Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis

Membrane and secretory trafficking are essential for proper neuronal development. However, the molecular mechanisms that organize secretory trafficking are poorly understood. Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. BICDR-1 expression is high during early neuronal development and strongly declines during neurite outgrowth. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation

A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo

expression. variants. that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish. variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function

The Urogynecology Section of the Polish Society of Gynecologists and Obstetricians Guideline for the diagnostic assessment of stress urinary incontinence in women

Objectives: The aim of the Urogynecology Section of the Polish Society of Gynecologists and Obstetricians (PSGO) was to develop an updated Guideline for the diagnostic assessment of stress urinary incontinence (SUI) in women. Material and methods: Earlier PSGO guidelines and the literature about the diagnostic assessment of SUI, including current international guidelines, were reviewed. Results: As in the earlier guidelines, the diagnostic process was subdivided into the initial and the specialized diagnostics. Patients who required specialized diagnostic testing were identified. Functional diagnostic tests, performed by physiotherapists, were included. Attention was paid to new diagnostic possibilities. Conclusions: Initial diagnostic assessment is sufficient to devise the optimal treatment plan in a number of patients. It also allows to identify which patients will require specialized diagnostics, whose scope is individually tailored to the patient needs and depends on symptom complexity, surgical history, treatment plan, experience of the physician, availability of the equipment, and cost-effectiveness ratio

The Urogynecology Section of the Polish Society of Gynecologists and Obstetricians Guidelines for the diagnostic assessment of pelvic organ prolapse

Objectives: The aim of the team appointed by the Board of the Urogynecology Section of the Polish Society of Gynecologists and Obstetricians (PSGO) was to develop this interdisciplinary Guideline for the diagnostic assessment of pelvic organ prolapse (POP) in women, based on the available literature, expert knowledge and opinion, as well as everyday practice. Material and methods: A review of the literature, including current international guidelines and earlier PSGO recommendations (2010-2020) about POP, was conducted. Results: The steps of the diagnostic assessment for patients with POP, subdivided into initial and specialized diagnostics, have been presented. Indications for specialized diagnostic assessment have also been listed. In case of surgical treatment, the patient may be referred solely based on the initial diagnostics or after certain elements of the specialized diagnostics have been completed. Conclusions: Due to inconclusive data, the scope of the diagnostic process for POP is individualized for each patient and depends on patient-reported symptoms, initial diagnostic findings, surgical history, management plan, availability of the equipment, and cost

Hirschsprung disease - genetics and development

Hirschsprung disease (HSCR) is a complex genetic disorder that is characterized by the lack of the Enteric Nervous System (ENS) in the myenteric and submucosal plexuses of the gastrointestinal tract. HSCR is a neurocristopathy and can result from aberrant migration, proliferation or differentiation of vagal neural crest cells. The length of the affected intestine classifies HSCR. The most common form of the disease (~80% of patients) is called shortsegment HSCR (S-HSCR), where aganglionosis does not extend beyond the sigmoid colon. Approximately 20% of the patients is diagnosed with long-segment HSCR (L-HSCR), in which aganglionosis extents proximal to the sigmoid. The population incidence is generally assumed to be 1/5000 live births, though it varies among patients of distinct ethnic origin. A sex bias is also present in this disorder as approximately three times more males are affected. The pattern of inheritance for L-HSCR is autosomal dominant with low penetrance whereas the inheritance of the much more common S-HSCR is believed to be multifactorial. The major gene in HSCR is RET. Nevertheless, mutations in the coding sequence of RET are hardly being found in the main classes of patients. The work included in this thesis had two main goals. Firstly, to elucidate further the role of RET in those cases where no coding sequence mutations were found. We focused on the most common group of patients, namely those with S-HSCR who lack a disease history in the family. We found, that the RET gene is involved in nearly all HSCR cases and that the majority of mutations are not lying within the coding regions, but in the regulatory sequences of the RET locus. Secondly, baring in mind that HSCR is genetically complex disease, we attempted to find new genes and loci involved in HSCR development and more generally genes encoding proteins, Scope which contribute to ENS development. In a collaborative effort with the Rotterdam group a new HSCR susceptibility locus was identified in a multigenerational HSCR family. Further, ENS precursors cells, isolated from mouse embryos’ intestines were studied and expression profiling was performed. Genes encoding proteins belonging to the RET pathway or genes encoding proteins affected by RET signaling in these cells, were identified. By this approach we hope to get a better insight in ENS development, and HSCR susceptibility.

Current concepts in RET-related genetics, signaling and therapeutics

The receptor tyrosine kinase RET is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation and survival during embryogenesis. Germline and somatic mutations in RET that produce constitutively activated receptors cause the cancer syndrome multiple endocrine neoplasia type 2 and several endocrine and neural-crest-derived tumors, whereas mutations resulting in nonfunctional RET or lower expression of RET are found in individuals affected with Hirschsprung disease. This review focuses on the genetics and molecular mechanisms underlying the different inherited human neural-crest-related disorders in which RET dysfunction has a crucial role and discusses RET as a potential therapeutic target.

Urogynecology Section of the Polish Society of Gynecologists and Obstetricians guidelines on the management of stress urinary incontinence in women

Objectives: The aim was to present an interdisciplinary Guideline of the Urogynecology Section of the Polish Society of Gynecologists and Obstetricians (PSGO) for the management of stress urinary incontinence (SUI).Material and methods: A review of the literature, including current international guidelines and earlier recommendations of the PSGO Urogynecology Section, about the treatment of SUI was conducted.Results: Management of SUI is presented. Four lines of therapy were identified: line 1 — the so-called ‘conservative treatment’, which should always be attempted, regardless of SUI symptom severity; line 2 — surgical intervention; lines 3 and 4 — reoperations after unsuccessful surgeries from line 2. The literature reports which provided supporting evidence for this Guideline, including the practical aspects, were discussed.Conclusions: A systematic review of the guidelines and an analysis of SUI management were conducted. The need for an individualized approach was emphasized

The Urogynecology Section of the Polish Society of Gynecologists and Obstetricians guidelines on the management of non-neurogenic overactive bladder syndrome in women

Objectives: The aim of the publication was to present the interdisciplinary guidelines of the Urogynecology Section of thePolish Society of Gynecologists and Obstetricians (PSGO) for the treatment of overactive bladder (OAB) syndrome basedon the available literature, expert knowledge, and everyday practice.Material and methods: A review of the literature, including current recommendations for the treatment of overactivebladder syndrome, urinary incontinence, urgency and mixed urinary incontinence, as well as the earlier recommendationsof the PSGO Urogynecology Section, was conducted.Results: Management of the patients with OAB is presented. Four lines of therapy were identified: 1) educating the patient,behavioral therapy with pelvic floor muscle training, 2) pharmacotherapy, 3) botulinum toxin injection and tibial nervestimulation; and sacral nerve stimulation even though so far it has been used only in selected populations, 4) surgical intervention.The literature reports which provided supporting evidence and presented various aspects of the therapy werediscussed. OAB pharmacotherapy-related issues which are vital in everyday clinical practice were presented.Conclusions: A systematic review of the available guidelines and an analysis of OAB (including urgency urinary incontinence)management were conducted. The Polish Society of Gynecologists and Obstetricians issued the guidelines for thetherapeutic management of OAB patients. The need for an individualized approach was emphasized