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Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Recently long non-coding RNAs (lncRNAs) have emerged as possible molecular hubs in the diverse pathomechanisms of the disease. Among them, NEAT1 gained particular interest due to findings suggesting both protective and deleterious effects of this lncRNA in PD models.The aim of this study was to clarify some of the contradictions among data that appeared in recent publications concerning NEAT1 effects. For this, we determined whether pharmacological increase of NEAT1 levels worsened the detrimental effect of MPP + in the SH-SY5Y cell model, and whether the levels of the short and long isoform of the lncRNA changed differently upon short and extended MPTP treatment in an MPTP-induced mouse model of PD. Our findings suggest differential expression of NEAT1/Neat1 isoforms in MPP + /MPTP-induced PD models, which is in accord with the proposed role of the lncRNA in the general stress response. We propose that first an early up-regulation of Neat1_2 is dominant. The level of Neat1_2 then decreases as pathology progresses, resulting in a shift in the ratio of the two isoforms towards a higher level of Neat1_1 accompanied by damage of the central nervous system.

Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1 + aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca 2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.

Clinical trials revealed significant antitumor activity for immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC). Due to their strict eligibility criteria, clinical trials include selected patient cohorts, and thus do not necessarily represent real-world population outcomes. In this multicentric, retrospective study, we investigated real-world data to assess the effectiveness of pembrolizumab and atezolizumab and to evaluate the prognostic value of routinely available clinicopathological and laboratory parameters. Clinical and follow-up data from mUC patients who received ICIs (01/2017-12/2021) were evaluated. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) were used as endpoints. Patients’ (n = 210, n = 76 atezolizumab and 134 pembrolizumab) median OS and PFS were 13.6 and 5.9 months, respectively. Impaired ECOG-PS, the presence of visceral, liver or bone metastases, and hemoglobin levels were independently associated with poor OS and DCR. Furthermore, Bellmunt risk factors and the enhanced Bellmunt-CRP score were shown to be prognostic for OS, PFS and DCR. In conclusion, ICIs are effective treatments for a broad range of mUC patients. Our results confirmed the prognostic value of numerous risk factors and showed that Bellmunt risk scores can further be improved when adding CRP to the model.

Given the wide diversity of causes of hematuria, ranging from simple urinary tract infections with rapid recovery to severe glomerulonephritis with fast decline in kidney function, it is essential to recognize the underlying disease. The first objective of the assessment is to determine whether the cause of the hematuria is medically significant. The combination of hematuria with proteinuria, the presence of hypertension, or worsening kidney function can represent signs of progressive kidney disease. Differentiating the various causes of hematuria is often simple and obvious based on the clinical signs and gross appearance of the urine. However, in some instances, additional non-invasive investigations, such as ultrasound imaging, urinary red cell morphology, measurement of calcium and other solutes in the urine, evaluation of kidney function, and protein excretion, are needed to elucidate the nature of the hematuria. Taking a detailed family history can help in establishing the underlying cause in cases of familial hematuria. On the other hand, the decision to perform a kidney biopsy in children with asymptomatic hematuria remains a challenging issue for clinicians. Ultimately, the frequency of diagnosis of glomerular involvement causing hematuria may depend on the threshold for performing a kidney biopsy. The following review will focus on the diagnostics of hematuria, starting with difficulties regarding its definition, followed by various means to differentiate between urinary, glomerular, and other causes, and finally reviewing the most common diseases that, due to their frequency or their effect on kidney function, present a diagnostic challenge in everyday practice.

In Sub-Saharan Africa, African giant pouched rats ( Cricetomys gambianus ) are trained to identify TB patients by smelling sputum. We conducted a systematic review and meta-analysis of the data to see if this novel method is comparable to traditional laboratory screening and detection methods like Ziehl–Neelsen stain-based assays (ZN) and bacterial culture. The search and data processing strategy is registered at PROSPERO (CRD42019123629). Medline via PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically searched for the keywords “pouched rat” and “tuberculosis”. Data from 53,181 samples obtained from 24,600 patients were extracted from seven studies. Using sample-wise detection, the sensitivity of the studies was 86.7% [95% CI 80.4–91.2%], while the specificity was 88.4% [95% CI 79.7–93.7%]. For patient-wise detection, the sensitivity was 81.3% [95% CI 64.0–91.4%], while the specificity was 73.4% [95% CI 62.8–81.9%]. Good and excellent classification was assessed by hierarchical summary receiver-operating characteristic analysis for patient-wise and sample-wise detections, respectively. Our study is the first systematic review and meta-analysis of the above relatively inexpensive and rapid screening method. The results indicate that African giant pouched rats can discriminate healthy controls from TB individuals by sniffing sputum with even a higher accuracy than a single ZN screening.

Systemic immune changes have been implicated in amyotrophic lateral sclerosis (ALS), but precise mechanisms and cellular targets remain unknown. Neuromuscular junction (NMJ) denervation is another major pathophysiological event in ALS, but it remains unclear whether immune system dysregulation contributes to this process. Here, we report leukocyte and macrophage infiltration in ALS patient-derived skeletal muscle biopsies. Immune cell infiltration was replicated across the hTDP-43, TDP-43 A315T (male only) and TDP-43 M337V mouse models, occurring from pre-symptomatic stages and targeted to NMJ-enriched muscle regions. Proteomic analysis implicated the CCL2-CCR2 axis as a driving factor. CCL2 + cells were enriched around NMJs in hTDP-43 mice, and in ALS patient skeletal muscle. Local treatment with CCL2-neutralising antibodies or normal IgG antibodies in hTDP-43 mice reduced leukocyte infiltration and ameliorated NMJ denervation. These results demonstrate that the CCL2-CCR2 axis drives immune cell infiltration targeting NMJs in ALS, identifying a potential avenue for therapeutic intervention to prevent NMJ denervation. Neuromuscular junctions (NMJs) are denervated in amyotrophic lateral sclerosis (ALS) through unknown mechanisms. Here, the authors show immune cells infiltrating muscle of ALS patients and mouse models, driven by CCL2-CCR2, which can be blocked to protect NMJs.

The last two years, the period of the pandemic, have brought a significant change in the tourism of Hungary, which has been developing unbroken until then. The year 2019 broke all the peaks that were interrupted by the pandemic. This particularly affected our spa towns of international significance, including the examined settlements, Hévíz and Zalakaros. The aim of the study is to show what changes have taken place in the development of the number of visitors in the cities that have been based mainly on foreign traffic until then, what territorial reorganization has taken place in terms of sending areas, and what new target groups with modified attitude have emerged. In this study, we analyzed in detail the databases of the National Tourist Data Center, which has been operating since July 2019, and the monthly database of the Hungarian Central Statistical Office. The special, so-called unconventional tourism is carried out on the one hand by the methodology of statistical data collection and on the other hand by the explored tourism behavior. According to our results, it is clear that due to the domestic traffic, a completely new target group (age group and status) appeared in the two spa towns, their sending areas affected the metropolitan suburban zones, and the target group was high-status, younger guests. In our opinion, this offers a new opportunity for spa towns to generate more sustainable, future-oriented guests with a focus on local values, creating a new supply structure and image, as well as messages.

BackgroundIn atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known.Case-diagnosis/treatmentWe present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn’s disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses.ConclusionIn aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.

Background: Invasive fungal disease is a significant cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients. Posaconazole, a broad-spectrum triazole, is widely used as prophylaxis. Methods: We conducted a monocentric, retrospective study to present real-world data on posaconazole trough levels in paediatric alloHSCT patients. The main objective was to determine the required daily dose of posaconazole in paediatric patients. We analysed factors influencing posaconazole levels, and the association between posaconazole levels and breakthrough fungal infection. Results: Among 102 allogeneic HSCT recipients, we measured posaconazole plasma concentrations in 548 blood samples. The required daily doses to reach a target range of 0.7–2.0 mg/L were 15.22 (suspension), 7.52 (tablet), and 7.84 mg/kg (intravenous). Patients aged < 13 years needed higher doses to achieve the target range. The presence of enteral symptoms during prophylaxis was associated with lower plasma concentrations (p < 0.001), while co-administration of proton pump inhibitors did not (p = 0.09). Eight breakthrough infections occurred; low levels of posaconazole (<0.7 mg/L) were observed in five out of eight cases. The Cox regression model showed that higher mean plasma concentrations decreased the hazard of breakthrough infections. Conclusions: The tablet and intravenous formulations of posaconazole outperformed the suspension in terms of predictability. Our analyses on breakthrough infections and posaconazole plasma levels suggest an exposure–response relationship.