Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with "healthy" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.

• MeSH
• Models, Biological MeSH
• Ceramides * metabolism   MeSH
• Phosphorylcholine analogs & derivatives   MeSH
• Skin * metabolism   MeSH
• Fatty Acids, Nonesterified metabolism   MeSH
• Humans MeSH
• Lysophospholipids metabolism   MeSH
• Permeability drug effects   MeSH
• Sphingosine analogs & derivatives   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND & AIMS: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.

• MeSH
• alpha 1-Antitrypsin * genetics   blood   MeSH
• Biomarkers blood   MeSH
• Time Factors MeSH
• alpha 1-Antitrypsin Deficiency * genetics   diagnosis   complications   MeSH
• Adult MeSH
• Elasticity Imaging Techniques MeSH
• Genotype MeSH
• Homozygote MeSH
• Liver Cirrhosis * genetics   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Mutation MeSH
• Lung physiopathology   pathology   diagnostic imaging   MeSH
• Lung Diseases genetics   etiology   diagnosis   MeSH
• Disease Progression * MeSH
• Risk Factors MeSH
• Severity of Illness Index MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

BACKGROUND AND OBJECTIVES: En bloc sacrectomy is associated with sacral root transection causing loss of urinary bladder, rectum, and sexual function. The aim of the study was to determine the position of the pudendal branches (sensorimotor) and pelvic splanchnic nerves (parasympathetic) on the sacral roots relative to the sacrum, and the minimal and maximal defects in the sacral roots that can be reconstructed by grafting after various types of sacrectomy. METHODS: Five cadaveric pelves were dissected bilaterally. The lengths and widths of the S1-S4 roots and their branches were measured. Then, the minimal and maximal defects between the proximal and distal stumps of the sacrificed roots were measured following 3 models of sacrectomy (below S2, below S1, and total sacrectomy). RESULTS: The mean distance of the splanchnic nerves from the S2 and S3 anterior sacral foramina was 17.7 ± 7.3 and 23.6 ± 11.1 mm, respectively, and the mean distance of the pudendal S2 and S3 branches was 36.8 ± 13.7 and 30.2 ± 10.8 mm, respectively. The mean widths of the S2 and S3 roots were 9.3 ± 1.9 and 5.4 ± 1.2 mm, respectively. The mean maximal defects in S2 and S3 roots after various types of sacrectomies were between 61.8 ± 16.3 and 100.7 ± 14.3 mm and between 62.7 ± 20.2 and 84.7 ± 25.1 mm, respectively. There were no statistically significant differences between sides or sexes for all obtained measurements. CONCLUSION: The reconstruction of the S2-S3 roots is anatomically feasible after partial or total sacrectomies in which the resection of the soft tissue does not extend further than approximately 1.5 to 2 cm ventrally from the sacrum.

• MeSH
• Sacrum * surgery   anatomy & histology   innervation   MeSH
• Middle Aged MeSH
• Humans MeSH
• Spinal Nerve Roots * anatomy & histology   surgery   MeSH
• Cadaver * MeSH
• Aged MeSH
• Splanchnic Nerves anatomy & histology   surgery   MeSH
• Plastic Surgery Procedures methods   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Resection of the vestibular schwannoma causes acute peripheral vestibular loss. The process of central compensation starts immediately afterward. The rehabilitation goal is to support this process and restore the quality of life. MATERIALS AND METHODS: In this prospective single-center study, 67 consecutive patients underwent vestibular schwannoma resection (40 females, mean age 52 ± 12 years). The patients were divided into three groups: the prehabilitation with intratympanic gentamicin group, the virtual reality group (optokinetic stimulation via virtual reality goggles in the first ten days after the surgery), and the control group. All patients were examined with objective methods and completed questionnaires before the prehabilitation, before the surgery, at the hospital discharge, and after three months. RESULTS: Intratympanic gentamicin prehabilitation leads ipsilaterally to a significant aVOR reduction in all semicircular canals (p < 0.050), the increase of the unilateral weakness in air calorics (p = 0.026), and loss of cVEMPs responses (p = 0.017). Prehabilitation and postoperative exposure to virtual reality scenes improved the patient's perception of vertigo problems according to Dizziness Handicap Inventory (p = 0.039 and p = 0.076, respectively). These findings conform with the optokinetic testing results, which showed higher slow phase velocities at higher speeds (40 deg/s) in both targeted groups compared to the control group. CONCLUSION: Preoperative intratympanic gentamicin positively affects peripheral vestibular function, influencing balance perception after VS resection. In long-term follow-up, prehabilitation and postoperative exposure to virtual reality improve patients' quality of life in the field of vertigo problems.

• MeSH
• Anti-Bacterial Agents administration & dosage   MeSH
• Adult MeSH
• Gentamicins * administration & dosage   MeSH
• Injection, Intratympanic MeSH
• Quality of Life MeSH
• Middle Aged MeSH
• Humans MeSH
• Postoperative Care methods   MeSH
• Preoperative Care methods   MeSH
• Prospective Studies MeSH
• Aged MeSH
• Virtual Reality Exposure Therapy methods   MeSH
• Vestibular Function Tests MeSH
• Neuroma, Acoustic * surgery   MeSH
• Virtual Reality MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

OBJECTIVES: Asymmetric or unilateral hearing loss (AHL) may cause irreversible changes in the processing of acoustic signals in the auditory system. We aim to provide a comprehensive view of the auditory processing abilities for subjects with acquired AHL, and to examine the influence of AHL on speech perception under difficult conditions, and on auditory temporal and intensity processing. DESIGN: We examined peripheral and central auditory functions for 25 subjects with AHL resulting from vestibular schwannoma, and compared them to those from 24 normal-hearing controls that were matched with the AHL subjects in mean age and hearing thresholds in the healthy ear. Besides the basic hearing threshold assessment, the tests comprised the detection of tones and gaps in a continuous noise, comprehension of speech in babble noise, binaural interactions, difference limen of intensity, and detection of frequency modulation. For the AHL subjects, the selected tests were performed separately for the healthy and diseased ear. RESULTS: We observed that binaural speech comprehension, gap detection, and frequency modulation detection abilities were dominated by the healthy ear and were comparable for both groups. The AHL subjects were less sensitive to interaural delays, however, they exhibited a higher sensitivity to sound level, as indicated by lower difference limen of intensity and a higher sensitivity to interaural intensity difference. Correlations between the individual test scores indicated that speech comprehension by the AHL subjects was associated with different auditory processing mechanisms than for the control subjects. CONCLUSIONS: The data suggest that AHL influences both peripheral and central auditory processing abilities and that speech comprehension under difficult conditions relies on different mechanisms for the AHL subjects than for normal-hearing controls.

• MeSH
• Adult MeSH
• Hearing Loss, Unilateral * physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Speech Perception * physiology   MeSH
• Aged MeSH
• Auditory Perception physiology   MeSH
• Auditory Threshold * MeSH
• Case-Control Studies MeSH
• Neuroma, Acoustic * physiopathology   complications   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND & AIMS: Despite strong evidence for improved preservation of donor livers by machine perfusion, longer post-transplant follow-up data are urgently needed in an unselected patient population. We aimed to assess long-term outcomes after transplantation of hypothermic oxygenated machine perfusion (HOPE)-treated donor livers based on real-world data (i.e., IDEAL-D stage 4). METHODS: In this international, multicentre, observational cohort study, we collected data from adult recipients of HOPE-treated livers transplanted between January 2012 and December 2021. Analyses were stratified by donation after brain death (DBD) and donation after circulatory death (DCD), sub-divided by their respective risk categories. The primary outcome was death-censored graft survival. Secondary outcomes included the incidence of primary non-function (PNF) and ischaemic cholangiopathy (IC). RESULTS: We report on 1,202 liver transplantations (64% DBD) performed at 22 European centres. For DBD, a total number of 99 benchmark (8%), 176 standard (15%), and 493 extended-criteria (41%) cases were included. For DCD, 117 transplants were classified as low risk (10%), 186 as high risk (16%), and 131 as futile (11%), with significant risk profile variations among centres. Actuarial 1-, 3-, and 5-year death-censored graft survival rates for DBD and DCD livers were 95%, 92%, and 91%, vs. 92%, 87%, and 81%, respectively (log-rank p = 0.003). Within DBD and DCD strata, death-censored graft survival was similar among risk groups (log-rank p = 0.26, p = 0.99). Graft loss due to PNF or IC was 2.3% and 0.4% (DBD), and 5% and 4.1% (DCD). CONCLUSIONS: This study shows excellent 5-year survival after transplantation of HOPE-treated DBD and DCD livers with low rates of graft loss due to PNF or IC, irrespective of their individual risk profile. HOPE treatment has now reached IDEAL-D stage 4, which further supports its implementation in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05520320. IMPACT AND IMPLICATIONS: This study demonstrates the excellent long-term performance of hypothermic oxygenated machine perfusion (HOPE) treatment of donation after circulatory and donation after brain death liver grafts irrespective of their individual risk profile in a real-world setting, outside the evaluation of randomised-controlled trials. While previous studies have established safety, feasibility, and efficacy against the current standard, according to the IDEAL-D evaluation framework, HOPE treatment has now reached the final IDEAL-D stage 4, which further supports its implementation in routine clinical practice.

• MeSH
• Tissue Donors statistics & numerical data   MeSH
• Adult MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Perfusion * methods   instrumentation   MeSH
• Graft Survival * MeSH
• Aged MeSH
• Hypothermia, Induced methods   MeSH
• Liver Transplantation * methods   adverse effects   MeSH
• Organ Preservation * methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

V kazuistice prezentujeme případ patnáctiletého chlapce se vzácnou primární imunodeficiencí, tzv. syndromem XMEN. Tento syndrom je charakterizován zvýšenou náchylností k chronické EBV infekci a lymfoproliferacím asociovaným s EBV, dalšími klinickými znaky bývají sinopulmonární infekce, otitidy, lymfadenopatie, dysgamaglobulinemie a autoimunitní cytopenie. XMEN syndrom je způsoben mutacemi genu MAGT1, který kóduje přenašeč hořečnatých kationtů magnesium transporter protein 1. Klíčovým bodem kazuistiky je strastiplná diagnostická cesta pacienta, jemuž přes postupné návštěvy celé řady specialistů chybělo komplexní zhodnocení stavu a zachycení souvislostí různých klinických symptomů, které přinesla až návštěva v ambulanci alergologa/klinického imunologa

In this case report, we present a case of a 15 year old boy with a rare primary immunodeficiency called XMEN syndrome. XMEN syndrom is characterized by increased susceptibility to chronic EBV infection and EBV-associated lymphoproliferation, sinopulmonary and ear infections, lymphadenopathy, dysgammaglobulinemia, and autoimmune cytopenias. XMEN disease is caused by loss of function mutations in the gene MAGT1, which codes magnesium transporter protein 1.The critical point of the case report is the difficult diagnostic journey of the patient, who, despite a series of visits to several specialists, lacked a comprehensive assessment of his condition. A visit to an allergist/ clinical immunologist only gave a grasp of the context of various clinical symptoms.

Idiopatické střevní záněty, ulcerózní kolitida a Crohnova nemoc jsou celoživotní zánětlivá onemocnění s genetickým podkladem. Při kontaktu imunitního systému trávicí trubice s antigeny zevního prostředí a za spoluúčasti vlastní přirozené mikroflóry dochází ke ztrátě imunitní tolerance, selhání bariérové funkce střeva a k rozvoji poškozujícího zánětu s manifestací idiopatických střevních zánětů. Optimálních výsledků léčby dosahuje i přes pokroky ve vývoji biologické a cílené terapie cca třetina pacientů. Mirikizumab je první monoklonální protilátka proti p19 podjednotce IL-23, schválená pro léčbu UC v ČR. V naší kazuistice přinášíme zkušenosti s mirikizumabem v léčbě pacienta s refrakterní ulcerózní kolitidou.

Inflammatory bowel disease, ulcerative colitis and Crohn’s disease, are lifelong inflammatory diseases with a genetic basis. When the immune system of the digestive tract comes into contact with antigens from the external environment and the participation of its own natural microflora, there is a loss of immune tolerance, failure of the intestinal barrier function and the development of damaging inflammation with the manifestation of inflammatory bowel disease. Optimal treatment results, despite advances in the development of biological and targeted therapy, are achieved by approximately 1/3 of patients. Mirikizumab is the first monoclonal antibody against the p19 subunit of interleukin 23 approved for the treatment of ulcerative colitis in the Czech Republic. In our case study, we present our experience with mirikizumab in the treatment of a patient with refractory ulcerative colitis.

Smrt mozku definujeme jako stav po katastrofálním poškození mozku s trvalou nevratnou ztrátou všech funkcí celého mozku, včetně kmene. Stanovení diagnózy je založeno na klinickém vyšetření, kdy je zcela nepřípustná falešná negativita jednotlivých testů, které podporují ireverzibilní postižení mozkového kmene od mesencefala (fotoreakce) přes pons Varoli (korneální, okulocefalický reflex a algické podráždění v obličeji) až po prodlouženou míchu (dávivý a kašlací reflex). V současné době není jasně stanovena metodika provedení jednotlivých vyšetření. Tento článek pojednává o základním klinickém vyšetření při stanovení smrti mozku a apnoickém testu. Součástí publikace je rovněž soubor videí, která ukazují pozitivní nález při stanovení smrti mozku (čili areflexii) a nález, který není kompatibilní se smrtí mozku (přítomnost normální odpovědi).

We define brain death as a condition following catastrophic brain injury with permanent irreversible loss of all functions of the entire brain, including the brain stem. Diagnosis is based on clinical examination, where are completely unacceptable false negative individual tests that support irreversible brainstem involvement from the mesencephalon (photoreaction) to the pons Varoli (corneal, oculocephalic reflex and facial alginic irritation) to the medulla oblongata (gag and cough reflex). At present, the methodology for performing each exa­mination is not clearly established. This article discusses the basic clinical examination in the determination of brain death and the apnea test. The publication also includes a set of videos that show a positive finding in the determination of brain death (absence of reflex) and a finding that is not compatible with brain death (presence of a normal response).

• Keywords
• apnoický test, funkce mozkového kmene, reflexy mozkového kmene,
• MeSH
• Diagnostic Techniques, Neurological MeSH
• Humans MeSH
• Brain Death * diagnosis   MeSH
• Brain Stem MeSH
• Neurologic Examination MeSH
• Reflex MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND: Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease. METHODS: In this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR-Cas9 editing and standard cell biology techniques. FINDINGS: Between Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of <1·25 × 10:sup>-6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1-8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling. INTERPRETATION: PTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population. FUNDING: The UK Medical Research Council, the European Research Council, and the Agence Nationale de la Recherche.

• MeSH
• Child MeSH
• Haploinsufficiency * genetics   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation genetics   MeSH
• Brain Diseases genetics   MeSH
• Neuroinflammatory Diseases genetics   MeSH
• Child, Preschool MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 * genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH