European expert consensus statement on the systemic treatment of alopecia areata.

Alopecia areata is an autoimmune form of non-scarring hair loss. It is usually characterized by limited areas of hair loss. However, the disease may progress to complete scalp and body hair loss (alopecia totalis, alopecia universalis). In patients with alopecia areata hair loss significantly impacts the quality of life. Children and adolescents with alopecia areata often experience bullying, including physical aggression. The disease severity evaluation tools used in clinical practice are: the Severity of Alopecia Tool (SALT) score and the Alopecia Areata Scale (AAS). A SALT score equal to or greater than 20 constitutes a commonly accepted indication for systemic therapy in alopecia areata. When using the AAS, moderate to severe alopecia areata should be considered a medical indication for systemic treatment. Currently, the only two EMA-approved medications for alopecia areata are baricitinib (JAK 1/2 inhibitor) for adults and ritlecitinib (JAK 3/TEC inhibitor) for individuals aged 12 and older. Both are EMA-approved for patients with severe alopecia areata. Other systemic medications used off-label in alopecia areata include glucocorticosteroids, cyclosporine, methotrexate and azathioprine. Oral minoxidil is considered an adjuvant therapy with limited data confirming its possible efficacy. This consensus statement is to outline a systemic treatment algorithm for alopecia areata, indications for systemic treatment, available therapeutic options, their efficacy and safety, as well as the duration of the therapy.

Therapeutic management in paediatric alopecia areata: A systematic review.

Alopecia areata is the third most common cause of dermatology consultations in children but the treatment of paediatric alopecia areata remains challenging. A systematic review of the literature about the treatment of alopecia areata in children (≤18 years old) was performed on 11 May 2020 by searching the PubMed, Scopus and EBSCO databases. The terms used for the search were: 'alopecia areata', 'alopecia totalis' or 'alopecia universalis' combined with 'paediatric', 'children' or 'childhood'. A total of 89 articles were included in final evaluation. The most commonly assessed treatment options in paediatric alopecia areata were topical immunotherapy (response rate in monotherapy: 54%; 187/345) intralesional glucocorticosteroids (75%; 211/280), systemic glucocorticosteroids (73%; 102/140), and anthralin (42%; 31/74). Topical glucocorticosteroids (81%; 35/43), systemic Janus kinase (JAK) inhibitors (90%; 27/30), topical calcineurin inhibitors (42%; 8/19), topical JAK inhibitors (65%; 11/17), PUVA therapy (56%; 9/16) and 308-nm excimer laser (77%; 10/13) were also evaluated. Additionally, evaluation in smaller numbers of paediatric patients included methotrexate (100%; 10/10), topical minoxidil (44%; 4/9) and cyclosporine (83%; 5/6). There were limited data considering children with alopecia areata treated with azathioprine, hydroxychloroquine, topical sildenafil, topical prostaglandin analogues, fractional carbon dioxide laser, leflunomide, mesalazine, apremilast, dupilumab, ustekinumab, efalizumab, botulinum toxin, and compound glycyrrhizin. On the basis of the limited data available glucocorticosteroids (systemic, intralesional or topical) and JAK inhibitors (systemic or topical) may be considered the best documented and most effective treatment options in alopecia areata in children. There are no sufficient paediatric data to compare treatment safety and relapse rates in these therapeutic modalities.

Claudin-3 - a new intestinal integrity marker in patients with psoriasis: association with disease severity.

BACKGROUND: Gut dysbiosis and increased intestinal permeability play a significant role in the pathogenesis of psoriasis and its comorbidities. Claudin-3 is a key component of tight junctions, which may serve as marker of gut barrier integrity. OBJECTIVES: The aim of the study was to investigate circulating plasma claudin-3 in patients with psoriasis and to evaluate clinical and metabolic factors, which determine its concentration. METHODS: This cross-sectional study included 60 patients with psoriasis (39 men and 21 women, mean age: 45.6 ± 12.1 years) and 30 healthy controls (18 men and 12 women, mean age: 46.3 ± 15.5 years) age, sex and body mass index-matched. Plasma claudin-3 concentration was measured using an enzyme-linked immunosorbent assay. RESULTS: Plasma claudin-3 concentration was significantly higher in patients with psoriasis in comparison with healthy control [median (interquartile range), 50.7 ng/mL (47.3-54.2) vs. 43.3 ng/mL (42.3-44.2), P < 0.001]. Patients who achieved ΔPASI90 response after 16 weeks of treatment showed tendency to decrease in circulating claudin-3 plasma concentration. Positive correlations between claudin-3 concentration and the PASI score (r = 0.828; P < 0.001) as well as claudin-3 and neutrophil-to-lymphocyte ratio (r = 0.847; P < 0.001) were found. A multivariable linear regression analysis confirmed association of claudin-3 with the PASI score (P < 0.001), neutrophil-to-lymphocyte ratio (P < 0.01) and active smoking (P < 0.05). CONCLUSION: Claudin-3, a biomarker for gut permeability, is increased in psoriasis and correlates with disease severity and smoking. Further investigations are needed to determine whether reinforcing intestinal barrier may be a new therapeutic target in psoriasis.

The value of dermoscopy in diagnosing eyebrow loss in patients with alopecia areata and frontal fibrosing alopecia.

INTRODUCTION: Alopecia areata and frontal fibrosing alopecia are common causes of eyebrow loss (madarosis). OBJECTIVE: Assessment of trichoscopic markers of eyebrow loss in alopecia areata and frontal fibrosing alopecia. MATERIALS AND METHODS: The analysis included 50 patients with scalp alopecia areata with madarosis, 50 patients with scalp frontal fibrosing alopecia with madarosis and 50 healthy controls. In every case, trichoscopy of the eyebrow area was performed. RESULTS: Empty follicular and eccrine duct openings were observed in all patients and presented predominantly as yellow dots. Exclamation mark hairs were only detected in patients with alopecia areata (30%). Tapered hairs, broken hair, black dots and Pohl-Pinkus constrictions were observed in 14%, 36%, 26% and 4% of patients with alopecia areata, respectively, 4%, 16%, 2% and 0% of patients with frontal fibrosing alopecia, respectively, and they were not present in healthy controls. Dystrophic hairs and whitish areas were observed only in patients with frontal fibrosing alopecia (28% and 32%, respectively). Eyebrow regrowth in distinct directions was present in 32% of patients with frontal fibrosing alopecia, 8% of patients with alopecia areata and 4% of healthy controls. Diffuse erythema was detected in 60% of patients with alopecia areata and frontal fibrosing alopecia and 56% of healthy controls. Vellus hairs and upright regrowing hairs were observed in patients with alopecia areata (62% and 58%, respectively), frontal fibrosing alopecia (60% and 84%, respectively) and healthy controls (100% and 100%, respectively). CONCLUSION: Trichoscopy of the eyebrow area is useful in diagnosing patients with isolated eyebrow loss. The most characteristic trichoscopic features of eyebrow loss in alopecia areata include exclamation mark hairs, tapered hairs, broken hairs and black dots. Frontal fibrosing alopecia of the eyebrows is characterized by the presence of dystrophic hairs, white areas and eyebrow regrowth in distinct directions.

Reflectance confocal microscopy as a non-invasive diagnostic tool for Hailey-Hailey disease.

BACKGROUND/PURPOSE: Reflectance confocal microscopy (RCM) is a non-invasive method for high-resolution, in vivo imaging of the epidermis and upper dermis. The purpose of the study was to evaluate the potential usefulness of RCM as a non-invasive diagnostic tool for Hailey-Hailey disease (familial benign chronic pemphigus). METHODS: Four patients with Hailey-Hailey disease were examined by RCM. Subsequently, punch biopsies were taken to compare RCM images with corresponding histopathologic findings. RESULTS: On RCM images, the most sticking feature was acantholysis at the level of the granular and spinous layer, resembling a 'dilapidated brick wall'. We suggest the term 'dilapidated brick wall RCM sign' to describe this feature and to distinguish from the corresponding histopathology finding. Other RCM features included: epidermal disarray, intraepidermal clefts, inflammatory cells in the epidermis and in the superficial dermis. These RCM abnormalities correlated with analogous histopathology findings. CONCLUSION: Reflectance confocal microscopy is a promising non-invasive diagnostic tool for Hailey-Hailey disease. The method may also be considered useful for choosing the best site for biopsy, which may aid pathology evaluation and spare time needed to establish the diagnosis.

'Black dots' seen under trichoscopy are not specific for alopecia areata.

BACKGROUND: 'Black dots' are macrocomedo-like round structures localized to the follicular ostium, and are considered a specific trichoscopic feature of alopecia areata (AA). AIM: To characterize specific features of 'black dots', and assess their possible presence in common hair and scalp disorders. METHODS: In total, 107 patients with hair loss [30 with alopecia areata (AA), 37 with androgenetic alopecia (AGA), 17 with chronic telogen effluvium (TE), 23 with other hair and scalp diseases] and 93 healthy controls were examined, using a videodermoscope with 20-70 times magnification. RESULTS: There was a correlation between the black dots and the early acute phase of the various alopecia types with the presence of the black dots. Black dots were found in 11% (22/107) of patients with hair loss, including 53.3% (16/30) with AA; in 40% (2/5) of patients with severe chemotherapy-induced alopecia, and in 100% of patients with dissecting cellulitis of the scalp (n = 2), hypotrichosis simplex (n = 1), and congenital aplasia cutis (n = 1). No black dots were seen in patients with AGA or TE. CONCLUSIONS: Black dots are not specific for AA, and may be present in other hair and scalp diseases.

Fractal-like behaviour of the BCC/FCC phase separation in the iron-gold alloys.

Iron-gold alloys with compositions Fe(70)Au(30) and Fe(50)Au(50) were prepared by arc melting. The alloys were investigated by means of the high-resolution scanning electron microscopy (SEM-FEG) in the as-cast state and upon annealing in two steps, i.e. at 250 degrees C for 24 h and subsequently at 500 degrees C for 48 h. The alloys were composed of two phases, i.e. a BCC phase rich in iron and a FCC phase rich in gold. The single-phase regions have equivalent diameter of about 50 nm. SEM images show self-similar structure for the spatial distribution of the above phases on scales ranging from about 1 mm till about 100 nm. The roughness of the images has been used to estimate a fractal dimension of the phase mixture. For larger scales of the as-cast samples one finds fractal dimension of about 1.7 for Fe(70)Au(30) composition, i.e. very close to the dimension of typical diffusion limited aggregation (DLA) fractals. For annealed samples, dimension 1.1 was found.

Modifiable risk factors for erectile dysfunction: an assessment of the awareness of such factors in patients suffering from ischaemic heart disease.

Up to 40% of cases of erectile dysfunction (ED) originate from vascular disturbances associated with atherosclerotic disease, leading to the previously proven concomitance between ischaemic heart disease (IHD) and ED. The aim of this study was to evaluate patients' knowledge about modifiable risk factors for ED. The evaluated group of patients was composed of 502 male patients undergoing cardiac rehabilitation and receiving treatment for IHD. The patients' knowledge of risk factors for ED linked to IHD was assessed with an original survey. The presence of ED was assessed using an abridged version of the International Index of Erectile Function-5 questionnaire. Increase in leisure-time physical activity was estimated using a leaflet based on the Framingham questionnaire. In all, 189 participants were unable to name any modifiable ED risk factors, and only 31 patients knew all 6 of them. The most frequently mentioned ED risk factor was smoking, whereas the least frequently mentioned was sedentary lifestyle. Awareness of smoking as an ED risk factor was closely related to the patients' level of education, place of residence, smoking and underlying ED in the individual patient. The ability to classify diabetes as a risk factor for ED was significantly related to the patients' level of education, place of residence, and the prevalence of diabetes in the evaluated group of respondents. The same relations were observed regarding hyperlipidaemia. Awareness of the negative impact a sedentary lifestyle has on the erectile process was found to be closely related to the patients' age, as well as their level of education. The performed study demonstrates the poor knowledge of IHD patients about the modifiable risk factors for ED. The factor that patients are the least aware of is sedentary lifestyle, which, simultaneously, is the risk factor that most frequently affects the respondents.

High frequency ultrasonography: a complementary diagnostic method in evaluation of primary cutaneous melanoma.

AIM: The aim of our study was to assess the usefulness of high frequency ultrasonography in the diagnosis of melanoma. METHODS: We examined 84 patients with suspicious melanocytic skin lesions, including 19 cases of melanoma. In vivo high-resolution ultrasonography (30 MHz) was performed prior to excision. RESULTS: In ultrasound scans early melanomas presented as flat oval or fusiform shaped structures and were clearly demarcated, while advanced melanomas were characterized by a roundish shape with less distinct borders. The ultrasonographic thickness of in situ melanomas ranged from 0.02 to 0.85 mm. In the case of invasive tumors, the mean thickness evaluated by high frequency ultrasonography was 10.7% higher compared to the Breslow Score (1.44±0.8 mm and 1.3±0.88 mm, respectively). In all melanomas of Breslow Score of 1 mm or more ultrasound also indicated a Breslow Score of 1 mm or more. CONCLUSION: High frequency ultrasound examination has limited value in differential diagnosis of melanoma, but it gives a clear picture of the size and depth of the tumor. The method should be used as a complementary method (after dermoscopy and, where applicable, reflectance confocal microscopy) in preoperative evaluation of the tumor. In some cases of locally advanced melanoma, ultrasound examination may allow to reduce the number of surgical procedures and favor the decision of a one-time surgical treatment (removal of primary tumor and sentinel lymph node biopsy at the same time).

Changes in motor unit action potentials during the fatigue test.

The studies were performed on medial gastrocnemius motor units of the rat. Changes in amplitude, duration and latency of motor unit action potentials were monitored in the course of fatigue test in the three types of motor unites: FF (fast twitch, fatigable), FR (fast twitch, resistant), and S (slow twitch, resistant) motor unit. In a majority of the motor units the amplitude of action potential decreased. The most pronounced decrease took place in FF units, less pronounced one in FR units, while in S type motor units the decrease was insignificant. However, in a part of investigated motor units the amplitude of their action potential transiently increased at the beginning of the fatigue test and, then decreased or was maintained at the same level till the end of the fatigue test. In a few motor units, particularly the slow ones, no changes in action potential amplitude were observed. In the studied material, a decrease in action potential amplitude was on the average less pronounced than a decrease in tetanus tension in the course of the fatigue test. In a majority of studied motor units the duration of action potential was becoming prolonged, which was most pronounced in FF type motor units and least pronounced in S type ones. In few slow motor units the duration showed no alterations. Changes in action potential duration were much more marked than changes in their amplitude. The changes in action potential in fast motor units were less pronounced than changes in their tetanus tension, while in the slow motor units they resembled each other in intensity. Comparison of motor unit action potential changes with changes in their tetanic tension in the course of fatigue test demonstrated no clear-cut relationship between the two phenomena.

Ca2+ antagonists reveal a novel inhibitory effect of caerulein on guinea pig ileum.

The peptide caerulein (CK) is a potent muscle stimulant of guinea pig ileum and its effect is Ca2+-dependent. Ca2+ antagonist drugs administered to the organ perfusion solution diminished the twitches of the electrically stimulated ileum. Subsequent administration of caerulein reinforced this inhibition of contraction and acetylcholine (ACh) release by the ileum. This effect was antagonized by cholecystokinin antagonists (i.e., proglumide and loxiglumide) and by dibutyryl-cyclic-guanosine monophosphate, which overcame the stimulant effect of the peptide. These findings indicated that in the guinea pig ileum, caerulein exerts two opposite effects, both of which are mediated by the same receptor: a stimulation effect, with an increase in acetylcholine release when the organ is incubated in normal saline, and a relaxation effect, with a reduction in acetylcholine release when the ileum is bathed with calcium antagonist drugs.

[Typology of towns and gminas of Suwalskie voivodship from the perspective of population changes during the years 1976-1986]. / Typologia miast i gmin wojewodztwa suwalskiego z punktu widzenia zmian ludnosci w latach 1976-1986.

PIP: Population change within Suwalskie voivodship, Poland, for the periods 1976-1980, 1981-1985, and 1986 is analyzed. The focus is on natural growth, migration, and the differences between urban and rural areas. (SUMMARY IN ENG AND RUS)^ieng

ATP-Induced shape change of nuclear pores visualized with the atomic force microscope.

Bidirectional transport of molecules between nucleus and cytoplasm through the nuclear pore complexes (NPCs) spanning the nuclear envelope plays a fundamental role in cell function and metabolism. Nuclear import of macromolecules is a two-step process involving initial recognition of targeting signals, docking to the pore and energy-driven translocation. ATP depletion inhibits the translocation step. The mechanism of translocation itself and the conformational changes of the NPC components that occur during macromolecular transport, are still unclear. The present study investigates the effect of ATP on nuclear pore conformation in isolated nuclear envelopes from Xenopus laevis oocytes using the atomic force microscope. All experiments were conducted in a saline solution mimicking the cytosol using unfixed nuclear envelopes. ATP (1 mM) was added during the scanning procedure and the resultant conformational changes of the NPCs were directly monitored. Images of the same nuclear pores recorded before and during ATP exposure revealed dramatic conformational changes of NPCs subsequent to the addition of ATP. The height of the pores protruding from the cytoplasmic surface of the nuclear envelope visibly increased while the diameter of the pore opening decreased. The observed changes occurred within minutes and were transient. The slow-hydrolyzing ATP analogue, ATP-gamma-S, in equimolar concentrations did not exert any effects. The ATP-induced shape change could represent a nuclear pore "contraction."

The atomic force microscope detects ATP-sensitive protein clusters in the plasma membrane of transformed MDCK cells.

Plasma membrane proteins are supposed to form clusters that allow 'functional cross-talk' between individual molecules within nanometre distance. However, such hypothetical protein clusters have not yet been shown directly in native plasma membranes. Therefore, we developed a technique to get access to the inner face of the plasma membrane of cultured transformed kidney (MDCK) cells. The authors applied atomic force microscopy (AFM) to visualize clusters of native proteins protruding from the cytoplasmic membrane surface. We used the K+ channel blocker iberiotoxin (IBTX), a positively charged toxin molecule, that binds with high affinity to plasma membrane potassium channels and to atomically flat mica. Thus, apical plasma membranes could be 'glued' with IBTX to the mica surface with the cytosolic side of the membrane accessible to the scanning AFM tip. The topography of these native inside-out membrane patches was imaged with AFM in electrolyte solution mimicking the cytosol. The plasma membrane could be clearly identified as a lipid bilayer with the characteristic height of 4.9 +/- 0.02 nm. Multiple proteins protruded from the lipid bilayer into the cytosolic space with molecule heights between 1 and 20 nm. Large protrusions were most likely protein clusters. Addition of the proteolytic enzyme pronase to the bath solution led to the disappearance of the proteins within minutes. The metabolic substrate ATP induced a shape-change of the protein clusters and smaller subunits became visible. ADP or the non-hydrolysable ATP analogue, ATP-gamma-S, could not exert similar effects. It is concluded that plasma membrane proteins (and/or membrane associated proteins) form 'functional clusters' in their native environment. The 'physiological' arrangement of the protein molecules within a cluster requires ATP.

Using atomic force microscopy to investigate patch-clamped nuclear membrane.

Nuclear patch clamp is an emerging research field that aims to disclose the electrical phenomena underlying macromolecular transport across the nuclear envelope (NE), its properties as an ion barrier and its function as an intracellular calcium store. The authors combined the patch clamp technique with atomic force microscopy (AFM) to investigate the structure-function relationship of NE. In principle, patch clamp currents, recorded from the NE can indicate the activity of the nuclear pore complexes (NPCs) and/or of ion channels in the two biomembranes that compose the NE. However, the role of the NPCs is still nuclear because the observed NE current in patch clamp experiments is lower than expected from the known density of the NPCs. Therefore, AFM was applied to link patch clamp currents to structure. The membrane patch was excised from the nuclear envelope and, after electrical evaluation, transferred from the patch pipette to a substrate. We could identify the native nuclear membrane patches with AFM at a lateral and a vertical resolution of 3 nm and 0.1 nm, respectively. It was shown that complete NE together with NPCs can be excised from the nucleus after their functional identification in patch clamp experiments. However, we also show that membranes of the endoplasmic reticulum can contaminate the tip of the patch pipette during nuclear patch clamp experiments. This possibility must be considered carefully in nuclear patch clamp experiments.

[Erythropoietin in the pathogenesis of anemia in patients with multiple myeloma]. / Erytropoetyna w patogenezie niedokrwistosci u chorych na szpiczaka mnogiego.

UNLABELLED: Anemia is a common symptom in multiple myeloma (MM) patients but the pathogenesis of it is still unknown. The aim of the study was to explain the causes of anemia in MM patients. Peripheral blood count, bone marrow aspirate, iron and ferritin level, serum erythropoietin (EPO) level, T cell subsets and in vitro CFU-E count were analyzed in the group od 31 MM patients. Erythropoietin and iron deficiency in the study group were not observed. EPO serum level was not significantly different in patients with multiple myeloma and in comparison to patients with sideroblastic anemia with solid tumors. Absolute CD8 T lymphocyte count was not significantly increased in the study group. CFU-E colonies count in vitro was not decreased in these patients. CONCLUSIONS: In the study group of the MM patients anemia probably does not depend on EPO production. Diminished proliferative response of erythropoietic cells on normal serum level of EPO and abnormal iron utilisation probably occur in these patients. Replacement of normal erythropoiesis by tumor plasma cells is probably not decisive.