseases are still the major issue not only due to antibiotic resistance but also causing deaths if not diagnosed at early-stages. Different approaches including nanosized drug delivery systems and theranostics are researched to overcome antibiotic resistance, decrease the side effects of antibiotics, improve the treatment response, and early diagnose. Therefore, in the present study, nanosized, radiolabeled with 99m Tc, colistin encapsulated, neutral and cationic liposome formulations were prepared as the theranostic agent for Pseudomonas aeruginosa infections. Liposomes exhibited appropriate physicochemical properties thanks to their nano-particle size (between 173 and 217 nm), neutral zeta potential value (about - 6.5 and 2.8 mV), as well as encapsulation efficiency of about 75%. All liposome formulations were radiolabeled with over 90% efficiency, and the concentration of stannous chloride was found as 1 mg.mL -1 to obtain maximum radiolabeling efficiency. In alamar blue analysis, neutral liposome formulations were found more biocompatible compared with the cationic formulations. Neutral colistin encapsulated liposomes were found to be more effective against P. aeruginosa strain according to their time-dependent antibacterial effect, in addition to their highest bacterial binding capacity. As conclusion, theranostic, nanosized, colistin encapsulated, neutral liposome formulations were found as promising agents for the imaging and treating of P. aeruginosa infections., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Rosacea is a chronic inflammatory cutaneous disease that can be associated with cardiometabolic disorders. Oxidative stress is included in the pathogenesis of rosacea, and thiol-disulfide homeostasis (TDH) acts as antioxidants., Objective: To evaluate the TDH and metabolic parameters in patients with rosacea., Material and Methods: A total of 42 rosacea patients and 50 controls participated in this prospective study. Demographic data, clinical entities, anthropometric measurements, and laboratory findings were recorded. Additionally, TDH was measured by an automated spectrophotometric method., Results: Rosacea patients had greater body mass index values (27.9 ± 5.2 kg/m² vs. 23 ± 1.4 kg/m², p < 0.001), waist-hip ratios (0.87 ± 0.1 vs. 0.77 ± 0.8, p < 0.001), and insulin resistance (3.0 ± 2.0 vs. 1.3 ± 0.5, p < 0.001) compared with controls. Disulfide levels, the disulfide/native thiol ratio (DNTR), and the disulfide/total thiol ratio (DTTR) were increased (p < 0.05) in rosacea patients. Native thiol and total thiol levels and the native/total thiol ratio (NTTR) were decreased in rosacea patients (p < 0.05). Different rosacea subtypes had no effect on oxidative stress markers. The duration of illness and insulin resistance values significantly correlated with DNTR and DTTR in the rosacea group (p < 0.05)., Conclusion: Rosacea has a metabolic milieu with increased oxidative stress and insulin resistance., (© 2021 Wiley Periodicals LLC.)

We performed a prospective longitudinal cohort study in two healthcare settings. In total, 909 HCWs out of 3982 (23.35%) were diagnosed with COVID-19 before the vaccination era. Eighty-five per cent of COVID-19 positive HCWs (n = 774) were asymptomatic or mild, and 15% were moderate or severe. The mean age of the infected HCWs in the moderate or severe group was higher than the mild or asymptomatic group (35.4 vs. 31.3 years, p < 0.001). Thirty-two per cent of HCWs were male and the rate of male gender was more frequent in the moderate/severe group (p = 0.009). The rate of those who have cardiovascular diseases (p = 0.003) and diabetes mellitus (p = 0.044) were significantly higher among the HCWs with moderate or severe COVID-19. In multivariate analysis, male gender (OR:1.65, CI:1.11−2.46, p = 0.013), BMI > 30 (OR: 1.9, CI: 1.09−3.51, p = 0.024), and being physician (OR: 2.56, CI:1.45−4.52, p = 0.001) were found to be associated with moderate or severe COVID-19.

The lack of safe and effective delivery across the blood-brain barrier and the profound immune suppressive microenvironment are two main hurdles to glioblastoma (GBM) therapies. Extracellular vesicles (EVs) have been used as therapeutic delivery vehicles to GBM but with limited efficacy. We hypothesized that EV delivery to GBM can be enhanced by (i) modifying the EV surface with a brain-tumor-targeting cyclic RGDyK peptide (RGD-EV) and (ii) using bursts of radiation for enhanced accumulation. In addition, EVs were loaded with small interfering RNA (siRNA) against programmed cell death ligand-1 (PD-L1) for immune checkpoint blockade. We show that this EV-based strategy dramatically enhanced the targeting efficiency of RGD-EV to murine GBM, while the loaded siRNA reversed radiation-stimulated PD-L1 expression on tumor cells and recruited tumor-associated myeloid cells, offering a synergistic effect. The combined therapy significantly increased CD8 + cytotoxic T cells activity, halting tumor growth and prolonging animal survival. The selected cell source for EVs isolation and the presented functionalization strategy are suitable for large-scale production. These results provide an EV-based therapeutic strategy for GBM immune checkpoint therapy which can be translated to clinical applications.

This study is focused on the preparation and characterization of erucic acid (EA) and phytosphingosine (PS) containing cationic nanoemulsions (NEs) for plasmid DNA (pDNA) delivery. Repurposing of cationic agents guided us to PS, previously used for enhanced interaction with negatively charged surfaces. It was reported that EA might act anti-tumoral on C6 glioma, melanoma, neuroblastoma, and glioblastoma. However, there is only one study about mixed oleic acid-EA liposomes. This gap attracted our interest in the possible synergistic effects of PS and EA on MDA-MB-231 and MCF-7 breast cancer cells. Three cationic NEs (NE 1, NE 2, and NE 3) were prepared and characterized in terms of droplet size (DS), polydispersity index (PDI), and zeta potential (ZP) before and after complexation with pDNA, long-term stability, SDS release, cytotoxicity, and transfection studies. The cationic NEs had DSs of <200 nm, PDIs <0.3, and ZPs > +30 mV. Long-term stability studies revealed that NE 2 and NE 3 were stable. NE 1-pDNA had appropriate particle properties. NE 2 reduced the viability of MDA-MB-231 cells to 11% and of MCF-7 cells to 13% and resulted in the highest number of transfected cells. To sum up, NE 2 containing PS and EA is appropriate for delivering pDNA.

Hypoparathyroidism is an orphan disease with ill-defined epidemiology that is subject to geographic variability. We conducted this study to assess the demographics, etiologic distribution, treatment patterns and complication frequency of patients with chronic hypoparathyroidism in Turkey. This is a retrospective, cross-sectional database study, with collaboration of 30 endocrinology centers located in 20 cities across seven geographical regions of Turkey. A total of 830 adults (mean age 49.6 ± 13.5 years; female 81.2%) with hypoparathyroidism (mean duration 9.7 ± 9.0 years) were included in the final analysis. Hypoparathyroidism was predominantly surgery-induced (n = 686, 82.6%). The insulting surgeries was carried out mostly due to benign causes in postsurgical group (SG) (n = 504, 73.5%) while patients in nonsurgical group (NSG) was most frequently classified as idiopathic (n = 103, 71.5%). The treatment was highly dependent on calcium salts (n = 771, 92.9%), calcitriol (n = 786, 94.7%) and to a lower extent cholecalciferol use (n = 635, 76.5%) while the rate of parathyroid hormone (n = 2, 0.2%) use was low. Serum calcium levels were most frequently kept in the normal range (sCa 8.5-10.5 mg/dL, n = 383, 46.1%) which might be higher than desired for this patient group. NSG had a lower mean plasma PTH concentration (6.42 ± 5.53 vs. 9.09 ± 7.08 ng/l, p < 0.0001), higher daily intake of elementary calcium (2038 ± 1214 vs. 1846 ± 1355 mg/day, p = 0.0193) and calcitriol (0.78 ± 0.39 vs. 0.69 ± 0.38 mcg/day, p = 0.0057), a higher rate of chronic renal disease (9.7% vs. 3.6%, p = 0.0017), epilepsy (6.3% vs. 1.6%, p = 0.0009), intracranial calcifications (11.8% vs. 7.3%, p < 0.0001) and cataracts (22.2% vs. 13.7%, p = 0.0096) compared to SG. In conclusion, postsurgical hypoparathyroidism is the dominant etiology of hypoparathyroidism in Turkey while the nonsurgical patients have a higher disease burden with greater need for medications and increased risk of complications than the postsurgical patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Although the age at diagnosis has been suggested as a major determinant of disease-specific survival in the recent TNM staging system, it is not included in the recent American Thyroid Association (ATA) guidelines to estimate the risk of recurrence. Nevertheless, the effect of sex on differentiated thyroid carcinoma (DTC) recurrence is controversial. Therefore, this multicenter study was conducted to assess whether age at diagnosis and sex can improve the performance of the ATA 3-tiered risk stratification system in patients with DTC with at least 5 years of follow-up., Methods: In this study, the computer-recorded data of the patients diagnosed with DTC between January 1985 and January 2016 were analyzed. Only patients with proven structural persistent/recurrent disease were selected for comparisons., Results: This study consisted of 1691 patients (female, 1367) with DTC. In Kaplan-Meier analysis, disease-free survival (DFS) was markedly longer in females only in the ATA low-risk category (P = .045). Nevertheless, a markedly longer DFS was observed in patients aged <45 years in the ATA low- and intermediate-risk categories (P = .004 and P = .009, respectively), whereas in patients aged <55 years, DFS was markedly longer only in the ATA low-risk category (P < .001). In the Cox proportional hazards model, ages of ≥45 and ≥55 years at diagnosis and the ATA risk stratification system were all independent predictors of persistent/recurrent disease., Conclusion: Applying the age cutoff of 45 years in the ATA intermediate- and low-risk categories may identify patients at a higher risk of persistence/recurrence and may improve the performance of the ATA risk stratification system, whereas sex may improve the performance of only the ATA low-risk category., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to evaluate the current situation of hypoparathyroid patients and to investigate the relationship between treatment adherence and quality of life., Study Design: Prospective, multicentre study., Methods: Adult patients presenting with the diagnosis of hypoparathyroidism to 20 different endocrinology clinics were included. They were receiving conventional therapies for hypoparathyroidism, using calcium, active vitamin D, and magnesium. We collected data on demographic features, disease- and treatment-related information, and results of routine laboratory tests, treatment adherence, and presence of complications. Beck Depression Inventory, Beck Anxiety Inventory, and Short Form-36 quality of life assessments were administered., Results: Among the 300 patients studied, 60.7% were adherent to their treatment, and 34.1% had complications. Anxiety and depression scores were significantly higher in non-adherent versus treatment-adherent patients (p<0.001 and p=0.001, respectively). Most of the domains of quality-of-life scores were also significantly lower in non-adherent patients. Both anxiety and depression scores showed significant, negative correlations with serum calcium and magnesium concentrations ( r =-0.336, p<0.001 and r =-0.258, p<0.001, respectively)., Conclusions: Nearly 40% of the patients were non-adherent to conventional treatment for hypoparathyroidism, and such patients had higher anxiety and depression scores and poorer quality of life scores. Conventional treatment might not be sufficient to meet the needs of patients with hypoparathyroidism. In addition to seeking new therapeutic options, factors influencing quality of life should also be investigated and strategies to improve treatment adherence should be developed., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Developing an alternative and efficient therapy for wound healing has been an important research topic for pharmaceutical sciences. A straightforward but effective system for delivering fibroblast growth factor-2 (FGF-2) encoding plasmid DNA (pFGF-2) for wound healing therapy was aimed to develop in this study., Methods: In order to provide the delivery of pFGF-2, a delivery vector, namely, cationic lipid nanoparticle (cLN) was developed by the melt-emulsification process, complexed with pFGF-2 to form a lipoplex system and further characterized. The pFGF-2 binding and protecting ability of lipoplexes were evaluated. The cytotoxicity and transfection efficiency of the lipoplexes, FGF-2 expression levels, and in vitro wound healing ability have been investigated on the L929 fibroblast cell line., Results: The obtained lipoplex system has a particle size of 88.53 nm with a low PDI (0.185), and zeta potential values of 27.8 mV with a spherical shape. The ability of cLNs to bind pFGF-2 and protect against nucleases was demonstrated by gel retardation assay. Furthermore, the developed FGF-2 carrying lipoplexes system showed significant transfection and FGF-2 expression ability comparing naked plasmid. Finally, scratch assay revealed that the developed system is able to promote in vitro cell proliferation/migration in 48 h., Conclusion: Promising results have been achieved with the use of lipoplexes carrying pFGF-2, and this approach could be considered as a potentially applicable concept for the future gene-based wound healing therapies., (© 2021. Springer Nature Switzerland AG.)

Background: The frequency of autoimmune diseases and thyroid cancer has been increasingly reported in association with rosacea. However, studies investigating thyroid diseases in rosacea are scarce with conflicting results., Objective: To investigate the relationship between thyroid disorders and rosacea., Methods: A large case-control study on age- and gender-matched 2091 rosacea patients and 9572 controls was conducted. Rosacea patients using the rosacea-specific ICD codes were compiled from the hospital records. Additionally, all participants were evaluated in terms of the presence of hypothyroidism and hyperthyroidism. Conditional logistic regression analysis was used to compute case-control odds ratios (OR) with 95% confidence intervals., Results: The analysis comprehended 2091 rosacea patients (1546 female, 545 male; mean 48.73 ± 14.53 years) and 9572 controls (7009 female, 2563 male; mean 48.73 ± 15.1 years). Whereas the rate of hypothyroidism was significantly higher in rosacea patients (OR = 1.3, 95% CI 1.13-1.49, p < 0.001), there was no significant difference in the rate of hyperthyroidism between the groups (OR = 1.12, 95% CI 0.81-1.53, p = 0.497). Stratification for gender revealed a significant association between hypothyroidism and rosacea in females (OR = 1.27, 95% CI 1.1-1.47, p = 0.002) and males (OR = 1.58, 95% CI 1.04-2.4, p = 0.032). The frequency of hypothyroidism in rosacea patients increased towards the age range of 40-49 and then decreased, parallel with the hypothyroidism frequency of the study population., Study Limitations: Different subtypes and severities of rosacea were not distinguished., Conclusions: Hypothyroidism may be a comorbidity of rosacea and investigation for hypothyroidism may be appropriate when evaluating rosacea patients., (Copyright © 2021 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: Gene therapy approaches have become increasingly attractive in the medical, pharmaceutical, and biotechnological industries due to their applicability in the treatment of diseases with no effective conventional therapy. Non-viral delivery using cationic solid lipid nanoparticles (cSLNs) can be useful to introduce large nucleic acids to target cells. A careful selection of components and their amounts is critical to obtain a successful delivery system. In this study, solid Witepsol nanoparticles were formulated, characterized, and evaluated in vitro for gene delivery purposes., Materials and Methods: Solid Witepsol nanoparticles were formulated through the microemulsion dilution technique using two grades of Witepsol and three surfactants, namely Cremephor RH40, Kolliphor HS15, and Peceol. Dimethyldioctadecylammonium bromide was incorporated into the system as a cationic lipid. Twelve combinations of these ingredients were formulated. The obtained nanoparticles were then evaluated for particle size, zeta potential, DNA binding and protection ability, cytotoxicity, and transfection ability., Results: Particle sizes of the prepared cationic cSLNs were between 13.43±0.06 and 68.80±0.78 nm. Their zeta potential, which is important for DNA binding efficiency, was determined at >+40 mV. Gel retardation assays revealed that the obtained cSLNs can form a compact complex with plasmid DNA (pDNA) encoding green fluorescent protein and that this complex can protect pDNA from DNase I-mediated degradation. Cytotoxicity evaluation of nanoparticles was performed on the L929 cell line. In vitro transfection data revealed that solid Witepsol nanoparticles could effectively transfect fibroblasts., Conclusion: Our findings indicate that solid Witepsol nanoparticles prepared using the microemulsion dilution technique are promising non-viral delivery systems for gene therapy.

Aim: The CRISPR/Cas9 system is a promising gene-editing tool for various anticancer therapies; however, development of a biocompatible, nonviral and efficient delivery of CRISPR/Cas9 expression systems remains a challenge. Materials & methods: Solid lipid nanoparticles (SLNs) were produced based on pseudo and 3D ternary plots. Obtained SLNs and their complexes with PX458 plasmid DNA were characterized and evaluated in terms of cytotoxicity and transfection efficiency. Results: SLNs were found to be nanosized, monodispersed, stable and nontoxic. Furthermore, they revealed similar transfection efficiency as the positive control. Conclusion: Overall, we have achieved a good SLN basis for CRISPR/Cas9 delivery and have the potential to produce SLNs with targeted anticancer properties by modifying production parameters and components to facilitate translating CRISPR/Cas9 into preclinical studies.

Purpose: Paclitaxel is a first-line drug for the therapy of lung cancer, however, drug resistance is a serious limiting factor, related to overexpression of anti-apoptotic proteins like survivin. To overcome this phenomenon, developing novel ultrasound responsive nanobubbles - nanosized drug delivery system- for the delivery of paclitaxel and siRNA in order to silence survivin expression in the presence of ultrasound was aimed., Methods: Paclitaxel-carrying nanobubble formulation was obtained by modifying the multistep method. Then, the complex formation of the nanobubbles - paclitaxel formulation with survivin-siRNA, was examined in terms of particle size, polydispersity index, zeta potential, and morphology. Furthermore, siRNA binding and protecting ability, cytotoxicity, cellular uptake, gene silencing, and induction of apoptosis studies were investigated in terms of lung cancer cells., Results: Developed nanobubbles have particle sizes of 218.9-369.6 nm, zeta potentials of 27-34 mV, were able to protect siRNA from degradation and delivered siRNA into the lung cancer cells. Survivin expression was significantly lower compared with the control groups and enhanced apoptosis was induced by the co-delivery of survivin-siRNA and paclitaxel. Furthermore, significantly higher effects were obtained in the presence of ultrasound induction., Conclusion: The ultrasound responsive nanobubble system carrying paclitaxel and survivin-siRNA is a promising and effective approach against lung cancer cells.

Introduction: The outcome of medical treatment in patients with Graves' disease (GD) is generally difficult to predict. In this study, we examined the hypothesis that gender may affect the outcome of treatment with antithyroid drugs (ATDs)., Material and Methods: This is a retrospective multicentre study including 717 (514 female and 203 male) patients with the first episode of GD treated for at least 12 months. Patients were classified as relapse, poorly controlled (several episodes of hyperthyroidism followed by euthyroidism and rarely hypothyroidism, occurring after titration of ATDs), and remission., Results: During the mean follow-up time of 26.75 ± 21.25 months (between 1 and 120 months), 269 (37.5%), 176 (24.5%), and 272 (37.9%) patients experienced a relapse, a poorly controlled disease, and remained in remission, respectively. During the follow-up time, 223 (43.4%) of the female and only 49 (24%) of the male patients remained in remission. Relapse and poorly controlled disease (non-remitting GD) were more common in male compared to female patients with GD (hazard ratio 1.26, 95% CI: 1.03-1.53, p = 0.025). Graves' disease in male patients tended to relapse earlier, and male patients tended to have larger goiter sizes at diagnosis as well. The smoking habit was also significantly more frequent in males compared to female patients with GD., Conclusion: Male patients with GD have a markedly higher frequency of relapse and poorly controlled disease, as compared to female patients. Larger goiter sizes and higher frequency of smoking may contribute to the higher frequency of relapse and poorly controlled disease in male patients.

Recently, the Graves' Recurrent Events After Therapy score (GREAT) was proposed as a useful tool to predict relapse before starting antithyroid drugs (ATD) in patients with Graves' disease (GD). Therefore, we intended to assess the validity of the GREAT score in Turkish patients with GD, including patients who experienced a poorly controlled disease (multiple episodes of hyperthyroidism followed by euthyroidism or rarely hypothyroidism) during ATD dose titration. This is a retrospective multicenter study including 517 patients with the first episode of GD who were treated for at least 12 months. The patients were classified as relapse+poorly controlled disease (non-remission) and remission groups. During a median follow-up time of 35 months (12-144 months), 191 (37%) patients experienced a relapse, 136 (26.3%) a poorly controlled disease, and 190 (36.7%) remained in remission. Patients with non-remission disease tended to have significantly higher serum levels of TRAb, fT4, and fT3, and have larger goiter sizes on palpation at baseline, as compared with the remission group. Non-remission disease occurred in 12, 35, and, 53% of the patients falling into GREAT class I, II, and III, respectively (hazard ratio 2.56, 95% CI 2.02-3.51, p=0.012, and hazard ratio 3.54, 95% CI 2.12-5.91, p<0.001, for GREAT class II and III against class I, respectively). According to our study, the GREAT score is a useful tool to predict the risk of relapse as well as the occurrence of poorly controlled disease before starting treatment with ATDs., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Lung cancer remains 23% of cancer-related death worldwide, ranking on first place for men and second place for women. Almost each cancer type has a great deal in common, overexpression of the apoptosis inhibitor survivin. Chemotherapy with anticancer drugs is leading to side effects. Drug targeting by the use of nanobubbles is a useful strategy to reduce side effects. Nanobubbles in cancer are one of the most investigated carriers in the last years. The size of nanobubbles (1-500 nm) is bigger than the pore size of healthy tissues, but smaller than the pores of cancer tissues. Thus, it is not possible for the drug to leave the blood stream and enter the tissue, but it can enter the cancer tissue through the pores, where it can accumulate. Therefore, the probability of undesired side effects decreases. For that reason, the development of nanobubbles containing paclitaxel and survivin inhibitor sepantronium bromide (YM155) were carried out. Characterization studies in terms of particle size, size distribution, zeta potential and morphology, and investigation of their effects on lung cancer cells were performed. To the best of our knowledge, there is no information in the literature about combining paclitaxel and YM155 loaded nanobubbles with ultrasound exposure., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Context: Dopamine agonist (DA)-induced impulse control disorder (ICD) in patients with prolactinomas is not sufficiently known., Objective: To evaluate the prevalence of DA-induced ICDs and possible risk factors related to these disorders in patients with prolactinoma., Design, Setting, and Participants: This is a cross-sectional multicenter study involving 308 patients with prolactinoma followed up in tertiary referral centers who received at least three months of DA therapy. DA-induced ICDs (pathological gambling, hypersexuality, compulsive shopping, and compulsive eating) and impulsivity were assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease and the Barratt Impulsiveness Scale-11, respectively. Patients were evaluated in terms of parameters related to ICD development., Results: Any ICD prevalence was 17% (n = 51). Hypersexuality was most common (6.5%). Although any ICD and hypersexuality were more common in male patients (P = 0.009, P < 0.001, respectively), compulsive eating was more common in female patients (P = 0.046). Current smoking, alcohol use, and gambling history were more frequent (P = 0.033, P = 0.002, P = 0.008, respectively) in patients with any ICD. In Barratt Impulsiveness Scale-11 total, attentional, motor, and nonplanning scores were higher in patients with any ICD (P < 0.001). Current smoking and alcohol use were more frequent (P = 0.007, P = 0.003, respectively) and percentage increase of testosterone levels at last visit was higher (P = 0.021) in male patients with prolactinomas with hypersexuality., Conclusion: Any ICD may be seen in one of six patients with prolactinoma who are receiving DA therapy. Endocrinology specialists should be aware of this side effect, particularly in male patients with a history of gambling, smoking, or alcohol use., (Copyright © 2019 Endocrine Society.)

Targeted therapy against the programmed cell death ligand-1 (PD-L1) blockade holds considerable promise for the treatment of different tumor types; however, little effect has been observed against gliomas thus far. Effective glioma therapy requires a delivery vehicle that can reach tumor cells in the central nervous system, with limited systemic side effect. In this study, we developed a cyclic peptide iRGD (CCRGDKGPDC)-conjugated solid lipid nanoparticle (SLN) to deliver small interfering RNAs (siRNAs) against both epidermal growth factor receptor (EGFR) and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in tumor-associated macrophage-dependent fashion, we showed that low-dose radiation primes targeted SLN uptake into the brain tumor region, leading to enhanced downregulation of PD-L1 and EGFR. Bioluminescence imaging revealed that radiation therapy followed by systemic administration of targeted SLN leads to a significant decrease in glioblastoma growth and prolonged mouse survival. This study combines radiation therapy to prime the tumor for nanoparticle uptake along with the targeting effect of iRGD-conjugated nanoparticles to yield a straightforward but effective approach for combined EGFR inhibition and immunotherapy against glioblastomas, which can be extended to other aggressive tumor types.

Our aim is to demonstrate any correlation between gestational diabetes mellitus (GDM) and polymorphism of the selenoprotein P (SEPP1) gene encoding the SEPP1 protein, having a role in the insulin resistance in GDM. Forty pregnant women with GDM and 40 healthy pregnant women were included in the study. In both groups, single nucleotide polymorphisms (SNPs), specifically, rs4987017, rs13154178, rs146125471, rs28919926, and rs16872762 were studied. There was no difference between the groups in terms of polymorphism rs146125471, rs28919926, or rs16872762 (p > .05). There was a significant difference in SNP rs13154178 polymorphism between the two groups (p < .01). When rs13154178 gene polymorphism was compared with AA homozygous individuals, fasting blood glucose levels were significantly higher in carriers of either polymorphism than in those with no polymorphism (p < .001). We suggest rs13154178 gene polymorphism may lead to GDM in the Turkish society.

Background/aim: To examine changes in paratracheal lymph nodes (PLNs) and the relationship with the course of the disease in patients with chronic autoimmune thyroiditis (CAT) 5 years after diagnosis. Materials and methods: A total of 169 patients with newly diagnosed CAT and 53 healthy subjects were included in the study. All patients underwent ultrasonographic (US) examinations of the thyroid, paratracheal regions, and examined thyroid function tests. Eighty-four patients who were euthyroid at baseline and who were contacted 5 years after the diagnosis were reevaluated by US and thyroid function tests. Results: The PLNs frequency was significantly higher in the CAT group than the controls (75.1 % vs. 30.1 %, P < 0.001). Among the 84 patients who were euthyroid at the time of diagnosis and were contacted again after 5 years, 15 developed hypothyroidism. Initially, PLNs were present in all patients who developed hypothyroidism and were significantly higher than in those who remained euthyroid (respectively 100% vs. 68.7%, P = 0.009). PLN presence and PLN volume in patients who were euthyroid at baseline predicted hypothyroidism at the end of 5 years. Conclusion: PLNs may be used as an indicator of disease progression. In addition, patient age and baseline TSH levels are other factors that predict the development of hypothyroidism in time.

Background: Subclinical hypothyroidism (SH) occurs when serum thyroid stimulating hormone (TSH) concentrations are raised and serum thyroid hormone concentrations are normal. The effect of SH on the proinflammatory adipose cytokine releasing visceral adipose tissue (VAT) is not clear. The aim of this study is to identify the difference between the pre and posttreatment levels of VAT, leptin, and resistin in SH patients., Methods: There were 51 SH patients and 43 age- and gender-matched healthy subjects included in the study. Thyroid functions, biochemical tests, leptin, resistin, and visceral and subcutaneous fat measurements were made. The measurements were repeated in the SH group in the third month following L-thyroxin treatment., Results: Initially, high sensitivity C-reactive protein, carotid artery intima-media thickness (mm), leptin, and resistin levels were significantly higher in the SH group compared to the controls, while the other parameters were similar. While no correlation was observed between TSH levels and adipokines, a positive correlation was detected between waist circumference and leptin levels (r = 0.549, p < 0.01). Visceral adipose tissue was positively correlated to age, waist circumference, and leptin levels, but negatively correlated to free thyroxin (T4) levels (r = 0.419, p = 0.009; r = 0.794, p < 0.01; r = 0.515, p < 0.01 and r = - 0.416, p = 0.009, respectively). A significant decrease was observed in VAT volume, leptin, and resistin levels of SH patients following levothyroxine treatment. Conclusion The reduced VAT volume, leptin, and resistin levels in SH patients following treatment may support the idea that TSH affects adipose tissue functions.