Impact of Bepanthen® and dexpanthenol on human nasal ciliary beat frequency in vitro.

BACKGROUND: Dexpanthenol-containing ointments/fluids are recommended to restore impaired nasal mucosa. To date, there are no data about the influence of dexpanthenol or formulations including dexpanthenol on ciliary beat frequency (CBF) of nasal epithelial cells. METHODS: We tested the ciliary beat frequency of human nasal epithelial cells in RPMI 1640 cell solution using in vitro high-frequency video microscopy every 60 s over a period of 15 min (min). Bepanthen® solution and dexpanthenol in two clinically relevant concentrations (1.67% and 3.33%) were added to the cells. Addition of sterile water served as control group. To get a better overview, the measurements after 1 min, 5 min and 15 min were combined. RESULTS: The CBF in the control group (n = 17) after 15 min was 7.3 ± 2.6 Hz. In comparison, the CBF after 15 min was 1.8 ± 1.0 Hz in the 3.33% Bepanthen® group (n = 17) and 3.2 ± 1.2 Hz in the 1.67% group, which was statistically significantly lower in both groups (p < 0.001). With regard to the dexpanthenol group (n = 17) a CBF of 6.0 ± 2.6 Hz with 3.33% and 6.1 ± 2.4 Hz with 1.67% dexpanthenol, was detected, which was again statistically significantly lower (p = 0.06) compared to the control group except CBF at 15 min with 1.57% (n = 17; p = 0.04). In general, the effect on CBF was less pronounced with dexpanthenol compared with Bepanthen® with a statistically significant difference between the two formulations. The results were verified by calculating an analysis of variance (ANOVA). CONCLUSIONS: Bepanthen® as an ointment, solution or inhalation is commonly used in ENT for mucosal care. Our results have shown that both substances reduce CBF in clinically relevant concentrations, although the effect was more pronounced with Bepanthen® compared to dexpanthenol solution, which could be related to additives or change of physical properties in the solution. Further research is needed to assess potential clinical relevance.

Opportunities and challenges in delivering remote primary care during the Coronavirus outbreak.

BACKGROUND: Social distancing and lockdowns were implemented during the first period of the COVID-19 pandemic. Primary care physicians needed to adapt quickly to deliver remote care/telemedicine. METHODS: A cross-sectional, 47-item online Google Survey was distributed through the Israel Association of Family Physicians (IAFP) mailing list between March 31-May 5, 2020. The questionnaire included demographics, physician characteristics, and information on usage and perceived telemedicine quality. Sampling weights by sex and age groups were applied. RESULTS: One hundred fifty-nine primary care physicians (10.6% of registered IAFP members; 63.5% women; mean age 53.4 ± 10.4 years and median professional experience 21.3 years) replied to the survey. The majority (59.7%) of the participants performed a mixture of in-person along with phone counseling. About 40% had no former telemedicine experience. The majority indicated that telephone and video formats were inferior to in-person consultation (68%, 57.1% online and phone, respectively). The overall counseling quality grade (on a 1-10 scale,)median (IQR)) was 6.2 (3) for telephone and 7(2) for video. While 66.9% reported experiencing no challenges, 10% had technical problems, 10% interpersonal problems, 5.6% scheduling difficulties, and 7.5% other difficulties. Majority of 56.6% physicians indicated they prescribed more antibiotics,16.4% sent more blood tests, 24.5% referred more to experts, and 49.7% referred more to imaging in comparison to usual counseling. Higher phone quality score was significantly associated with physicians who indicated not prescribing more antibiotics during the pandemic (OR = 0.30, 95%CI 0.134-0.688, p = 0.004). Higher online quality score was associated with physicians who indicated not sending more blood tests during the pandemic (OR = 0.06 95%CI 0.008-0.378, P = 0.003). CONCLUSIONS: Our findings suggest telehealth holds considerable promise for counseling in the primary care setting. However, interpersonal challenges raised by physicians should be understood in-depth to develop tailored training and further examine it in randomized trials while integrating patient-reported outcomes. Finally, further research on utility, cost, and cost-efficiency during remote counseling with follow-ups, medical prescribing, and additional referrals is needed.

Effects of tranexamic acid on human nasal ciliary beat frequency.

BACKGROUND: Patients with recurrent epistaxis, particularly due to hereditary hemorrhagic telangiectasia (HHT) are recommended to apply topical tranexamic acid (TXA) to reduce bleeding events. Those patients may suffer ciliary dysfunction due to TXA's effects on ciliary beating frequency (CBF) and their consequences. METHODOLOGY/PRINCIPAL: Human nasal epithelial cells were harvested with a nasal brush in 30 healthy subjects. We investigated the CBF in RPMI medium using high-frequency video microscopy. TXA was added to the cells in various concentrations ranging from 2 to 5%, including the therapeutic concentration (2%) and a control (0%). RESULTS: CBF in the control condition was 6.1 ± 1.6 Hz. TXA reduces CBF in a time and concentration dependent manner, to, e.g. 4.3 ± 1.2 Hz with 2% TXA and 3.3 ± 0.9 Hz with 5% TXA after 16-20 min. The differences in CBF were statistically significant for all concentrations of TXA. CONCLUSIONS: TXA has the potential to significantly impair nasal epithelial function. Therefore, frequent or regular topical nasal application of TXA should be done under close monitoring of nasal function, especially in patients with co-morbidities like chronic rhinosinusitis.

[Differential diagnosis of hypersomnia in surgical sleep medicine-more than just sleep apnea!] / Differenzialdiagnostik der Hypersomnie in der operativen Schlafmedizin ­ mehr als nur Schlafapnoe!

Otorhinolaryngologists play a vital role in the management of patients with obstructive sleep apnea (OSA) in Germany, particularly with regards to outpatient diagnostics as well as conservative and surgical treatment of patients with intolerance to ventilation therapy. Although establishment of differential indications for surgical therapy and performance of additional preoperative drug-induced sleep endoscopy in patients with sleep-disordered breathing are among the core competencies of otorhinolaryngologists, differential diagnostic considerations and detection of comorbid sleep disorders can be challenging, particularly for those without extensive sleep medicine training and experience. However, detection of comorbid sleep disorders is of particular importance when permanent surgical treatment is considered. Daytime sleepiness is the typical leading symptom of OSA; nevertheless, other disorders of hypersomnolence need to be considered in these patients and can easily be overlooked. This may lead to inadequate indications for surgical treatment. Based on two case reports, narcolepsy is presented as a comorbid disorder and differential diagnosis in patients with OSA.

Paraoxonase 1 (PON1) attenuates sperm hyperactivity and spontaneous acrosome reaction.

BACKGROUND: Sperm capacitation is essential for proper fertilization and is associated with increased sperm hyperactivity (HA) and acrosome reaction (AR). For successful fertilization, AR timing is critical; accordingly, early spontaneous AR may not facilitate fertilization. Paraoxonase 1 (PON1) possesses antioxidant properties which affect sperm capacitation. The association between PON1, semen parameters, and capacitation is not fully understood. OBJECTIVE: To study PON1 activity in relation to human sperm hyperactivity and AR. MATERIALS AND METHODS: Semen samples were collected, and parameters were determined (volume, concentration, total sperm count, percentage total motility, and percentage normal morphology) according to World Health Organization (WHO) guidelines. AR and hyperactivity were evaluated using FITC-PSA, staining, and computer-aided sperm analysis (CASA). PON1 activity was assessed using arylesterase activity assay. RESULTS: Purified PON1 inhibited both sperm hyperactivity and AR in a dose-dependent manner. Native semen PON1 activity was positively associated with higher sperm concentration and negatively associated with spontaneous acrosome reaction (sAR). DISCUSSION AND CONCLUSION: PON1 may have a positive effect on fertility via its ability to prevent early spontaneous sperm capacitation and AR before reaching the female genital tract.

Influence of MP 29-02 on ciliary beat frequency in human epithelial cells in vitro.

PURPOSE: MP 29-02, which contains fluticasone propionate and azelastine hydrochloride, is used as a topical nasal application for the treatment of seasonal and perennial allergic rhinitis. Although a multitude of data is available on the clinical symptom reduction and treatment safety of MP 29-02, the effect of MP 29-02 on ciliary beat frequency (CBF) has not been evaluated thus far. METHODS: MP 29-02-containing solution was applied at concentrations of 2.5, 5, 10, and 20% to 14 healthy subjects, and nasal ciliated epithelial cells were then visualized using a phase-contrast microscope. CBF was measured after the application of MP 29-02. For a comparison, fluticasone propionate was used. CBF measurements were then performed for 15 min at 22 °C. Ringer's solution was applied as a negative control. RESULTS: MP 29-02 significantly reduced CBF at all the tested concentrations compared with that of the control group within the observation time. At a 2.5% concentration, MP 29-02 significantly reduced CBF from 6.81 Hz (SD ± 1.35 Hz) at baseline to 4.88 Hz (SD ± 1.52 Hz, p < 0.001) after 15 min. In contrast, for fluticasone propionate, a significant reduction was observed only with the 20% concentration after 5, 10, and 15 min. CONCLUSIONS: MP 29-09 significantly reduced CB, with an almost linear relationship between the MP 29-09 concentration and reduction in CBF. For fluticasone propionate, a significant reduction of CBF was observed only at the highest analyzed concentration. The findings have implications for the long-term use of the MP 29-02. Yet, further clinical studies are needed to confirm these results in vivo, especially in patients with seasonal or perennial allergic rhinits.

Pancreatic stellate cell activation is regulated by fatty acids and ER stress.

INTRODUCTION: Pancreatic pathologies are characterized by a progressive fibrosis process. Pancreatic stellate cells (PSC) play a crucial role in pancreatic fibrogenesis. Endoplasmic reticulum (ER) stress emerges as an important determinant of fibrotic remodeling. Overload of fatty acids (FA), typical to obesity, may lead to lipotoxic state and cellular stress. AIM: To study the effect of different lipolytic challenges on pancreatic ER stress and PSC activation. METHODS: Primary PSCs were exposed to different FAs, palmitate (pal) and oleate (ole), at pathophysiological concentrations typical to obese state, and in acute caerulein-induced stress (cer). PSC activation and differentiation were analyzed by measuring fat accumulation (oil-red staining and quantitation), proliferation (cells count) and migration (wound- healing assay). PSC differentiation markers (α-sma, fibronectin, tgf-ß and collagen secretion), ER stress unfolded protein response and immune indicators (Xbp1, CHOP, TNF-α, IL-6) were analyzed at the transcript and protein expression levels (quantitative RT-PCR and western blotting). RESULTS: PSC exposure to pal and ole FAs (500µM) increased significantly fat accumulation. Proliferation and migration analysis demonstrated that ole FA retained PSC activation, while exposure to pal FA significantly halted proliferation rate and delayed migration. Cer significantly augmented PSC differentiation markers α- sma, fibronectin and collagen, and ER stress and inflammation markers including Xbp1, CHOP, TNF-α and IL-6. The ole FA treatment significantly elevated PSC differentiation markers α-sma, fibronectin and collagen secretion. PSC ER stress was demonstrated following pal treatment with significant elevation of Xbp1 splicing and CHOP levels. CONCLUSION: Exposure to pal FA halted PSC activation and differentiation and elevated ER stress markers, while cer and ole exposure significantly induced activation, differentiation and fibrosis. Thus, dietary FA composition should be considered and optimized to regulate PSC activation and differentiation in pancreatic pathologies.

[Treatment of supine position-related obstructive sleep apnea with smartphone applications]. / Therapie rückenlagebezogener obstruktiver Schlafapnoe mittels Smartphone-App.

BACKGROUND: Positional obstructive sleep apnea (POSA) is common in mild and moderate forms of obstructive sleep apnea (OSA). Two smartphone applications (apps) professing to avoid the supine position (SP) are available: for Android the "Apnea Sleep Position Trainer" and for iOS the "SomnoPose-Sleep Position Monitor". The smartphone needs to be attached to the chest to recognize SP, which then triggers a vibration alarm. This is intended to encourage the patient to change position and the vibration stops as soon as SP is left. These apps, however, have not yet undergone a systematic evaluation. METHODS: Adult patients with polysomnographically diagnosed POSA were invited to participate in the study. POSA was defined as an apnea-hypopnea index (AHI) in SP >10, with AHI in a lateral position <10 and doubling of the AHI in SP. After 1 month, a control polysomnography (PSG) was performed and compliance (at least 4 h/night on 5 of 7 days) was evaluated after 6 months by phone. A sufficient therapy was defined as reduction in SP to <10% of the total sleep time and to an overall AHI <10. RESULTS: Although 57 patients entered the study, 24 did not appear to the PSG control; therefore, 33 patients finished the study, of whom 25 were treated successfully. The overall AHI in 33 patients was reduced from 14.5 ± 9.0 to 9.5 ± 12.6 and the time in SP decreased significantly from 71.1 ± 50.5 to 25.4 ± 65.0 min. Compliance among the 25 continuously treated patients after 6 months was 79.2%. CONCLUSION: Both smartphone apps have the capability to prevent PS in POSA patients and can potentially offer a cost-effective option in the treatment of POSA.

Mupirocin reduces ciliary beat frequency of human nasal epithelial cells.

Mupirocin is used worldwide for topical treatment of infected skin lesions, impetigo, and especially for nasal decolonization of patients with carriage of Staphylococci, including methicillin-resistant Staphylococcus aureus. Nevertheless, data regarding the effects of mupirocin on the nasal mucosa, in particular on ciliary beat frequency (CBF), is lacking to date. We tested the CBF of ciliated nasal epithelial cells under the influence of Mupirocin-calcium dissolved in tert-butyl alcohol (TBA) containing media in different concentrations comparable to clinical use. Ringer's lactate solution and TBA served as negative control. Cells were visualized with a phase contrast microscope, and the CBF was measured with the SAVA system's region of interest method. Mupirocin-calcium dissolved in TBA led to a statistically significant time- and concentration-dependent decrease in CBF compared to the negative control. TBA addition without mupirocin also led to a significant decrease in CBF, although to a lesser extent than mupirocin/TBA. In conclusion, CBF of human nasal epithelia is significantly reduced by mupirocin-calcium-containing solutions in therapeutic concentrations. Due to our results in this study, mupirocin as a nasal decolonization agent should be used only with care, with a strictly set medical indication, and additional care measures should be considered.

Late successful weight reduction and maintenance among overweight and obese adults--a two-year retrospective study.

AIMS: Our purpose was to identify those factors associated with successful late weight reduction and maintenance among overweight and obese adults who failed to achieve initial weight reduction success. METHODS: Medical computerized files of 5254 participants, who failed to achieve ≥ 5% weight reduction after an initial 6-month period, were retrospectively analyzed to identify predictors associated with late successful weight reduction and maintenance (≥ 5% during the first and second years, respectively). Over 40 independent variables were analyzed. The main outcome was the percentage of weight change. RESULTS: Significant predictors of late success in weight reduction were as follows: more visits to a dietitian, higher baseline BMI, and any initial weight reduction (0-5%) (OR=3.69, compared with participants who initially gained weight). The use of insulin (OR=0.499) and the presence of hypertension (OR=0.75) were significantly correlated with failure to reduce weight. Predictors of late maintenance were as follows: more visits to a dietitian, higher baseline BMI, any initial weight reduction, a younger age, not being treated with insulin (OR=0.316), and more weighings (OR=1.68). CONCLUSIONS: A substantial sub-group of obese and overweight patients was able to reduce their weight at a slower rate than the defined successful time of 6 months. Significant specific predictors were identified. Diabetic and hypertensive patients are at a significantly higher risk of failure to reduce and maintain weight. Using regression models, we calculated the probability of successful late weight reduction. This calculation could serve as a clinical tool for a professional team.

The C allele in NOS3 -786 T/C polymorphism is associated with elite soccer player's status.

The NOS3-786 T/C polymorphism (rs2070744) is a candidate to explain individual variations in sports related phenotypes. We determined the genotype and allele frequency of NOS3-786 T/C in a group of 60 male professional elite soccer players. Their results were compared with those of 100 world-class endurance athletes, 53 elite power athletes, and 100 sedentary, healthy men (controls) of the same Caucasian (Spanish) origin. There were significant differences in genotype frequencies between soccer players, controls, endurance and power elite athletes (all P ≤ 0.02). These results were confirmed when we analysed allelic frequencies (all P<0.01). The likelihood of having the C allele was higher in soccer players compared with (i) controls [odds ratio (OR), 2.165, 95% confidence interval (CI): 1.362-3.441], (ii) endurance athletes (OR: 1.879, 95%CI: 1.184-2.984), and (iii) power athletes (OR: 4.032, 95%CI: 2.307-7.047). In conclusion, the -786C allele is associated with the status of being an elite soccer player, compared with non-athletic controls and also with elite endurance and power athletes. More research is needed in other groups of elite soccer players in order to replicate the results of the present study.

Docosahexaenoic acid significantly stimulates immediate early response genes and neurite outgrowth.

Docosahexaenoic acid (22:6n - 3, DHA) is known to enhance neurogenesis. However, the immediate-early effect of DHA on neurogenesis is not fully elucidated. We studied the effect of DHA supplementation (10 and 30 microM) on morphological and molecular changes at different time points of nerve growth factor (NGF, 50 ng/ml)-induced differentiation of PC12 (pheochromocytoma) cells. Cells were analyzed throughout the differentiation process (2 h, 1, 2, 3, 4, and 10 days), for neurite outgrowth (light microscopy and computer image analysis), and for mRNA levels of the immediate molecular differentiation markers Egr1, Egr3, PC3 and PC4 (quantitative real-time PCR). DHA induced significant accelerated neurite outgrowth beginning as early as 2 h post-DHA supplementation and throughout differentiation. Transcripts of the neurogenesis immediate early biomarkers Egr3 and PC3 were significantly (P < 0.05) elevated following DHA supplementation within 0.5 and 1 h post-supplementation (respectively). In conclusion, we show that DHA significantly stimulates immediate-early neurogenesis events, as is evident by both morphological and molecular markers.

Palmitate induced lipoapoptosis of exocrine pancreas AR42J cells.

Chronic surplus of dietary consumption, typical to obesity, results in overflow of fat to non-adipose tissues. Intracellular accumulation of fat in non-adipose tissues is associated with cellular dysfunction and cell death and ultimately contributes to the pathogenesis of chronic diseases. The influence of fat overflow on the exocrine pancreas is not known. The purpose of this research was to study the lipotoxic and lipoapoptotic effect of prolonged (72 h) long chain saturated palmitic fatty acid (0.1 mM) on the survival of exocrine pancreas AR42J cells. We demonstrate that chronic exposure of AR42J cells to palmitic acid results in significant increase in triglycerides accumulation (up to 25% of cells area), compared to untreated cultures. Lipid accumulation prompted a typical apoptotic process, demonstrated by both DNA fragmentation and condensed chromatin appearance (DAPI staining). Quantitative real-time PCR studies demonstrated that prolonged palmitic acid supplementation induced down-regulation of the anti-apoptotic Bcl2 mRNA levels (22%) and up-regulation of the pro-apoptotic Bax mRNA levels (300%), leading to disruption of the pro/anti apoptotic balance (Bax/Bcl2=3). No major change was detected in iNOS mRNA expression. In conclusion, prolonged exposure to saturated palmitic acid induces lipoapoptosis in exocrine pancreatic AR42J cells, through disturbance of the Bax/Bcl-2 balance.

[Alternative activation of antigen-presenting cells: concepts and clinical relevance]. / Alternative Aktivierung antigenpräsentierender Zellen. Konzept und klinische Bedeutung.

Lymphocytes do not just act as immunological effector cells, but also play an important role in the regulation of the immune response. They are able to induce or suppress inflammatory reactions and this balancing function is reflected in the well-known Th1/Th2 concept. Lymphocytes depend on antigen presenting cells (APC) for induction of differentiation and specific activation mediated by antigen capture, processing and presentation. Thus, APC represent a link between innate and acquired immunity. In parallel to the Th1/Th2 dichotomy, APC may be subdivided into (a) pro-inflammatory, classically activated APC such as mature dendritic cells and IFN-gamma-activated effector macrophages, and (b) into anti-inflammatory, alternatively activated APC such as IL-10-activated immature dendritic cells and IL-4-induced suppressor macrophages. Alternatively activated APC may mediate induction and maintenance of tolerance towards allergens and environmental substances, control the course of inflammatory reactions, and participate in healing processes by enhancing angiogenesis. Malignant tumors and certain infectious agents may misuse alternatively activated APC for their purposes, thereby requiring counter-action by Th1 lymphocytes and classically activated APC. The concept of alternative activation thus confirms the important role of APC in maintaining the balance between induction and suppression of both inflammation and immunity and it opens new perspectives for the development of specific immunotherapeutic approaches.

Beyond inflammation: tolerance, immunotherapy and more.

Inflammatory skin diseases such as allergic contact dermatitis, atopic dermatitis, and psoriasis are together the most frequent dermatoses and are of great medical and economic significance. Despite impressive progress in recent years, the immune pathogenesis of these diseases is not yet fully understood. In particular, it remains an open question which anti-inflammatory mechanisms can be activated to prevent development of such abnormal immune reactions in the still healthy organism, and how these anti-inflammatory processes may be enhanced and instrumentalized for treatment of these disease states.

[Pseudo-scabies transmitted by red fox]. / Pseudoskabies durch Rotfuchs übertragen.

Pseudoscabies, i.e. infestation of human skin with animal mites may occasionally occur and should be considered in the differential diagnosis of pruritic and papular skin disease. We report here on a 52-year-old woman with pseudoscabies or canine scabies (Sarcoptes scabiei var. canis), transmitted by indirect contact with a red fox in the urban area of Berlin. Red foxes may live in unhabited areas of metropolitan large cities, i.e. in garages, car wrecks and cellars. Full remission of the prolonged and pruritic rush was seen after topical administration of lindane together with systemic corticosteroids.

Alternative versus classical activation of macrophages.

In parallel to the Th1/Th2 paradigm, antigen-presenting cells (APC) are divided into classically activated APC (dendritic cells/effector macrophages) and alternatively activated APC (IL-4-induced, alternatively activated macrophages/IL-10-induced, immature dendritic cells). Alternatively activated APC share a special molecular repertoire including receptors of innate immunity with broad specificity for foreign antigen and anti-inflammatory cytokines such as IL-1Ra and alternative macrophage activation-associated CC-chemokine-1. Alternatively activated APC mediated tolerance and downregulated inflammation. Abuse of alternatively activated APC in support of infectious susceptibility or tumor immune escape is counteracted by the classical pathway. Thus, classically and alternatively activated APC secure the balance between proinflammatory and anti-inflammatory immune reactions.

Synthesis of isopropyl-1-thio-beta-D-glucopyranoside (IPTGlc), an inducer of Aspergillus niger B1 beta-glucosidase production.

Production of beta-glucosidase in Aspergillus niger B1 is subjected to catabolic repression by glucose. Aspergillus niger B1 grown on bran as a carbon source secreted beta-glucosidase. The maximum level of the enzyme was reached after 7 d of fermentation. Addition of 1% glucose to the medium suppressed beta-glucosidase production to undetectable levels. In this study, the organic synthesis of a potential inducer of beta-glucosidase production by A. niger B1's reported. Isopropyl-1-thio-beta-D-glucopyranoside (IPTGlc) was synthesized using a two-step organic synthesis protocol. The H-NMR data agreed with those reported previously for the galactoside analog. When IPTGlc was added 24 h after inoculation at a final concentration of 0.4 mM, similar levels of beta-glucosidase were reached 3 to 4 d earlier as compared to fermentation without IPTGlc induction. In practice, this may translate to a more efficient method of producing beta-glucosidase from this fungus.