Real-life effectiveness of dupilumab in chronic rhinosinusitis with nasal polyps. Results from eight Hungarian centres with 12-month follow-up.

BACKGROUND: Research on the immune mechanism behind chronic rhinosinusitis (CRS) has revealed various new endotypes, leading to targeted therapies, especially for severe uncontrolled CRS. Biologics are novel therapeutic strategies providing targeted treatment for the difficult-to-treat recalcitrant CRSwNP patients. Dupilumab is a fully human-derived monoclonal antibody that binds to IL4Rα, inhibiting the signalling of both IL-4 and IL-13. In Hungary, it is approved for the treatment of uncontrolled CRSwNP according to criteria based on the EPOS2020 and the Hungarian guidelines. METHODOLOGY: This study aimed to collect and evaluate real-world therapeutic data of CRSwNP patients treated with dupilumab. One hundred thirty-five patients from eight different referral centres have been enrolled in this study, who received dupilumab since 2020. All subjects were adult patients (over 18 years) with uncontrolled CRSwNP. Baseline data collection included demographics, medical history, previous surgeries, related comorbidities, total endoscopic nasal polyp score (NPS), SNOT22, nasal congestion parameters measured with visual analogue scale (VAS) and nasal obstruction evaluation scale (NOSE), loss of smell score (LSS) and eosinophil count. 300 mg dupilumab was administered subcutaneously every second week. Follow up visits were performed after 6 and 12 months. RESULTS: After 6 and 12 months of treatment significant improvement was detected in all clinical parameters. Safety was proved, no severe side effects occurred, and no rescue treatment was necessary. CONCLUSIONS: Our real-life findings show that continuous dupilumab treatment is effective and safe in daily clinical practice in CRSwNP and other type 2 comorbidities such as bronchial asthma and NERD.

Management of thoracic trauma.

Managing major thoracic trauma begins with identifying and anticipating injuries associated with the mechanism of injury. The key aims are to reduce early mortality and the impact of associated complications to expedite recovery and restore the patient to their pre-injury state. While imaging is imperative to identify the extent of thoracic trauma, some pathology may require immediate treatment. The majority can be managed with adequate pleural drainage, but respiratory failure and poor gas exchange may require either non-invasive or invasive ventilation. Ventilation strategies to protect from complications such as barotrauma, volutrauma and ventilator-induced lung injury are important to consider. The management of pain is vital in reducing respiratory complications. A multimodal strategy using local, regional and systemic analgesia may mitigate respiratory side effects of opioid use. With optimal pain management, physiotherapy can be fully utilised to reduce respiratory complications and enhance early recovery. Thoracic surgeons should be consulted early for consideration of surgical management of specific injuries. With a greater understanding of the mechanisms of injury and the appropriate use of available resources, favourable outcomes can be reached in this cohort of patients. Overall, a multidisciplinary and holistic approach results in the best patient outcomes.

Identification of putative genetic modifying factors that influence the development of Papillon-Lefévre or Haim-Munk syndrome phenotypes.

BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndrome (HMS; OMIM 245010), which are both characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. AIM: To identify putative genetic modifying factors responsible for the differential development of the PLS or HMS phenotypes, we investigated two Hungarian patients with different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X). METHODS: To gain insights into phenotype-modifying associations, whole exome sequencing (WES) was performed for both patients, and the results were compared to identify potentially relevant genetic modifying factors. RESULTS: WES revealed two putative phenotype-modifying variants: (i) a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and (ii) a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. CONCLUSION: Our study contributes to the accumulating evidence supporting the clinical importance of phenotype-modifying genetic factors, which have high potential to aid the elucidation of genotype-phenotype correlations and disease prognosis.

On-axis versus off-axis Transmission Kikuchi Diffraction technique: application to the characterisation of severe plastic deformation-induced ultrafine-grained microstructures.

A new configuration for Transmission Kikuchi Diffraction (TKD) in a scanning electron microscope is presented; called 'on-axis TKD'. Compared to the usual off-axis configuration, the scintillator is placed perpendicular to the incident beam under the electron-transparent sample, not in vertical position. In this way, the setup benefits from intense forward scattered electrons enabling short acquisition times. At equivalent diffraction pattern quality, the electron dose needed on the sample is estimated to be 20 times lower in comparison to the off-axis configuration. The technique is particularly suited to the characterisation of severe plastic deformation induced ultrafine grained microstructures. The evolution of the microstructure of an Al-Mg alloy deformed by high pressure tube twisting was analysed. It is shown that the grain refinement was in the steady state stage for a shear strain of 24 with a mean grain size of 120 nm.

One mutation, two phenotypes: a single nonsense mutation of the CTSC gene causes two clinically distinct phenotypes.

BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndromes (HMS; OMIM 245010) are phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene, and they exhibit autosomal recessive inheritance. AIMS: To identify diseases caused by mutations of the CTSC gene in two Hungarian patients and to perform haplotype analysis to elucidate any familial relationship between them. METHODS: Mutation screening and polymorphism analysis were performed by direct sequencing of the CTSC gene. RESULTS: Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation (c.748C/T; p.Arg250X). However, one patient exhibited the PLS phenotype and the other the HMS phenotype. Although these patients were not aware that they were related, haplotype analysis, especially the genotypes of the rs217116 and the rs217115 polymorphisms, clearly indicated that the patients carry the same haplotype, whereas the unrelated healthy controls carried several different haplotypes. CONCLUSIONS: Our results demonstrate that PLS and HMS are phenotypic variants of the same disease and, additionally, exclude the presence of a putative genetic modifier factor within the CTSC gene that is responsible for the development of the two phenotypes. We suggest that this putative genetic modifier factor is located outside the CTSC gene, or alternatively, that the development of the different phenotypes is the consequence of different environmental or lifestyle factors.

The beneficial effect of plasmapheresis in mixed connective tissue disease with coexisting antiphospholipid syndrome.

The authors report a rare case of a female patient with mixed connective tissue disease (MCTD) with coexisting antiphospholipid syndrome (APS). Five years after the diagnosis of MCTD high concentrations of anticardiolipin (anti-CL) and anti-ß2-glycoprotein (anti-ß2GPI) autoantibodies were present in the patient's serum without thrombotic events. Epstein-Barr virus (EBV) reactivation provoked APS, with the clinical manifestations of livedo reticularis, digital gangrene and leg ulcers. Skin biopsy from the necrotic area showed multiple fibrin microthrombi in the superficial vessels. Corticosteroid pulse therapy, and plasma exchange in combination with synchronized cyclophosphamide was administered, which led to improvement of the digital gangrenes, while no new lesions developed. The number of CD27high plasma cells decreased, and the previous high levels of autoantibodies also normalized in the peripheral blood. In the case of MCTD with coexisting APS combination therapy, including plasmapheresis has beneficial effects.

Bilateral juvenile fibroadenosis of the breast: management with subcutaneous mastectomy and silicone implant placement.

Bilateral fibroadenosis is a rare, benign disorder, affecting adolescents or women of childbearing age. Choosing the most optimal therapy that manages both the physical and psychological aspects of the disease is a challenge. The goals of the treatment are complete resection of the lesions with optimal cosmesis. Options range from cryoablation, ultrasound-guided vacuum-assisted eradication and simple excision of the lesions to subcutaneous mastectomy with reconstruction. We present a case of a 25-year-old woman with 37 complex fibroadenomas affecting both breasts who was treated with nipple-sparing subcutaneous mastectomy and silicone implant reconstruction to both the surgeons' and patient's satisfaction.

Measurement-induced chaos with entangled states.

The dynamics of an ensemble of identically prepared two-qubit systems is investigated which is subjected to the iteratively applied measurements and conditional selection of a typical entanglement purification protocol. The resulting dynamics exhibits strong sensitivity to initial conditions. For one class of initial states two types of islands characterize the asymptotic limit. They correspond to a separable and a fully entangled two-qubit state, respectively, and their boundaries form fractal-like structures. In the presence of incoherent noise an additional stable asymptotic cycle appears.

Granular cell tumour of the breast: case series and review of the literature.

Granular cell tumours (GCTs) are uncommon rare neoplasms that may occur in any part of the body. Approximately 5-8% of granular cell tumours occur within the breast. Although nearly always benign in behaviour, granular cell tumours of the breast can often mimic breast malignancies both clinically and on the basis of imaging techniques. This article reports five cases of benign granular cell tumours appearing in the breast, mimicking a malignant breast lesion. In addition to reporting the cases, the relevant literature was reviewed.

Screening of common Plantago species in Hungary for bioactive molecules and antioxidant activity.

Five species of Plantago genus, namely P. lanceolata, P. major, P. media, P. altissima and P. maritima were screened for iridoid content (CE-MEKC), total caffeoyl phenylethanoid glycoside (CPG) content and antioxidant activity (CUPRAC assay). The five species could be distinguished by TLC pattern analysis in a single run in a system commonly used for quality management of P. lanceolata leaves, as shown by cluster analysis of major bands; with the exception, that P. altissima and P. lanceolata did not show enough pattern difference to be fully separated. P. maritima was shown to have the highest antioxidant capacity (0.42 µmol ascorbic acid equivalent (AAE)/g DW), and the highest level of CPGs (4.29%). P. altissima was shown to be chemically indistinguishable from P. lanceolata with repsect to iridoid content (aucubin 0.55 ± 0.04%, 0.68 ± 0.23%, catalpol 0.66 ± 0.13% and 0.89 ± 0.22%, respectively), CPG content (2.40 ± 0.38% and 2.54 ± 0.56%, respectively) and antioxidant capacity (0.2206 ± 0.0290 and 0.2428 ± 0.0191 µmol AAEAC/g DW). The presented data show the potency of medicinal use of Hungarian wild populations of the studied five species, especially in the case of P. maritima, and that P. altissima can be a potential replacement of P. lanceolata in herbal mixtures.

Orientation selectivity of cortical neurons during intracellular blockade of inhibition.

Neurons in the primary visual cortex of the cat are selectively activated by stimuli with particular orientations. This selectivity can be disrupted by the application of antagonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to a local region of the cortex. In order to determine whether inhibitory inputs are necessary for a single cortical neuron to show orientation selectivity, GABA receptors were blocked intracellularly during whole cell recording. Although the membrane potential, spontaneous activity, subfield antagonism, and directional selectivity of neurons were altered after they were perfused internally with the blocking solution, 18 out of 18 neurons remained selective for stimulus orientation. These results indicate that excitatory inputs are sufficient to generate orientation selectivity.

A mouse homeo box gene is expressed in spermatocytes and embryos.

The MH-3 gene, which contains a homeo box that is expressed specifically in the adult testis, was identified and mapped to mouse chromosome 6. By means of in situ hybridization with adult testis sections and Northern blot hybridization with testis RNA from prepuberal mice and from Sl/Sld mutant mice, it was demonstrated that this gene is expressed in male germ cells during late meiosis. In the embryo, MH-3 transcripts were present at day 11.5 post coitum, a stage in mouse development when gonadal differentiation has not yet occurred. The MH-3 gene may have functions in spermatogenesis and embryogenesis.

Increased expression of TRPV1 in squamous cell carcinoma of the human tongue.

OBJECTIVES: Recent reports have unambiguously identified the presence and the growth-modulatory role of transient receptor potential vanilloid-1 (TRPV1), a central integrator of pain sensation, on numerous non-neuronal cell types and, of great importance, in certain malignancies. In this study, we have investigated the molecular expression of TRPV1 in the human tongue and its high-incidence malignant (squamous cell carcinoma, SCC) and premalignant (leukoplakia) conditions. METHODS: Immunohistochemistry, Western blotting and quantitative 'real-time' Q-PCR were performed to define the expression of TRPV1. RESULTS: A weak and sparse TRPV1-specific immunoreactivity was identified in the basal layers of the healthy human tongue epithelium. By contrast, we observed a dramatically elevated TRPV1-immunoreactivity in all layers of the epithelium both in precancerous and malignant samples. Furthermore, statistical analysis revealed that the marked overexpression of TRPV1 found in all grades of SCC showed no correlation with the degree of malignancy of the tumours. Finally, the molecular expression of TRPV1 was also identified in an SCC-derived cell line and was shown to be increased in parallel with the accelerated growth of the cells. CONCLUSION: Collectively, our findings identify TRPV1 as a novel, promising target molecule in the supportive treatment and diagnosis of human tongue SCC.

[Vertebroplasty and kyphoplasty--treatment of osteoporotic vertebral fractures]. / Vertebroplastika a kyfoplastika - metoda lécby osteoporotických zlomenin pátere.

PURPOSE OF THE STUDY The surgical treatment of osteoporotic vertebral body fractures is associated with many complications. Vertebroplasty (VP) and kyphoplasty (KP) are minimally invasive procedures allowing us to strengthen the vertebral body and thus stabilize it. The aim of this non-randomized study is to evaluate a group of patients treated by VP and KP procedures and to discuss related risks. MATERIAL Between September 2005 and October 2007, a total of 32 patients (37 vertebrae) were treated by the VP and KP techniques. Vertebroplasty was used in 21 and kyphoplasty in 11 patients. In this initial group, four patients were excluded from evaluation because of a tumour aetiology of the fracture. The remaining 28 patients who had an osteoporotic vertebral body fracture verified by CT scan findings were followed up and evaluated. METHODS The evaluation was based on modified Oswestry disability index (ODI) and visual analogue scale (VAS) scores recorded at 6 weeks, 3 and 6 months and 1 year postoperatively. Cement leakage detected by X-ray was assessed by means of the classification used by Yeom et al. and, at the same time, the occurrence of adjacent vertebral fracture, if any, was detected by 1 year after surgery. RESULTS Radiographic cement leakage was found in eight patients (21.6%), with clinical manifestation in two (5.4%). One had an incomplete motor lesion due to cement leakage into the spinal column, and the other had pulmonary embolism due to cement leakage into the mediastinum. The whole group showed marked improvement in clinical condition, as assessed by the ODI. When expressed as per cent, the average ODI was 57% pre- and 15.7 % post-operatively. All patients reported pain relief in the affected spine. The average VAS score of 8.1 pre-operatively decreased to an average of 2.6 post-operatively. There were no radiographic findings of adjacent vertebral body fracture. DISCUSSION Vertebroplasty and kyphoplasty are currently used to treat osteoporotic vertebral fracture. Their advantages include an immediate stabilization of the vertebra by cement solidification, possibility of percutaneous application under local anaesthesia, and early patient mobilization without any external fixation. However, when evaluating these techniques, safety of the surgical procedure should be taken into consideration. The most frequent risk is cement leakage. CONCLUSIONS Vertebroplasty and kyphoplasty can, under strict adherence to the operative protocol, be an effective approach to the treatment of osteoporotic vertebral body fracture. It permits early mobilization of the patient without the necessity of external fixation. Key words: vertebroplasty, kyphoplasty, osteoporotic spine fracture, osteoporosis.

The unprecedented loss of Florida's reef-building corals and the emergence of a novel coral-reef assemblage.

Over the last half century, climate change, coral disease, and other anthropogenic disturbances have restructured coral-reef ecosystems on a global scale. The disproportionate loss of once-dominant, reef-building taxa has facilitated relative increases in the abundance of "weedy" or stress-tolerant coral species. Although the recent transformation of coral-reef assemblages is unprecedented on ecological timescales, determining whether modern coral reefs have truly reached a novel ecosystem state requires evaluating the dynamics of reef composition over much longer periods of time. Here, we provide a geologic perspective on the shifting composition of Florida's reefs by reconstructing the millennial-scale spatial and temporal variability in reef assemblages using 59 Holocene reef cores collected throughout the Florida Keys Reef Tract (FKRT). We then compare the relative abundances of reef-building species in the Holocene reef framework to data from contemporary reef surveys to determine how much Florida's modern reef assemblages have diverged from long-term baselines. We show that the composition of Florida's reefs was, until recently, remarkably stable over the last 8000 yr. The same corals that have dominated shallow-water reefs throughout the western Atlantic for hundreds of thousands of years, Acropora palmata, Orbicella spp., and other massive coral taxa, accounted for nearly 90% of Florida's Holocene reef framework. In contrast, the species that now have the highest relative abundances on the FKRT, primarily Porites astreoides and Siderastrea siderea, were rare in the reef framework, suggesting that recent shifts in species assemblages are unprecedented over millennial timescales. Although it may not be possible to return coral reefs to pre-Anthropocene states, our results suggest that coral-reef management focused on the conservation and restoration of the reef-building species of the past, will optimize efforts to preserve coral reefs, and the valuable ecosystem services they provide into the future.

Electrical and memory properties of Si3N4 MIS structures with embedded Si nanocrystals.

Memory structures with an embedded sheet of separated Si nanocrystals were prepared by low pressure chemical vapour deposition using a Si3N4 control layer and different Si2O2 or Si3N4 tunnel layers. It was obtained that Si nanocrystals improve the charging behaviour of the MNOS structures. Memory window width of 1.3 V and 2.0 V were obtained for pulse amplitudes of +/-9 V and +/-10 V, 100 ms, respectively. The extrapolated memory window after 10 years is about 15% of its initial value.

Formation of ge nanocrystals in SiO2 by electron beam evaporation.

Ge nanocrystals were formed by electron beam evaporation on SiO2 covered Si substrates. The size and distribution of the nanocrystals were studied by atomic force microscopy, scanning electron microscopy and cross-sectional transmission electron microscopy. Dependencies of the nanocrystal size, of the nanocrystal surface coverage, and sheet resistance obtained by van der Pauw method of the Ge layer have been found on the evaporation time. The suggested growth mechanism for the formation of nanocrystals is the Volmer-Weber type. The sheet resistance exhibited a power dependence on the nanocrystal size.

[Surgical treatment of spondylodiscitis]. / Operacní lécba spondylodiscitidy.

PURPOSE OF THE STUDY: Surgical treatment of spondylodiscitis is associated with many complications and raises a number of issues for discussion. The aim of the study was to evaluate a group of patients who had undergone surgery for inflammation of the spine, and to discuss the optimal operative procedure. MATERIAL: Between January 2000 and February 2005, a total of 81 patients were treated at our department for pyogenic or tuberculous spondylodiscitis. Of these, 31 (11 women and 20 men) underwent surgery. Patients treated by CT-guided abscess drainage puncture with antibiotic therapy were not included. Indications for surgery included neurological deficit in 20 patients, deformity or mechanic instability in six, and progressing septic condition in three patients. METHODS: Simple decompression of nerve structures from the posterior approach, combined with drainage, was performed in seven patients, revision surgery from the posterior approach and fusion completed with suction drainage was done in five, anterior radical debridement and stabilization of the anterior column by replacement of the vertebral body was performed in 15 patients, and an anterior procedure completed with posterior instrumentation and fusion was carried out in four patients. The patients were followed up and evaluated at 3, 6 and 12 months post-operatively. RESULTS: Improvement in neurological deficit by one or more Frankel grades was recorded in 30 % of the patients treated by posterior decompression and suction drainage, and in 83 % of the patients undergoing anterior debridement and stabilization. Further progression of deep infection requiring revision surgery and implant removal occurred in one patient. Clinical outcomes assessed as good or satisfactory were found in 68 % and poor results were in 32 % of the patients. DISCUSSION: The selection of an optimal surgical procedure in spondylodiscitis depends on the primary localization of infectious lesions. In a typical anterior form of spondylodiscitis, anterior debridement and suction drainage are preferred. Reconstruction of the anterior spinal column in the presence of major destruction, and stabilization of an infected spine still remain challenging issues. CONCLUSIONS: Radical debridement with deformity correction and segmental stabilization provide an efficient method of treatment for the most frequent anterior forms of pyogenic and tuberculous spondylodiscitis. The use of titan implants does not significantly increase the risk of persistent infection or its recurrence.

Reduced basal and lipopolysaccharide-stimulated adenosine A1 receptor expression in the brain of nuclear factor-kappaB p50-/- mice.

Adenosine promotes cytoprotection under conditions of infection, ischemic preconditioning and oxidative stress. Previous studies from our laboratory indicate that the expression of the adenosine A1 receptor (A1AR) is induced by oxidative stress via activation of nuclear factor (NF)-kappaB. The prototypic transcription factor is composed of homo- or heterodimers of p50 and p65 subunits. To determine the role of NF-kappaB in the regulation of the A1AR in vivo, we compared the A1AR RNA and protein levels in the brains of mice lacking the p50 subunit of NF-kappaB (p50-/- mice) and age-matched B6129PF2/J (F2) controls. Radioligand binding assays in the cortex revealed a significantly lower number of A(1)AR (maximal binding capacity, Bmax) in the cortex of p50-/- mice (151+/-62 fmol/mg protein) versus 479+/-181 fmol/mg protein in the F2 (N=5 per strain, P<0.05), but no change in the equilibrium dissociation constant. Similar reductions in A1AR were measured in the hippocampus, brain stem and hypothalamus and in peripheral tissues, such as the adrenal gland, kidney and spleen. Estimation of the A1AR following purification by antibody affinity columns also indicated reduced A1AR in the p50-/- mice cortex, as compared with the F2 mice. A1AR immunocytochemistry indicates distinct neuronal labeling in the F2 cortex, which was substantially reduced in similar sections obtained from p50-/- mice. The p50-/- mice expressed lower levels of A1AR mRNA than F2 mice, as determined by real time PCR. Quantitation of the A1AR transducing G proteins by Western blotting show significantly less Galphai3, no change in Galphai1, but higher levels of Galphao and Gbeta in the cortices of p50-/-, as compared with F2 mice. Administration of bacterial lipopolysaccharide (LPS), an activator of NF-kappaB, increased A1AR expression in the cortices of F2 mice but not p50-/- mice. Cortical neurons cultures prepared from p50-/- mice showed a greater degree of apoptosis, compared with neurons from F2 mice. Activation of the A1AR reduced apoptosis with greater efficacy in cultures from F2 than p50-/- mice. Taken together, these data support a role for NF-kappaB in determining both the basal and LPS-stimulated A1AR expression in vivo which could contribute to neuronal survival.

Murine Hox-1.7 homeo-box gene: cloning, chromosomal location, and expression.

A new murine homeo-box, called Hox-1.7, has been identified in a rare cDNA from F9 teratocarcinoma stem cells. The Hox-1.7 homeo-box is 68 and 72% homologous to the Drosophila antennapedia (Antp) and iab-7 homeo-boxes, respectively. A major 2.5-kilobase transcript and several minor transcripts were detected by Northern blot (RNA blot) analysis in adult tissues as well as in midgestational embryos. The posterior spinal cord was found to be a major site of Hox-1.7 expression in 12.5-day-old embryos. Somatic cell hybrids were used to map the Hox-1.7 gene to mouse chromosome 6. Restriction fragment length polymorphisms associated with either the Hox-1.7 gene or the previously known Hox-1 complex were identified. Their distribution patterns in recombinant inbred mouse strains were used to determine the linkage between the two loci as well as to other loci on chromosome 6. This maps Hox-1 and Hox-1.7 close to two mouse loci that affect morphogenesis, postaxial hemimelia (px) and hypodactyly (Hd).