Nowa era w farmakologicznym leczeniu pęcherza nadreaktywnego (OAB): mirabegron – selektywny agonista receptora β3

Overactive bladder is defined by ICS as urgency, frequency and nocturia, with or without urgency urinary incontinence in the absence of urinary tract infection, or other obvious causative pathology. Lower urinary tract symptoms (LUTS) are highly prevalent, especially in aging populations. Epidemiological studies reported LUTS in 62% of men and 67% of women, rising to 81% and 79%, respectively in adults over 60 years old. However, the actual burden of LUTS remains relatively unrecognized. LUTS, mainly due to considerable distress including almost all aspects of social functioning, impact on sleep and mental health, may significantly affect quality of life. Management of LUTS including OAB has undergone dramatic changes since 1972, when the first antimuscarinic drug – oxybutynin, was introduced into clinical practice. In the last two decades, six new antimuscarinic drugs entered OAB field and this was accompanied by introduction of botulinum toxin into clinical practice in patients resistant to or not compliant with antimuscarinics. Nowadays, it is recognized that OAB is progressive, age-related and non sex-specific condition with most patients experiencing a combination of storage, voiding and post-micturition symptoms. In 2013, the next step was taken, with new therapeutic options for OAB, enabling an even more patient-tailored approach. This was possible for both, male and female OAB sufferers with new class of oral β3 adrenoreceptor agonist (mirabegron). This drug, by stimulation of β3-adrenoceptors, couples via Gs proteins to adenylyl cyclase, what results in an increase of intracellular cAMP levels and a subsequent activation of cAMP-dependent protein kinase A, which then phosphorylates myosin light chain kinase responsible for inhibition of calcium-calmodulin dependent interaction of myosin with actin. Moreover, the cAMP increase also leads to the reduction of cytoplasmic Ca2+ concentration by removal of calcium ions from cytoplasm. These both actions result in a significant increase in the storage bladder capacity and by this interval between micturitions is prolonged. Mirabegron was evaluated in three 12-week, double blind, randomized, placebo controlled, parallel-group, multicenter clinical trials in OAB patients with symptoms of urge urinary incontinence, urgency and frequency – study 046, 047 and 074. It should be pointed out that efficacy of mirabegron was maintained through the entire 12-month period in phase III long-term study. Discoveries on the physiology of the normal bladder and on the pathophysiology underlying OAB have led to the development of new treatment options for OAB. Pharmacological management of OAB should be tailored to patient’s characteristics. New and recent options of pharmacological treatment have undoubtedly expanded treatment possibilities, what should allow physicians to select the optimal treatment for each patient.Nadreaktywność pęcherza moczowego definiowana jest przez ICS jako uczucie parcia na pęcherz, częstomoczu i nokturii z obecnością lub bez naglącego nietrzymania moczu przy nieobecności infekcji układu moczowego lub innego znanego czynnika sprawczego. Zaburzenia funkcjonowania dolnych dróg moczowych są szeroko rozpowszechnione, zwłaszcza pośród starzejących się populacji. Z badań epidemiologicznych wynika, że cierpi na nie 62% mężczyzn i 67% kobiet, a w populacji osób powyżej 60 roku życia – odpowiednio 81% i 79%. Jednak rzeczywista skala problemu nie jest dokładnie znana. Zaburzenia dolnych dróg moczowych istotnie wpływają na komfort życia poprzez wpływ na funkcje społeczne, sen oraz zdrowie psychiczne. Przełomem w leczeniu tych zaburzeń, w tym OAB, było wprowadzenie do praktyki klinicznej w 1972 roku oksybutyniny, pierwszego leku antymuskarynowego. W okresie ostatnich 20 lat do farmakoterapii OAB wprowadzono sześć nowych leków antymuskarynowych, a także toksynę botulinową przeznaczoną dla pacjentów opornych na leczenie cholinolitykami lub osób, które rezygnowały z terapii z powodu nasilonych objawów ubocznych wywoływanych przez te leki. W 2013 roku nastąpił olbrzymi progres w farmakoterapii OAB dzięki pojawieniu się nowej opcji leczenia tej choroby, która umożliwia precyzyjne dostosowanie terapii do potrzeb pacjenta. Jest to możliwe dzięki mirabegronowi – nowemu, doustnemu agoniście receptorów β3-adrenergicznych. Lek ten poprzez stymulację receptorów adrenergicznych typu β3, aktywuje za pośrednictwem białka Gs cyklazę adenylową, czego wynikiem jest wzrost stężenia wewnątrzkomórkowego cAMP z następczą aktywacją zależnej od cAMP kinazy białkowej A, która z kolei fosforyluje lekkie łańcuchy miozyny odpowiedzialne za hamowanie interakcji aktyny z miozyną zależnej od kompleksu wapń – kalmodulina. Ponadto wzrost cAMP powoduje redukcję stężenia Ca2+ w cytoplazmie. W efekcie tych zmian dochodzi do istotnego wzrostu funkcjonalnej objętości pęcherza moczowego, co w konsekwencji pozwala na wydłużenie okresu pomiędzy mikcjami

Nanoscale spatially resolved infrared spectra from single microdroplets

Droplet microfluidics has emerged as a powerful platform allowing a large number of individual reactions to be carried out in spatially distinct microcompartments. Due to their small size, however, the spectroscopic characterisation of species encapsulated in such systems remains challenging. In this paper, we demonstrate the acquisition of infrared spectra from single microdroplets containing aggregation-prone proteins. To this effect, droplets are generated in a microfluidic flow-focussing device and subsequently deposited in a square array onto a ZnSe prism using a micro stamp. After drying, the solutes present in the droplets are illuminated locally by an infrared laser through the prism, and their thermal expansion upon absorption of infrared radiation is measured with an atomic force microscopy tip, granting nanoscale resolution. Using this approach, we resolve structural differences in the amide bands of the spectra of monomeric and aggregated lysozyme from single microdroplets with picolitre volume.Comment: 5 pages, 3 Figure

Assessment of knowledge on HPV infection among residents of the regions of Biała Podlaska and Parczew

Wstęp. Human papilloma virus (HPV) może być przyczyną łagodnych zmian skórnych, a także nowotworów złośliwych, takich jak rak szyjki macicy i rak prącia. Cel pracy. Ocena poziomu wiedzy na temat wirusa HPV wśród mieszkańców powiatu bialskiego i parczewskiego. Materiał i metody. Badaniami objęto 156 mieszkańców powiatu bialskiego i parczewskiego. Metodą badawczą był sondaż diagnostyczny. Narzę­dziem badawczym był autorski kwestionariusz ankiety. Wyniki. Mniej niż połowa badanych deklarowała znajomość zagadnień dotyczących HPV; 51% badanych z powiatu parczewskiego i 38% z bialskiego wiązało zakażenie HPV z rakiem szyjki macicy i występowaniem kłykcin kończystych. Za najskuteczniejszą metodę zapobiegania zakażeniu HPV ankietowani uznali prezerwatywy. Źródłem wiedzy dotyczącej HPV były dla ankietowanych informacje od znajomych i media. Wnioski. 1. Wiedza badanych na temat wirusa HPV jest niewystarczająca. 2. W śród ankietowanych istnieje konieczność uzupełnienia wiedzy dotyczącej dróg zakażenia HPV i sposobów zapobiegania tym zakażeniom.Introduction. Human papilloma virus (HPV) can cause mild skin lesions as well as malignancies such as cervical cancer and penile cancer. Aim of the study. Assessment of the level of knowledge on HPV among residents of the regions of Biała Podlaska and Parczew. Material and methods. The study included 156 residents of the regions of Biała Podlaska and Parczew. Diagnostic survey was a research method. An author’s questionnaire was a proprietary research tool. Results. Less than 50% respondents declared knowledge of issues related to HPV; 51% of the Parczew region and 38% of the Biała Podlaska region associated HPV with cervical cancer and the occurrence of genital warts. According to the respondents, the most effective method of preventing HPV infection is a condom. Information from friends and the media was the main source of knowledge about the HPV among the respondents. C onclusions. 1. The knowledge of respondents about HPV is insufficient. 2. Among the respondents, there is the need to supplement the knowledge on the methods of preventing HPV

Overactive bladder – a new insight into the pathogenesis of its idiopathic form

In the last few years cytokines have been shown to be the most important local cell signaling molecules, strongly involved in the pathogenesis of the overactive bladder symptoms. Proper bladder function is dependent on gap junction activity. The main gap junction proteins which can be found in bladder smooth muscle are Connexin 43 (Cx 43) and Connexin 45 (Cx45). Experimental studies focused on the influence of Basic Fibroblast Growth Factor on Connexin expression in bladder smooth muscle cells have shown an increased expression of Cx43, contrary to Cx45. Elevated level of Connexin 43 leads to overactivity of muscle fibers. It was also proved that expression of these proteins in tissues is modulated by cytokines. Regulation of the Cx43 promoter depends on an activating factor 1 (AP-1), cyclic monophosphate (cAMP) and retinoid concentration as well. AP-1 is induced by extracellular-signal-regulated kinases (ERK 1/2) through the activation of basic fibroblast growth factor (bFGF). Recent studies revealed that cytokine-induced modulation of gap junction plays an important role in the pathogenesis of OAB, whereas activation of sympathetic fibers via β adrenoreceptors (β –AR) causes relaxation of the bladder. The β-3 adrenoreceptors are divided into β-1, β-2, β-3 subtypes. β-3 adrenoreceptors have been found in fat and smooth muscle tissue. Density of β-3 AR is very high in urinary bladder detrusor. Activation of β-3 AR leads to the relaxation of smooth muscle fibers during the filling phase and is cAMP-dependent. Missense mutation of this receptor subtype in the human bladder, leading to the substitution of Tryptophan (Trp) by Arginine (Arg), occurs in about one-third of the world’s population. Studies have shown that about 50% of women with Trp 64 Arg polymorphism have OAB symptoms. Higher concentration of β3-AR with Trp 64 Arg polymorphism in bladders of women with diagnosed OAB is probably associated with a lower level of cAMP and weaker relaxation of the bladder smooth muscle. The role of the muscarinic receptors (M1-M5) in the pathogenesis of OAB has been widely described. Unfortunately, due to lack of selective muscarinic ligands, the function of each subtype of the receptor has not been fully elucidated yet. A mouse model lacking one or more muscarinic receptors types has been constructed recently. Animals were used to assess the real influence of various muscarinic receptors on bladder function. Studies have confirmed the importance of these receptors in the function of the urinary tract, offering a new insight in their mutual interactions and pathogenesis of OAB. Better understanding of these and new mechanisms may improve the process of diagnosis and treatment of the disease in the near future

Ocena efektywności klinicznej operacji typu T-Sling z fiksacją taśmy wykonywanej w ramach procedury jednodniowej i standardowej

Introduction: Nowadays, mid-urethral slings are considered the gold standard in surgical treatment of female stress urinary incontinence (SUI). Traditionally, this technique has been followed by short inpatient hospitalization and convalescence. From the perspective of both, the patient and the physician, this technique has become increasingly popular due to very high clinical effectiveness and fast recovery. Objectives: The aim of the study was to compare the efficacy and safety of transobturator monofilament sling (T-sling-Hernia Mesh, Italy) with additional 2-point tape fixation in the treatment of SUI in women operated on an inpatient and outpatient basis. Material and methods: A total of 200 women with stress urinary incontinence were included into the study. Clinical diagnosis was based on detailed medical history, voiding diary, gynecological examination, and positive cough test. Exclusion criteria were as follows: previous urogynecologic surgery, detrusor overactivity on urodynamics and advanced urogenital prolapse (pelvic organ prolapse-quantification [POP-Q] scale grades – II, III, IV). In both groups the surgery was performed by two (TR; AW) surgeons. Using identical surgical technique, all patients had a monofilament tape inserted at the mid-urethra with 2 absorbable sutures parallel to the urethra in order to fix the tape and prevent its displacement during tape tensioning. Patients were discharged home after the first spontaneous voiding (outpatient group) or 2 days (inpatient group) postoperatively. After 12 months, 192 patients (99 in outpatient and 93 in inpatient group) were available for assessment of clinical effectiveness of surgery. Success was defined as lack of any leakage during cough stress test. The subjective cure rate was determined by Sandvik scale also after 12 months. Statistical analysis was performed with Statistica 7.1 pl and Mann-Whitney U and Chi2 tests were used. P-level of ≤ 0.05 was considered as statistically significant. Results: There were no differences in demographical data of patients from both groups. The only difference between the two groups concerned the body mass index (mean 26.6±3.9 vs. 28.67±3.99; pCel pracy: Slingi podcewkowe stanowią złoty standard w leczeniu wysiłkowego nietrzymania moczu. Celem pracy było porównanie efektywności i bezpieczeństwa zabiegu typu T-sling z fiksacją taśmy w leczenia wysiłkowego nietrzymania moczu w ramach procedury jednodniowej (bez hospitalizacji) i standardowej (z hospitalizacją). Materiał i metody: W badaniu wzięło udział 200 pacjentek z rozpoznaniem wysiłkowego nietrzymania moczu ustalonym na podstawie szczegółowego wywiadu, dzienniczka mikcji i badania ginekologicznego uzupełnionego dodatnią próbą kaszlową. Pacjentki zostały losowo przydzielone do obu badanych grup w stosunku 1:1. Do kryteriów wykluczających z badania należały: przebyte zabiegi uroginekologiczne, nadreaktywność wypieracza pęcherza moczowego potwierdzona urodynamicznie i dużego stopnia zaburzenia statyki narządu rodnego (POPQ II, III i IV). Zabiegi wykonywane były przez dwóch lekarzy (TR, AW). Używając identycznej techniki operacyjnej w obu grupach zaimplantowano przezzasłonowo monofilamentowe taśmy pod środkowy odcinek cewki moczowej zakładając dodatkowo 2 szwy bocznie do cewki moczowej w celu fiksacji taśmy, co zapobiegało jej niekontrolowanemu przemieszczeniu podczas pozycjonowania taśmy. Pacjentki były wypisywane do domu po pierwszej mikcji (procedura jednodniowa) lub po 2 dniach (hospitalizacja standardowa). Ocenę efektywności klinicznej leczenia przeprowadzano po 12 miesiącach. Powodzenie zabiegu definiowano jako ujemny wynik testu kaszlowego. Subiektywną ocenę skuteczności leczenia oceniano za pomocą skali Sandvika. Analizę statystyczną przeprowadzono przy użyciu programu Statistica 7.1 pl stosując testy U Manna-Whitneya i Chi2. Wyniki: Finalnie oceniono skuteczność zabiegu u 192 kobiet (99 z grupy nie hospitalizowanych i 93 z grupy hospitalizowanych). Efektywność kliniczna operacji T-Sling w obu badanych grupach oceniana po 12 miesiącach nie różniła się istotnie statystycznie (chi2=4,039, p=0,133). Wnioski: Operacyjne leczenie niepowikłanej postaci wysiłkowego nietrzymania moczu za pomocą taśm implantowanych pod środkowy odcinek cewki moczowej wykonywane w ramach procedury jednodniowej zapewnia taki sam współczynnik wyleczeń i satysfakcji jak podczas standardowej hospitalizacji oraz pozwala zredukować koszty leczenia nie wpływając na jego efektywność

Is digit ratio (2D:4D) associated with a religious profession? An exploratory study on male Polish seminary students

Human females demonstrate higher religiosity than men in populations. Digit ratio (2D:4D), being a putative indicator of prenatal testosterone, is associated in varying degrees with characters that show sexual dimorphism. A small number of studies have indicated that religiosity may be associated with the biological basis of sex differences in humans. The objective of the present study was to ascertain whether 2D:4D in religiously oriented seminary students is different from individuals in other occupations. The study followed a cross-sectional design. Male participants of the study included 13 seminary students, 18 military chaplains and 91 control students from study courses relating to civil occupations. Lengths of second (2D) and fourth (4D) digits and their ratio (2D:4D) for each hand, height and weight were the variables and 2D:4D was the outcome measure. The results demonstrated that the seminary students had significantly higher 2D:4D than both the military chaplains and civil students. The military chaplains had the lowest 2D:4D. The study also revealed that the choice of religious occupation, and for that matter, religiosity, could be linked with the prenatal hormonal environment, particularly lower intrauterine testosterone compared to oestrogen

Fibrogenic fibroblasts increase intercellular adhesion strength by reinforcing individual OB-cadherin bonds

We have previously shown that the switch from N-cadherin to OB-cadherin expression increases intercellular adhesion between fibroblasts during their transition from a migratory to a fibrogenic phenotype. Using atomic force microscopy we here show that part of this stronger adhesion is accomplished because OB-cadherin bonds resist similar to twofold higher forces compared with N-cadherin junctions. By assessing the adhesion force between recombinant cadherin dimers and between native cadherins in the membrane of spread fibroblasts, we demonstrate that cadherin bonds are reinforced over time with two distinct force increments. By modulating the degree of lateral cadherin diffusion and F-actin organization we can attribute the resulting three force states to the single-molecule bond rather than to cadherin cluster formation. Notably, association with actin filaments enhances cadherin adhesion strength on the single-molecule level up to threefold; actin depolymerization reduces single-bond strength to the level of cadherin constructs missing the cytoplasmic domain. Hence, fibroblasts reinforce intercellular contacts by: (1) switching from N- to OB-cadherin expression; (2) increasing the strength of single-molecule bonds in three distinct steps; and (3) actin-promoted intrinsic activation of cadherin extracellular binding. We propose that this plasticity adapts fibroblast adhesions to the changing mechanical microenvironment of tissue under remodeling