Beyond the physico-chemical barrier: Glycerol and xylitol markedly yet differentially alter gene expression profiles and modify signalling pathways in human epidermal keratinocytes.

Polyols (e.g. glycerol, xylitol) are implicated as moisturizers of the skin and other epithelial tissues. However, we lack information about their exact cellular mechanisms and their effects on the gene expression profiles. Therefore, in this study, we aimed at investigating the effects of glycerol and xylitol on human epidermal keratinocytes. The polyols (identical osmolarities; xylitol: 0.0045%-0.45%; glycerol: 0.0027%-0.27%) did not alter cellular viability or intracellular calcium concentration. However, they exerted differential effects on the expression of certain genes and signalling pathways. Indeed, both polyols up-regulated the expression of filaggrin, loricrin, involucrin and occludin; yet, xylitol exerted somewhat more profound effects. Moreover, while both polyols stimulated the MAPK pathway, only xylitol induced the activation-dependent translocation of protein kinase Cδ, a key promoter of epidermal differentiation. Finally, in various keratinocyte inflammation models, both polyols (albeit with different efficacies) exerted anti-inflammatory effects. Taken together, these data strongly suggest that glycerol and xylitol differentially modulate expressions of multiple genes and activities of signalling pathways in epidermal keratinocytes. Thus, our findings invite clinical trials to explore the applicability and the impact of a combined glycerol-xylitol therapy in the management of various skin conditions.

Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment.

Acne is a common skin disease characterized by elevated sebum production and inflammation of the sebaceous glands. We have previously shown that a non-psychotropic phytocannabinoid ((-)-cannabidiol [CBD]) exerted complex anti-acne effects by normalizing 'pro-acne agents'-induced excessive sebaceous lipid production, reducing proliferation and alleviating inflammation in human SZ95 sebocytes. Therefore, in this study we aimed to explore the putative anti-acne effects of further non-psychotropic phytocannabinoids ((-)-cannabichromene [CBC], (-)-cannabidivarin [CBDV], (-)-cannabigerol [CBG], (-)-cannabigerovarin [CBGV] and (-)-Δ(9) -tetrahydrocannabivarin [THCV]). Viability and proliferation of human SZ95 sebocytes were investigated by MTT and CyQUANT assays; cell death and lipid synthesis were monitored by DilC1 (5)-SYTOX Green labelling and Nile Red staining, respectively. Inflammatory responses were investigated by monitoring expressions of selected cytokines upon lipopolysaccharide treatment (RT-qPCR, ELISA). Up to 10 µm, the phytocannabinoids only negligibly altered the viability of the sebocytes, whereas high doses (≥50 µm) induced apoptosis. Interestingly, basal sebaceous lipid synthesis was differentially modulated by the substances: CBC and THCV suppressed it, and CBDV had only minor effects, whereas CBG and CBGV increased it. Importantly, CBC, CBDV and THCV significantly reduced arachidonic acid (AA)-induced 'acne-like' lipogenesis. Moreover, THCV suppressed proliferation, and all phytocannabinoids exerted remarkable anti-inflammatory actions. Our data suggest that CBG and CBGV may have potential in the treatment of dry-skin syndrome, whereas CBC, CBDV and especially THCV show promise to become highly efficient, novel anti-acne agents. Moreover, based on their remarkable anti-inflammatory actions, phytocannabinoids could be efficient, yet safe novel tools in the management of cutaneous inflammations.

LINAC-based SBRT in treating early-stage NSCLC patients-single institution experience and survival data analysis.

Aim: This single institute prospective study aimed to evaluate the feasibility of LINAC-based stereotactic body radiotherapy (SBRT) in treating patients with early-stage non-small cell lung cancer (NSLSC). We focused on the survival data with the local and distant control profiles and the cancer- and non-cancer-specific survival. Treatment-related side effects were also collected and analyzed. Methods: Patients with early-stage NSCLC between January 2018 and October 2021 were included in our prospective study; a total of 77 patients receiving LINAC-based SBRT were analyzed. All patients had pretreatment multidisciplinary tumor board decisions on SBRT. The average patient age was 68.8 years (median: 70 years, range: 52-82); 70 patients were in ECOG 0 status (91%), while seven patients were in ECOG 1-2 status (9%). 52% of the patients (40) had histologically verified NSCLC, and the other 48% were verified based on PETCT results. We applied the SBRT scheme 8 x 7.5 Gy for central tumors (74%) or 4 x 12 Gy for peripheral tumors (26%). Results: The mean follow-up time was 25.4 months (median 23, range 18-50). The Kaplan-Meier estimation for overall survival in patients receiving LINAC-based SBRT was 41.67 months. Of the 77 patients treated by SBRT, death was reported for 17 patients (9 cases cancer-specific, 8 cases non-cancer specific reason). The mean local tumor control was 34.25 months (range 8.4-41), and the mean systemic control was 24.24 months (range 7-25). During the treatments, no Grade I-II were reported; in 30 cases, Grade I non-symptomatic treatment-related lung fibrosis and two asymptomatic rib fractures were reported. Conclusion: In the treatment of early-stage NSCLC, LINAC-based SBRT can be a feasible alternative to surgery. Although we reported worse OS data in our patient cohort compared to the literature, the higher older average age and the initial worse general condition (ECOG1-2) in our patient cohort appear to be the reason for this difference. With the comparable local control and survival data and the favorable side effect profile, SBRT might be preferable over surgery in selected cases.

Stereotactic body radiotherapy in lung cancer: a contemporary review.

The treatment of early stage non-small cell lung cancer (NSCLC) has improved enormously in the last two decades. Although surgery is not the only choice, lobectomy is still the gold standard treatment type for operable patients. For inoperable patients stereotactic body radiotherapy (SBRT) should be offered, reaching very high local control and overall survival rates. With SBRT we can precisely irradiate small, well-defined lesions with high doses. To select the appropriate fractionation schedule it is important to determine the size, localization and extent of the lung tumor. The introduction of novel and further developed planning (contouring guidelines, diagnostic image application, planning systems) and delivery techniques (motion management, image guided radiotherapy) led to lower rates of side effects and more conformal target volume coverage. The purpose of this study is to summarize the current developments, randomised studies, guidelines about lung SBRT, with emphasis on the possibility of increasing local control and overall rates in "fit," operable patients as well, so SBRT would be eligible in place of surgery.

[Reflections on the enforcement of the genetic code of Act No. XXI of 2008]. / Reflexiók a 2008. évi XXI. genetikai törvény végrehajtásához.

The genetic code of Act No. XXI of 2008 is a milestone in the national codification of Hungarian human genetic studies and research. The code is in conformity with international as well as EU legislations. It guarantees full enforcement of both the right to self-determination and the rules of the profession. The criteria of legal functioning are institutional accreditation, regular auditing, decreed government control, and coordinated network structure. Further government and ministerial decrees are necessitated for its enforcement.

[Dysgenetic male pseudohermaphroditism]. / Dysgeneticus pseudohermaphroditismus masculinus.

The authors report a case of a dysgenetic male pseudohermaphroditism with a 45,X/46,XY karyotype in a mosaic form, which was diagnosed in an infant. The one-week-old infant was evaluated because of proximal hypospadias and retention of the right testis. The results of hormonal tests were the followings: serum FSH 5.2 mU/ml; LH: 2.0 mU/ml; testosterone: 144.3 ng/dl; androstendione: 0.42 µg/l; 17-hydroxyprogesterone: 1.12 ng/ml. Chromosomal analysis revealed 45,X/46,XY karyotype. Fluorescent in vitro hybridization showed that 51% of the lymphocytes had the Y chromosome and the SRY gene. Analysis of the SRY showed no deletion in the AZF a,b,c regions. Pelvic magnetic resonance imaging indicated the presence of vagina between the bladder and the rectum, and it showed a mass measuring 15×8 mm in the right inguinal canal as well as an oval gonadal mass with a size of 13×7 mm in the left scrotum. During surgical intervention, performed at the age of one, the right gonad was removed and biopsy of the scrotal testis was performed. Histological examination revealed dysgenetic testis in both sides. The authors emphasize the necessity of cytogenetic and endocrinological investigations of newborns with perineoscrotal hypospadia and bilateral or unilateral maldescent testes immediately after birth. Surgical removal of the dysgenetic testicular tissue located in the abdominal cavity and its histological evaluation provides separation of mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, bilateral gonadal dysgenesis and ovotestis in the 45,X/46,XY mosaic cases. An accurate evaluation is necessary for a correct sex assignment and for surgical intervention to prevent neoplastic degeneration of the dysgenetic gonad.

Plan Quality Assessment of Fractionated Stereotactic Radiotherapy Treatment Plans in Patients With Brain Metastases.

Background and Purpose: The treatment options available in the management of brain metastases includes fractionated stereotactic radiotherapy (FSRT) and stereotactic radiosurgery (SRS) treatments. FSRT treatments have proved to be useful mainly in the treatment of larger volumes. This study aims to evaluate the FSRT treatment technique used in our department based on various plan quality indices. Methods and Materials: 24 treatment plans of 23 patients were analyzed. Volumetric modulated arc therapy (VMAT) plans were generated in line with the department protocol. The following parameters were extracted: Radiation Therapy Oncology Group conformity index (RTOG CI), Paddick conformity index (Paddick CI), gradient index (GI), quality index (Q), homogeneity index (HI), and V24.4 volume as a parallel index of V12 used at SRS plan evaluation. Results: Plan conformity was acceptable, RTOG CI mean was 0.942; Paddick CI mean was 0.824. The mean GI value was 6.146. The mean of HI and Q indices were 1.263 and 0.94, respectively. V24.4 mean was 33.434 cm3. All plans achieved clinically acceptable organs-at-risk (OAR) constraints. PTV volumes were clustered into either 10 cm3 or 15 cm3 bins depending on the plan quality metric we used. The mean values show a balanced distribution of plan indices along the various PTV bins. Discussion: Our results based on the derived indices show that our FSRT approach can achieve clinically acceptable treatment plans. Furthermore, the clustering of PTV volumes show that these plan quality metrics remain acceptable for a wide spectrum of PTV volumes.

CBCT Verification of SRT for Patients With Brain Metastases.

BACKGROUND: The aim of our work is to demonstrate the role of image guidance and volumetric imaging in stereotactic radiotherapy (SRT) of brain metastases. METHODS: Between 2018 and 2020, 106 patients underwent intracranial stereotactic radiotherapy. 10 patients with metastatic brain tumors treated with SRT were randomly selected and included in our study model. Patients were scanned pre- and post-treatment with cone beam CT. Total of 100 verifications of 50 stereotaxic treatments were performed and analyzed. RESULTS: Population mean X, Y, Z values were -0.13 cm, -0.04 cm, -0.03 cm, respectively, rotation values 0.81°, 0.51°, 0.46°, respectively. Systematic error components for translational displacements pre corrections were as follows: 0.14 cm for X, 0.13 cm for Y and 0.1 cm for Z. Systematic error components of the post-treatment HR 3D CBCTs were as follows: 0.01 cm for X, 0.06 cm for Y and 0.04 cm for Z. CONCLUSIONS: Population mean values close to 0 confirmed that there is no systematic variation in our system and the accuracy of our equipment and tools is reliable. HR 3D CBCT scans performed pre SRTs further refine patient and target volume setting, support medical decision making and eliminate the possibility of gross error.

FBN1 gene mutations in 26 Hungarian patients with suspected Marfan syndrome or related fibrillinopathies.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder mainly affecting the cardiovascular, ocular and musculo-skeletal systems. FBN1 gene mutations lead to MFS and related connective tissue disorders. In this work we described clinical and molecular data of 26 unrelated individuals with suspected MFS who were referred for FBN1 mutation analysis. FBN1 gene sequencing was performed by next generation sequencing and Sanger sequencing methods. We identified 23 causal or potentially causal (including variants of uncertain significance) FBN1 variants, seven of them was novel (˜30%). About 30% of the cases were sporadic. FBN1 mutations were associated with MFS in the majority of the patients, in two cases with severe and early onset manifestation of the syndrome. Missense mutations were detected in 69.6% (16/23), the majority of them were located in one of the cbEGF motifs and ˜70% of them substituted conserved cystein residues. Small deletions/duplications were identified in 13% of the cases (3/23), while splice site variants were detected in 17.4% (4/23). In three unrelated patients a low frequency recurrent silent variant (c.3294C > T (p.Asp1098=) was identified. FBN1 mRNA analysis showed that the mutation does not lead to aberrant splicing, based on available data the mutation was classified as benign.

Changes in oral anticoagulation for elective cardioversion: results from a European cardioversion registry.

Aims: In patients with atrial fibrillation (AF) pharmacological or electrical cardioversion may be performed to restore sinus rhythm. The procedure is associated with an increased risk of thromboembolic events, which can be significantly reduced by adequate anticoagulation (OAC). Our aim was to create a partly prospective, partly retrospective cardioversion registry, particularly focusing on OAC strategies in different European countries, and on emerging choice of OAC over time. Methods: From September 2014 to October 2015, cardioversions due to AF performed in six European city hospitals in five European countries (Hungary: Budapest-1 and -2; Italy: Bari and Pisa; France: Amiens; Spain: Madrid; and Lithuania: Kaunas) were recorded in the registry. Results: A total of 1101 patients (retrospective/prospective: 679/422, male/female: 742/359, mean age: 67.3 years ± 11.2) were registered. Most of the cardioversions were electrical (97%). Oral anticoagulants were administered in 87% of the patient, the usage of non-VKA oral anticoagulants (NOACs) vs Vitamin K antagonists (VKA) was 31.5% vs 68.5%, respectively. Seventy seven percent of the patients were given oral anticoagulants more than 3 weeks prior to the procedure, and 86% more than 4 weeks after the procedure. When using VKA, international normalized ratio (INR) at cardioversion was above 2.0 in 76% of the cases. A decline in VKA usage (P = 0.033) in elective cardioversion over approximately 1 year was observed. During the observation period, there was an increase in apixaban (P < 0.001), a slight increase in rivaroxaban (P = 0.028) and no changes in dabigatran (P = 0.34) usage for elective cardioversion. There were differences in use of OAC between the countries: Spain used most VKA (89%), while France used least VKA (39%, P < 0.001). Conclusion: According to current AF guidelines, NOACs are adequate alternatives to VKA for thromboembolic prevention in AF patients undergoing elective cardioversion. Our results indicate that NOAC use is increasing and there is a significant decrease in VKA use.

Altered microrheological parameters in Raynaud's phenomenon.

Raynaud's phenomenon is an episodic, painful attack of the acral parts caused by local diminished blood supply. The aim of our study was to examine hemorheological parameters, cold agglutinins, cryoglobulins and their relationship in patients suffering from Raynaud's phenomenon.Blood was taken from 74 patients (mean age: 48 years, female/male: 56/18). Cold agglutinins and cryoglobulins were determined. Hemorheological parameters were also measured such as hematocrit, plasma and whole blood viscosity, red blood cell aggregation and deformability. Results were compared to a group of 58 healthy controls (mean age: 31.5 years, female/male: 24/34).Cold agglutinins were positive in 70%, cryoglobulins in 43% of patients. When compared to healthy controls, increased red blood cell aggregation (64.54  ±  8.93 vs. 61.11  ±  7.05) and decreased red blood cell deformability (0.669  ±  0.002 vs. 0.681  ±  0.001) was observed in Raynaud's patients (p < 0.05), but there were no differences in hematocrit (43.27% ± 3.85 vs. 44.10% ± 3.70), plasma (1.27 mPas ± 0.08 vs. 1.24 mPas ± 0.09) and whole blood viscosity (4.12 mPas ± 0.52 vs. 4.26 mPas ± 0.46). No differences were found between the hemorheological profile of cold agglutinin/cryoglobulin positive and negative patients. Also primary and secondary Raynaud's patients had similar rheological profile.Erythrocyte aggregation and deformability seems to be unfavorable in Raynaud's patients that can play a role in the disturbance of the microcirculation.

Echinacea purpurea-derived alkylamides exhibit potent anti-inflammatory effects and alleviate clinical symptoms of atopic eczema.

BACKGROUND: Atopic eczema (AE) is a chronic inflammatory and pruritic skin disease. There is still an unmet need for topical anti-inflammatory and anti-pruritic substances exhibiting an excellent safety profile. The endocannabinoid system is known to regulate various aspects of cutaneous barrier and immune functions, thus targeting it may be a valid approach for alleviating the symptoms of AE. OBJECTIVE: To assess the putative efficacy of Echinacea purpurea-derived alkylamides (Ec. extract) activating cannabinoid (CB)-2 receptors in exerting anti-inflammatory effects and alleviating symptoms of AE. METHODS: In vitro anti-inflammatory efficiency was investigated by monitoring the effects of Ec. extract on poly-(I:C)-induced pro-inflammatory cytokine expression (Q-PCR) and release (ELISA) of HaCaT keratinocytes. Irritancy and sensitization potential (assessed by Human Repeat Insult Patch Test; Clinical trial 1); clinical efficiency in alleviating symptoms of AE (Clinical trial 2) as well as effects on human skin structure and lipid content (Clinical trial 3 followed by transmission electron microscopy and HPTLC) were investigated in randomized double blind clinical trials. RESULTS: Ec. extract significantly reduced mRNA expression as well as release of poly-(I:C)-induced pro-inflammatory cytokines (IL-6 and IL-8) in keratinocytes. Thus, not surprisingly, the well-tolerated (Clinical trial 1) Ec. extract-based cream reduced local SCORAD statistically significantly, not only compared to baseline, but also compared to the comparator (Clinical trial 2). Of great importance, besides the in vitro anti-inflammatory effects, administration of the Ec. extract-based cream also resulted in significantly higher levels of overall epidermal lipids, ceramide EOS (ω-esterified fatty acid+sphingosine sphingoid base), and cholesterol at Day 15 compared to baseline as well as significantly greater numbers of intercellular lipid lamellae in the intercellular space (Clinical trial 3). CONCLUSION: The investigated Ec. extract shows great potential in alleviating cutaneous symptoms of AE, and by exerting remarkable anti-inflammatory actions and restoring the epidermal lipid barrier, it will be very likely a well-tolerated, powerful novel ingredient for the adjuvant therapy of AE.

Gender differences in hemorheological parameters and in in vitro platelet aggregation in acetylsalicylic acid and clopidogrel treated vascular patients.

BACKGROUND: Sex-specific response to antiplatelet medications have been reported in several previous studies. OBJECTIVE: We investigated a possible connection between gender differences in hemorheological parameters and in vitro platelet aggregation in vascular patients treated with widely used antiplatelet agents. METHODS: In vitro platelet aggregation was assessed in 2687 patients treated with 100 mg acetylsalicylic acid (ASA), 1047 patients treated with 75 mg clopidogrel and 311 patients on dual antiplatelet therapy (100 mg aspirin and 75 mg clopidogrel) according to the method of Born. In subgroups of patients fibrinogen concentration, whole blood and plasma viscosity, red blood cell aggregation and hematocrit were simultaneously measured. The subjects were divided into groups according to their gender. RESULTS: ADP induced platelet aggregation was significantly higher in women in the case of ASA treatment (p<0.001). No gender differences could be observed in platelet function in patients treated with clopidogrel or on dual antiplatelet therapy. Hematocrit and whole blood viscosity were significantly higher in men in all groups (p<0.001), while no significant gender differences were observed in red blood cell aggregation indices in either group. Fibrinogen concentration was significantly higher in women than in men among patients treated with 100 mg ASA (p<0.05), but not in the other groups. CONCLUSIONS: Significantly higher fibrinogen concentration found in aspirin treated women than men may play a role in higher ADP induced platelet aggregation. Gender differences in response to monotherapy suggest that benefits from combination therapy may be greater in females. The clinical relevance of higher ADP induced platelet aggregation in women treated with ASA needs further investigation.

Nasal-air conditioning in patients with chronic rhinosinusitis and nasal polyposis.

OBJECTIVES: To compare nasal-air conditioning in patients with chronic rhinosinusitis with nasal polyposis with healthy control subjects without nasal pathologic conditions, to investigate nasal-air conditioning after endoscopic sinus surgery with and without septoplasty and turbinoplasty 4 to 6 weeks after surgery, to examine the parameters of nasal patency and nasal geometry that possibly influence nasal-air conditioning before and after endonasal surgery, and to determine their relationship to nasal-air conditioning parameters. DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PARTICIPANTS: Twenty-five patients (median age, 51 years; age range, 20-74 years) having a diagnosis of chronic rhinosinusitis with nasal polyposis refractory to medical treatment and 22 healthy control subjects (median age, 25 years; age range, 18-52 years). INTERVENTION: Patients underwent endoscopic sinus surgery with or without septoplasty and turbinoplasty during 6 months and were followed up 4 to 6 weeks after surgery. MAIN OUTCOME MEASURES: Nasal-air conditioning was measured and acoustic rhinometry and active anterior rhinomanometry were performed before and after nasal surgery. RESULTS: Nasal airflow and nasal volume were significantly higher postoperatively than preoperatively. The preoperative heat increase and water gradient were lower in the patients compared with the controls. The postoperative heat increase was significantly higher than the preoperative values. The water gradient did not change after endonasal surgery. Nasal patency and volume were positively correlated with nasal heating, whereas nasal humidification showed a significant negative correlation with nasal volume. CONCLUSIONS: Patients with chronic rhinosinusitis with nasal polyposis seem to benefit from endoscopic sinus surgery with or without septoplasty and turbinoplasty because nasal heating is improved postoperatively. Four to 6 weeks after endonasal surgery, nasal humidification is neither improved nor worsened compared with preoperative values.

Nasal conditioning after endonasal surgery in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Endoscopic sinus surgery (ESS) is a frequently performed operation for chronic rhinosinusitis (CRS). The aim of this study was to investigate nasal conditioning after ESS with/without septoplasty and turbinoplasty in patients with CRS with nasal polyps and to determine its relation to nasal patency and geometry. METHODS: Twenty-one patients were enrolled into this study. Nasal conditioning, AAR, and acoustic rhinometry were measured before and 4-8 months after endonasal surgery. RESULTS: The temperature and humidity gradient across the nose increased significantly after operation. High nasal volumes and patency were positively correlated with elevated nasal conditioning. No correlation between preoperative and postoperative changes in nasal geometry and nasal airflow with changes in conditioning values was found. CONCLUSION: Patients with CRS with nasal polyps seem to profit from ESS with/without septoplasty and turbinoplasty because nasal conditioning is improved postoperatively. Properly performed ESS has its importance within the variety of nasal surgical procedures ensuring improved nasal function.