A Multicenter Cohort Study Evaluating the Teratogenic Effects of Isotretinoin on Neonates.

(1) Background: Isotretinoin (ISO) is a systemic retinoid known for its teratogenic effects on embryos and fetuses. The aim of this study was to compare the pregnancy outcomes of women who were exposed to isotretinoin with those of women without such exposure from a teratogenic point of view. (2) Methods: A total of 1459 female patients from three clinical hospitals in Poland and Romania, segregated into two groups depending on their ISO exposure, were evaluated between January and December 2019. Medical records were screened to identify the pregnancy outcomes and congenital malformation rates. (3) Results: The congenital malformation rate for the exposed group was 1.2% (four cases), and no specific signs of Accutane embryopathy were identified. Women from the unexposed group were more likely to deliver preterm and through cesarean deliveries and had a higher rate of newborn congenital malformations as compared to women from the exposed group. (4) Conclusions: Even though we could not find a significant association between ISO exposure and teratogenic effects in newborns, effective contraceptive measures are key to preventing unfavorable pregnancy outcomes.

The use of isotretinoin in acne therapy in early childhood and its effect on the occurrence of acne symptoms later in life. Eight-year follow-up.

Introduction: Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous follicles that affects patients of all ages. Aim: Use of isotretinoin in the early stages of the disease to prevent subsequent lesions of acne, including prolonged treatment and acne scars at a later age. Material and methods: A retrospective, comparative study was carried between January 2010 and November 2018. The study population consisted of 90 children aged 9-18 years with acne. During treatment by isotretinoin the clinical evaluation was done every month. Patients were divided into three groups according to age. One of the qualification criteria was follow-up visits. Results: A total of 90 children (67.8% females; mean age: 13.5 years) were enrolled. In group A (30 individuals - aged 9-11) and B (30 individuals - aged 12-13), treatment was terminated 2 months after clinical improvement (mean: 3 months). In control group C (30 individuals - aged 14-18), treatment was carried out using average cumulative dose 135 mg/kg bw/day. All groups showed up for follow-up. after 1 to 8 years. In groups A and B, 13 people underwent a second acne treatment; in 3.33% oral isotretinoin was used, in 18.33% topical treatment. In group C, 30 (100%) individuals underwent a second acne treatment; in 20% oral isotretinoin was used, and 80% required a topical treatment. Acne scars and post acne hyperpigmentation have been documented in 73.33% in group C. Conclusions: Early, reasonable and short-term use of isotretinoin can reduce the incidence of acne in the future and reduce the occurrence of secondary acne symptoms.

4C Mortality Score correlates with in-hospital functional outcome after COVID-19-associated ischaemic stroke.

AIM OF THE STUDY: The 4C Mortality Score was created to predict mortality in hospitalised patients with COVID-19 and has to date been evaluated only in respiratory system disorders. The aim of this study was to investigate its application in patients with COVID-19-associated acute ischaemic stroke (AIS). CLINICAL RATIONALE FOR STUDY: COVID-19 is a risk factor for AIS. COVID-19-associated AIS results in higher mortality and worse functional outcome. Predictors of functional outcome in COVID-19-associated AIS are required. MATERIALS AND METHODS: This was a retrospective observational study of patients with AIS hospitalised in seven neurological wards in Malopolska Voivodship (Poland) between August and December 2020. We gathered data concerning the patients' age, sex, presence of cardiovascular risk factors, type of treatment received, and the presence of stroke-associated infections (including pneumonia, urinary tract infection and infection of unknown source). We calculated 4C Mortality Score at stroke onset, and investigated whether there was a correlation with neurological deficit measured using the National Health Institute Stroke Scale (NIHSS) and functional outcome assessed using the modified Rankin Scale (mRS) at discharge. RESULTS: The study included 52 patients with COVID-19-associated AIS. The 4C Mortality Score at stroke onset correlated with mRS (rs = 0.565, p < 0.01) at discharge. There was also a statistically significant difference in the mean 4C Mortality Score between patients who died and patients who survived the stroke (13.08 ± 2.71 vs. 9.85 ± 3.47, p = 0.04). CONCLUSIONS AND CLINICAL IMPLICATIONS: 4C Mortality Score predicts functional outcome at discharge in COVID-19-associated AIS patients.

Biotin-Containing Third Generation Glucoheptoamidated Polyamidoamine Dendrimer for 5-Aminolevulinic Acid Delivery System.

Polyamidoamine PAMAM dendrimer generation 3 (G3) was modified by attachment of biotin via amide bond and glucoheptoamidated by addition of α-D-glucoheptono-1,4-lacton to obtain a series of conjugates with a variable number of biotin residues. The composition of conjugates was determined by detailed 1-D and 2-D NMR spectroscopy to reveal the number of biotin residues, which were 1, 2, 4, 6, or 8, while the number of glucoheptoamide residues substituted most of the remaining primary amine groups of PAMAM G3. The conjugates were then used as host molecules to encapsulate the 5-aminolevulinic acid. The solubility of 5-aminolevulinic acid increased twice in the presence of the 5-mM guest in water. The interaction between host and guest was accompanied by deprotonation of the carboxylic group of 5-aminolevulinic acid and proton transfer into internal ternary nitrogen atoms of the guest as evidenced by a characteristic chemical shift of resonances in the 1H NMR spectrum of associates. The guest molecules were most likely encapsulated inside inner shell voids of the host. The number of guest molecules depended on the number of biotin residues of the host, which was 15 for non-biotin-containing glucoheptoamidated G3 down to 6 for glucoheptoamidated G3 with 8 biotin residues on the host surface. The encapsulates were not cytotoxic against Caco-2 cells up to 200-µM concentration in the dark. All encapsulates were able to deliver 5-aminolevulinic acid to cells but aqueous encapsulates were more active in this regard. Simultaneously, the reactive oxygen species were detected by staining with H2DCFDA in Caco-2 cells incubated with encapsulates. The amount of PpIX was sufficient for induction of reactive oxygen species upon 30-s illumination with a 655-nm laser beam.

Impact of percutaneous patent foramen ovale closure on migraine headaches in patients with history of ischemic neurological events.

INTRODUCTION: Observational studies have shown that migraine has been associated with patent foramen ovale (PFO). Whilst studies investigating PFO closure for the treatment of migraine have been neutral, there is some evidence that symptoms of migraine may improve if the PFO was closed after ischemic stroke. AIM: To establish whether closure of PFO in patients with stroke or transient ischemic attack (TIA) is associated with reduction in the severity of co-existent migraine headaches. MATERIAL AND METHODS: Patients with ischemic stroke or TIA, PFO suitable for percutaneous closure and migraine, were given migraine severity questionnaires prior to PFO closure. These were followed up at 6 and 12 months after closure with the same questionnaire. The primary endpoint was change in migraine severity using the Migraine Severity Scale (MIGSEV). Migraine episode frequency, disability (using the MIDAS scale), and pain intensity were also assessed. RESULTS: Sixty-two patients were included in the analysis. MIGSEV scores reduced from 7 (7-8) at baseline to 4 (3.25-6) at 6-month follow-up, and 3 (0-4) at 12-month follow-up (p < 0.001). Other measures of migraine headache were also improved at both 6- and 12-month follow-up. Twenty-four (38%) patients were rendered migraine free at 12 months. CONCLUSIONS: PFO closure for stroke or TIA prevention in patients with migraine was associated with a reduction in markers of migraine headache severity.

Adverse effects of isotretinoin: A large, retrospective review.

Acne is a very common and disfiguring disease that affects mostly adolescents and, to some extent, adults. The objective of our study was to estimate the adverse effects after isotretinoin by treatment of 3,525 patients due to acne vulgaris in a 5-year observation. Retrospective, comparative study was carried out in Poland and Romania from January 2012 to August 2016. Inclusion criteria into this study were moderate, severe, and nodulocystic inflammatory acne vulgaris. Exclusion criteria were mild acne, pregnant, and lactating women. Statistical analysis was carried out using T test and Chi square. All patients were treated with oral isotretinoin. Patient age ranged from 13-35 years. Dry lips was the most commonly reported adverse effect, affecting 100% of users, followed by xerosis (94.97%) and facial erythema (66.21%). Of all adverse effects, psychiatric symptoms accounted for 25.16%; eye lesions accounted for 8.96%. In lab investigations an increase in the level of total cholesterol and serum triglycerides was observed. This study documents the adverse effect profile of isotretinoin in a large number of patients collected over a period of 4 years. Side effects were mild and well tolerated and did not necessitate stopping the treatment. However, it is important to educate patients about this potential consequence.

STABILITY OF SOLUTIONS OF 2,3-DIPHENYLCYCLOPROPENONE IN VARIOUS SOLVENTS. A NOVEL FORMULA - DIPHENYLCYCLOPROPENONE IN ISOPROPANOL MAY BE USEFUL IN TOPICAL THERAPY OF PATIENTS WITH ALOPECIA AREATA.

The aim of this study was to evaluate the chemical stability of diphenylcyclopropenone (DCP) in var- ious solvents. DCP is being used in topical therapy in patients with alopecia areata (AA). The solvents for DCP used so far were acetone, ethanol and propylene glycol. DCP is supposed to be an immune-modulating thera- peutic agent, however the studies on it's pharmacokinetics including chemical stability are lacking. In a pres- ent study, DCP was dissolved in acetone (A), ethanol (E), propylene glycol (PG) and isopropanol (I). Solutions at two concentrations: 0.1 and 3.0% were prepared in each of these solvents. Then, the solutions were divided into two parts - one'of which was stored at room temperature and the other in a refrigerator (at about 4°C) with- out the access of light. In determined time intervals the solutions were analyzed and the content of DCP and it's main decomposition product DPA was assessed. The stability of solutions of DCP with all the solvents kept in a refrigerator (at about 4°C) without light was maintained, the decomposition rate after 60 days was negligible. In contrary, DCP solutions kept at room temperature after 60 days decomposed visibly and in different rates according to a solvent (PG > I > E > A). The most surprising finding was that DCP solutions in acetone, which was supposed to be a good solvent for the purpose of AA treatment, decomposed completely (100%) after just 45 days at room temperature. The most stable solutions at room temperature turned out to be the ones in propy- lene glycol and isopropanol. Results suggest: 1. the preferable storage condition for all DCP solutions is at a temperature of about 4°C without the access of light; 2. there is a limited benefit from'using acetone as a DCP solvent; 3. the novel solvent for DCP - isopropanol, showed good stability in both temperatures and has favor- able cosmetic qualities. In conclusion, authors suggest to make further investigations on DCP in isopropanol solutions in clinical studies regarding treatment of AA.

Possible advantage of imiquimod and diphenylcyclopropenone combined treatment versus diphenylcyclopropenone alone: An observational study of nonresponder patients with alopecia areata.

The topical contact sensitiser diphenylcyclopropenone (DCP) remains one of the most effective treatment modalities for alopecia areata (AA). However, some patients (nonresponders) do not respond to this treatment because they do not have an allergic reaction to DCP. The aim of this study was to investigate the potential role of imiquimod in inducing an allergic reaction to DCP in nonresponders. In all, 20 nonresponders were recruited from a group of DCP-treated AA patients. Of these patients, 10 were treated with DCP and topical imiquimod and 10 were treated with DCP alone. A significantly better therapeutic outcome was measured in the DCP plus imiquimod group than in the group treated with DCP alone. The potential mechanism of imiquimod may involve the role of interleukin-12, as previously suggested in an animal model. These findings suggest that imiquimod may have the potential to improve prognosis in nonresponder AA patients treated with DCP.

STUDIES ON STABILITY OF 2,3-DIPHENYLCYCLOPROPENONE IN CONTACT WITH WATER AND AQUEOUS NaCI SOLUTIONS. CONCLUSIONS FOR PURPOSE OF TOPICAL THERAPY OF PATIENTS WITH ALOPECIA AREATA.

Diphenylcyclopropenone (DCP) is a topically administered agent used for more than three decades for treatment of alopecia areata (AA). Moreover, numerous recent studies show it's efficiency in treatment of cutaneous metastatic melanoma. Despite being a potentially useful drug still very little is known about the pharmacokinetics of DCP. The authors investigated the stability of DCP solutions in propylene glycol with the addi- tion of 0.9% aquous solution of natrium chloride (0.9% NaCI) or with water. DCP was prepared in two concentrations: 0.1% and 3%. It's stability was then measured with different proportions of 0.9% NaCI or water added and in different temperatures. Contrary to common opinion that DCP solutions are extremely unstable, authors have found them to be relatively stable. DCP solutions with the addition of equal quantity of 0.9% NaCl decomposed slowly at the temperature of 37C but after 70 h all solutions still contained more than 80% of initial DCP. Solutions of DCP with the addition of 1% of water at the temperature of 4'C are in the present study stable, containing more than 98% of initial DCP after 20 days. Authors discuss the results in spite of possible metabolism of DCP on the surface of human skin during topical immunotherapy.

The evaluation of the biomedical effectiveness of poly(amido)amine dendrimers generation 4.0 as a drug and as drug carriers: a systematic review and meta-analysis.

The purpose of this study was to investigate the evaluation of the biomedical effectiveness of poly(amido)amine dendrimers generation 4.0 (PAMAM G4) as a drug and as drug carriers by a systematic review of literature and meta-analysis. The results obtained from meta-analysis concluded that drug therapy reduces the change of parameters in relation to the control. The impact of the drug administered to change the test parameters are dependent on the type of tissue. PAMAM G4 may be effective in vitro and in vivo as a drug and drug carriers and may have appropriate applications in various fields of medicine. PAMAM G4 dendrimers hold promises for nanomedicine.

Dietary intakes of iron and zinc assessed in a selected group of the elderly: are they adequate?

BACKGROUND: Many studies demonstrate that the elderly consume a nutritionally inadequate diet that includes deficiencies in macro- and microelements; iron and zinc being significant examples of the former. OBJECTIVES: To assess the adequacy of dietary iron and zinc intakes in the elderly. MATERIAL AND METHODS: The study was conducted on n = 102 elderly persons, participating in the PolSenior Project, aged over 65, of which 44 were women and 58 men. Consumption data were collected by using 3 day dietary record from which a usual intakes of energy, macroelements (iron and zinc) were calculated. The Estimated Average Requirement (EAR) cut point and z-scores methods were used to determine probabilities of whether iron and zinc uptake was adequate per subject. RESULTS: By using the EAR cut-point method it was stated that iron intake was inadequate for 5% of respondents, whereas 44% showed deficits in zinc (34% women and 52% men). The z-scores demonstrated that 3% of subjects had high probabilities of deficiencies in iron and 52% in zinc. Indeed, very high zinc deficiencies were observed in 20% of cases. CONCLUSIONS: The insufficient energy intake observed among respondents contributes to a high risk of zinc deficiency necessary to ensure health in the elderly. In most cases, the low risk of iron deficiency shows that there is no need to increase this nutrient uptake in the examined group of elderly. The study highlights the need for educating the elderly, especially focused on improving zinc intake without changing iron intake. It can be done through appropriate dietary choices so as to include products such as dairy products, wheat bran, pumpkin and sunflower seeds, beans, lentils and nuts.

Transdermal delivery of 8-methoxypsoralene mediated by polyamidoamine dendrimer G2.5 and G3.5--in vitro and in vivo study.

In this work, we have focused on 8-methoxypsoralene (8-MOP) complexed with G2.5 and G3.5 poly(amido amine) (PAMAM) dendrimers. The purpose of this study was to investigate the efficacy of half-generation G2.5 and G3.5 PAMAM dendrimers conjugated with 8-MOP for delivery of 8-MOP in vitro study through polivinyldifluoride membrane (PVDE) and prepared pig ear skin (PES) using Franz diffusion and in vivo study through the skin of experimental animals (hairless rat skin). The tissue concentration of 8-MOP in hairless rat skin was analyzed by high performance liquid chromatography (HPLC) after 1 and 2 h. Detailed distribution of 8-MOP in skin layers and cellular structures were analyzed using laser scanning microscopy (CLSM). In vitro and in vivo studies showed that half-generation G2.5 and G3.5 PAMAM dendrimers are able to facilitate transdermal delivery of 8-MOP. G2.5 PAMAM dendrimer appeared to be more effective 8-MOP penetration enhancer than G3.5 PAMAM dendrimer, but in vivo the differences are not statistically significant. The concept of using G2.5 and G3.5 PAMAM dendrimers as carriers seems to be a promising method for the delivery of 8-MOP for PUVA (psoralen-UV-A) therapy.

[Periprocedural and late complications after percutaneous closure of patent foramen ovale: a single centre experience].

BACKGROUND: Patent foramen ovale (PFO) is a potential risk factor for ischaemic stroke in young individuals. An interventional method of secondary stroke prevention in PFO patients is its percutaneous closure. AIM: To assess safety and effectiveness (i.e. lack of residual shunt) of percutaneous PFO closure in patients with history of cryptogenic cerebrovascular event. METHODS: 149 patients (56 men/93 women), aged 39 ± 12 years, underwent percutaneous PFO closure. The implantation was performed under local anaesthesia, guided by trans-oesophageal echocardiography (TEE) and fluoroscopy. Follow-up trans-thoracic echocardiography (TTE) was performed at 1 month and follow-up TEE at 6-months. In cases of residual shunt, additional TEE was performed after ensuing 6 months. RESULTS: Effective PFO closure (no residual shunt) was achieved in 91.3% patients at 6 months and 95.3% patients at 12 months. In 2 patients transient atrial fibrillation was observed during the procedure. In 2 patients, a puncture site haematoma developed and in 1 patient superficial thrombophlebitis was noted. In 1 patient a small pericardial effusion was observed, which resolved at day 3 post-procedurally, after administration of non-steroidal anti-inflammatory drugs. CONCLUSIONS: Percutaneous PFO closure seems to be a safe procedure when performed in a centre with adequate expertise with regard to these procedures.

Percutaneous closure of the left atrial appendage to prevent ischaemic stroke in patients with atrial fibrillation who require but have contraindications to oral anticoagulation.

Atrial fibrillation (AF) is associated with a five-fold increased risk for stroke due to cardioembolic events. Most strokes in patients with AF arise from thrombus formation in the left atrial appendage (LAA). Oral anticoagulation is a standard treatment of AF patients with high risk of stroke. However, the main drawbacks of oral anticoagulation are high risk of major bleeding and imperfect effectiveness dependent on a very narrow therapeutic range. In this article, based on two case reports, we describe a method of percutaneous closure of the LAA. We discuss indications, describe the procedure and mention possible complications. LAA closure seems to be a promising tool to prevent AF-related strokes in a selected group of patients.

Effect of polyamidoamine dendrimer G3 and G4 on skin permeation of 8-methoxypsoralene--in vivo study.

In the present study we have assessed the ability of (PAMAM) dendrimers G3 and G4 to facilitate transdermal delivery of 8-methoxypsoralen (8-MOP) in vivo. In vitro study using Franz diffusion cell revealed an enhanced transdermal flux for 8-MOP in complex with G3 and G4 dendrimer in relation to standard 8-MOP solution. In present study in vivo skin permeation potential of 8-MOP complex with G3 and G4 PAMAM dendrimer was assessed using confocal laser scanning microscopy (CLSM), which revealed an enhanced permeation of the 8-MOP to the deeper layers of the skin and significantly higher concentration in comparison with standard 8-MOP solution. Skin tissue 8-MOP concentration, evaluated by HPLC indicates that G3 and G4 PAMAM application significantly increase 8-MOP skin deposition in comparison with standard 8-MOP solutions after 1 and 2h. G4 appeared to be a more effective 8-MOP penetration enhancer than G3 PAMAM. Our results suggest the feasibility of G3 and G4 PAMAM dendrimers for transdermal delivery of 8-MOP resulting in better skin permeation and higher concentration of 8-MOP in epidermis and dermis of the drug that could help to improve effectiveness and safety of PUVA therapy.

PAMAM dendrimers as solubilizers and hosts for 8-methoxypsoralene enabling transdermal diffusion of the guest.

PAMAM dendrimers form host-guest complexes with 8-methoxypsoralene (8-MOP) - the photosensitizer for PUVA therapy. The stoichiometry of complexes was studied by (1)H NMR spectroscopy in solution and by differential scanning calorimetry in neat mixtures containing 8-MOP and dendrimers of generations G2.5, G3, G3.5, and G4. The dendrimers showed solubilization effect for 8-MOP resulting in increase of 8-MOP concentration in methanol up to 15 molecules of 8-MOP per G2.5 and G3 and 30 molecules of 8-MOP per G3.5, and G4. Isolation of oily host-guest complexes containing 3 or 7 molecules of 8-MOP per G3 and G4, respectively corroborate well with DSC results; glass transition temperature of neat host-guest complexes increases with number of host molecules in comparison with G3 or G4, until the capacity of host is exceeded. The oily host-guest complexes of stoichiometry 3:1 and 7:1 of 8-MOP to G3 and G4, respectively are well soluble in water. The 3:1 host-guest complexes diffused slowly through polyvinyldifluoride and pig ear skin membranes, when released from o/w emulsion. The host-guest complex 8-MOP-G3 was proposed as convenient formulation for psoralene skin administration in PUVA therapy.

Fluvastatin increases tyrosinase synthesis induced by UVB irradiation of B16F10 melanoma cells.

Statins are widely used to lower plasma concentrations of lipids, e.g. cholesterol. One of the main effects of statin treatment is inhibition of hydroxymethyl glutaryl-coenzyme A reductase. The role of fluvastatin, a frequently used statin, was examined in potential modulation of tyrosinase (key enzyme of melanogenesis) synthesis. Levels of tyrosinase mRNA induced by UVB irradiation of B16F10 melanoma cell line were measured by real time PCR. Fluvastatin increases tyrosinase mRNA production induced by UVB irradiation in B16F10 melanoma cell line. Fluvastatin treatment may potentially influence melanin synthesis and protection against UV irradiation.

[Photoaging of a skin]. / Fotostarzenie sie skóry.

Photoaging is a skin aging caused by long-term exposure to the ultraviolet radiations of the sun. Ultraviolet activates activating protein-1 and generate reactive oxygen species which play a substantial role in collagen degradation. Clinically, photoaged skin appears as a coarse with deep wrinkles. Presently there are available several agents to reverse the photodamage. There is conclusive evidence that synthetic vitamin A derivatives are the most effective in the treatment of photoaging. Erythema and scaling may be experienced initially.

[The role of integrins in the physiologic and pathogenic processes]. / Udzial integryn w procesach fizjo- i patologicznych.

Cell adhesion molecules (CAM) are a numerous, diverse group of cell surface proteins, which are both receptors and ligands for receptors. Their functions include adhesion, recognition, cell-cell interaction, and communication between mediate cells and extracellular matrix. The following groups of CAM can be distinguished: seletins, integrins, cadherins and other isoforms, including CD 44. Integrins are heterodimers formed from the alpha and beta chains. The a subclass is responsible for a specific bond with ligands. It defines the specificity of integrins. The 8 chain participates in the integration with cytoskeleton ptoteins. It determines the functions of the integrin receptor. The best recognized integrins include: integrin beta1, beta2 and beta3. The expression and activity of integrins have been found to be affected by a variety of factors being either activators or inhibitors. Adhesion molecules (including integrins) play a significant role in both physiological processes (embryogenesis, organogenesis, the normal growth and tissue development) and pathogenic ones. In the latter case, they are particularly involved in inflammatory, allergic and neoplastic diseases. The role of integrins is also emphasized in organ response to trauma and in skin lesion redevelopment. The knowlegde of the integrin molecular basis and that of other adhesion molecules can contribute significantly to the creation of new diagnostic and therapeutic perspectives. An adequate modification of cellular adhesion constitutes a promising way of the pathogenic processes control.