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Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same central and peripheral nervous system disorders that cause neuropathic pain, such as sensory polyneuropathy, radiculopathy, herpes zoster, stroke, or multiple sclerosis, and lesion location affects symptoms more than aetiology. The causes of neuropathic itch are heterogeneous, and thus diagnosis is based primarily on recognising characteristic, disease-specific clinical presentations. However, the diagnosis of neuropathic itch is challenging, different subforms exist (eg, focal vs widespread, peripheral vs central), and the mechanisms of neuropathic itch are poorly understood, resulting in reduced treatment availability. Currently available strategies include treating or preventing causal diseases, such as diabetes or herpes zoster, and topical or systemic medications that calm excess neuronal firing. Discovery of itch mediators such as gastrin releasing peptide, receptors (eg, neurokinin-1), and pathways (eg, Janus kinases) might encourage much needed new research into targeted treatments of neuropathic itch.

Sepsis is usually accompanied by changes of body temperature (Tb), but whether fever and hypothermia predict mortality equally or differently is not fully clarified. We aimed to find an association between Tb and mortality in septic patients with meta-analysis of clinical trials. We searched the PubMed, EMBASE, and Cochrane Controlled Trials Registry databases (from inception to February 2016). Human studies reporting Tb and mortality of patients with sepsis were included in the analyses. Average Tb with SEM and mortality rate of septic patient groups were extracted by two authors independently. Forty-two studies reported Tb and mortality ratios in septic patients (n = 10,834). Pearson correlation analysis revealed weak negative linear correlation (R2 = 0.2794) between Tb and mortality. With forest plot analysis, we found a 22.2% (CI, 19.2-25.5) mortality rate in septic patients with fever (Tb > 38.0°C), which was higher, 31.2% (CI, 25.7-37.3), in normothermic patients, and it was the highest, 47.3% (CI, 38.9-55.7), in hypothermic patients (Tb < 36.0°C). Meta-regression analysis showed strong negative linear correlation between Tb and mortality rate (regression coefficient: -0.4318; P < 0.001). Mean Tb of the patients was higher in the lowest mortality quartile than in the highest: 38.1°C (CI, 37.9-38.4) vs 37.1°C (CI, 36.7-37.4). Deep Tb shows negative correlation with the clinical outcome in sepsis. Fever predicts lower, while hypothermia higher mortality rates compared with normal Tb. Septic patients with the lowest (< 25%) chance of mortality have higher Tb than those with the highest chance (> 75%).

Transient Receptor Potential Ankyrin 1 (TRPA1) channels are localized on sensory nerves and several non-neural cells, but data on their functional significance are contradictory. We analysed the presence and alterations of TRPA1 in comparison with TRP Vanilloid 1 (TRPV1) at mRNA and protein levels in human and mouse intact and inflamed colons. The role of TRPA1 in a colitis model was investigated using gene-deficient mice. TRPA1 and TRPV1 expressions were investigated in human colon biopsies of healthy subjects and patients with inflammatory bowel diseases (IBD: ulcerative colitis, Crohn's disease) with quantitative PCR and immunohistochemistry. Mouse colitis was induced by oral 2% dextran-sulphate (DSS) for 10 days. For investigating the functions of TRPA1, Disease Activity Index (weight loss, stool consistency, blood content) was determined in C57BL/6-based Trpa1-deficient (knockout: KO) and wildtype (WT) mice. Sensory neuropeptides, their receptors, and inflammatory cytokines/chemokines were determined with qPCR or Luminex. In human and mouse colons TRPA1 and TRPV1 are located on epithelial cells, macrophages, enteric ganglia. Significant upregulation of TRPA1 mRNA was detected in inflamed samples. In Trpa1 KO mice, Disease Activity Index was significantly higher compared to WTs. It could be explained by the greater levels of substance P, neurokinins A and B, neurokinin 1 receptor, pituitary adenylate-cyclase activating polypeptide, vasoactive intestinal polypeptide, and also interleukin-1beta, macrophage chemoattractant protein-1, monokine induced by gamma interferon-1, tumor necrosis factor-alpha and B-lymphocyte chemoattractant in the distal colon. TRPA1 is upregulated in colitis and its activation exerts protective roles by decreasing the expressions of several proinflammatory neuropeptides, cytokines and chemokines.

Rapid and accurate identification of high-risk acute gastrointestinal bleeding (GIB) patients is essential. We developed two machine-learning (ML) models to calculate the risk of in-hospital mortality in patients admitted due to overt GIB. We analyzed the prospective, multicenter Hungarian GIB Registry’s data. The predictive performance of XGBoost and CatBoost machine-learning algorithms with the Glasgow-Blatchford (GBS), pre-endoscopic Rockall and ABC scores were compared. We evaluated our models using five-fold cross-validation, and performance was measured by area under receiver operating characteristic curve (AUC) analysis with 95% confidence intervals (CI). Overall, we included 1,021 patients in the analysis. In-hospital death occurred in 108 cases. The XGBoost and the CatBoost model identified patients who died with an AUC of 0.84 (CI:0.76–0.90; 0.77–0.90; respectively) in the internal validation set, whereas the GBS and pre-endoscopic Rockall clinical scoring system’s performance was significantly lower, AUC values of 0.68 (CI:0.62–0.74) and 0.62 (CI:0.56–0.67), respectively. ABC score had an AUC of 0.77 (CI:0.71–0.83). The XGBoost model had a specificity of 0.96 (CI:0.92–0.98) at a sensitivity of 0.25 (CI:0.10–0.43) compared with the CatBoost model, which had a specificity of 0.74 (CI:0.66–0.83) at a sensitivity of 0.78 (CI:0.57–0.95). XGBoost and the CatBoost models evaluate the mortality risk of acute GI bleeding better, than the conventional risk assessment tools.

Both acute kidney injury and chronic kidney disease are risk factors for many outcomes of gastrointestinal bleeding (GIB). These are associated with higher mortality, longer hospitalisation, and greater need for transfusion in case of overt GIB. Our study aimed to further evaluate the role of kidney function in several clinical outcomes of GIB patients. The Hungarian Gastrointestinal Bleeding Registry collected data on all-cause GIB between 2019 and 2022. A multi-level data-validation system provided high-quality data, which was retrospectively analysed. Numerous primary (in-hospital mortality, discharge, need for endoscopic intervention, in-hospital rebleeding, length of hospitalisation, need for emergency surgery, need for endoscopic examination and need for intensive care unit) and secondary (detection of Helicobacter pylori ( H. pylori ), recognition of cancer as the source of bleeding, need for any kind of transfusion or clotting factor, anticoagulation therapy) outcomes were observed. Descriptive statistical tools were used to summarize our data. Among others, estimated glomerular filtration rate (eGFR) (ml/min/1.73 m 2 ) was used as continuous variable, mean, standard deviation, median, interquartile range and minimum/maximum values were calculated. Reduced kidney function was associated with in-hospital mortality (eGFR: 42.63 ± 28.78 ml/min/1.73 m 2 vs. 57.08 ± 26.62 ml/min/1.73 m 2 , p < 0.001), need for red blood cells (RBC) transfusion (eGFR: 51.98 ± 27.90 ml/min/1.73 m 2 vs. 60.11 ± 25.06 ml/min/1.73 m 2 , p < 0.001) and clotting factor supplementation (eGFR: 47.40 ± 27.41 ml/min/1.73 m 2 vs. 56.68 ± 27.02 ml/min/1.73 m 2 , p < 0.001). Better eGFR values at admission were associated with discharge home after proper treatment, compared to any other outcome of the admission (eGFR: 58.12 ± 25.56 ml/min/1.73 m 2 vs. 50.23 ± 29.69 ml/min/1.73 m 2 , p < 0.001), H. pylori positivity (eGFR: 59.63 ± 25.24 ml/min/1.73 m 2 vs. 52.76 ± 25.44 ml/min/1.73 m 2 , p = 0.021) and the need for endoscopic intervention (eGFR: 58.65 ± 26.61 ml/min/1.73 m 2 vs. 54.31 ± 27.64 ml/min/1.73 m 2 , p = 0.008). At admission, patients with better eGFR than 36.64 ml/min/1.73 m 2 were discharged to their homes, mortality was higher with eGFR worse than 25.96 ml/min/1.73 m 2 , more RBC transfusion was needed if eGFR was lower than 49.61 ml/min/1.73 m 2 . Regulation of anticoagulation was examined extensively. Impaired kidney function at admission results higher in-hospital mortality in overt all-cause GIB and increases the need of RBC transfusion.

The aim of this study was to analyse the clinical characteristics of acute pancreatitis (AP) in a prospectively collected, large, multicentre cohort and to validate the major recommendations in the IAP/APA evidence-based guidelines for the management of AP. Eighty-six different clinical parameters were collected using an electronic clinical research form designed by the Hungarian Pancreatic Study Group. 600 adult patients diagnosed with AP were prospectively enrolled from 17 Hungarian centres over a two-year period from 1 January 2013. With respect to aetiology, biliary and alcoholic pancreatitis represented the two most common forms of AP. The prevalence of biliary AP was higher in women, whereas alcoholic AP was more common in men. Hyperlipidaemia was a risk factor for severity, lack of serum enzyme elevation posed a risk for severe AP, and lack of abdominal pain at admission demonstrated a risk for mortality. Abdominal tenderness developed in all the patients with severe AP, while lack of abdominal tenderness was a favourable sign for mortality. Importantly, lung injury at admission was associated with mortality. With regard to laboratory parameters, white blood cell count and CRP were the two most sensitive indicators for severe AP. The most common local complication was peripancreatic fluid, whereas the most common distant organ failure in severe AP was lung injury. Deviation from the recommendations in the IAP/APA evidence-based guidelines on fluid replacement, enteral nutrition and timing of interventions increased severity and mortality. Analysis of a large, nationwide, prospective cohort of AP cases allowed for the identification of important determinants of severity and mortality. Evidence-based guidelines should be observed rigorously to improve outcomes in AP.

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa 1 , 2 , 3 , 4 , 5 . They are also implicated in the growth of colonic polyps and cancers 6 . However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms 7 , 8 , 9 , we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E 2 (PGE 2 ) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)–mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE 2 -induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-α (TGF-α) or c-Src blocked PGE 2 -mediated EGFR transactivation and downstream signaling indicating that PGE 2 -induced EGFR transactivation involves signaling transduced via TGF-α, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE 2 transactivates EGFR reveal a previously unknown mechanism by which PGE 2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.

Patients with gastrointestinal bleeding (GIB) exhibit varying tolerances to acute blood loss. We aimed to investigate the effect of relative Hb decrease (ΔHb%) on GIB outcomes. Participants enrolled in the Hungarian GIB Registry between 2019 and 2022 were analyzed. The primary outcome, defined as a composite endpoint, included in-hospital bleeding-related mortality and the need for urgent intervention. Four groups were created based on the lowest Hb measured during hospitalization (nadirHb), along with four subgroups categorized by ΔHb%. Regardless of the nadirHb, participants with higher ΔHb% had a higher probability of reaching the composite endpoint. A 30–40% ΔHb% decrease to a nadirHb of 80–90 g/L resulted in a similar likelihood of reaching the primary endpoint as a 0–10% ΔHb% to 70–80 g/L or 60–70 g/L, respectively (10% vs. 12%, p  = 1.00; 10% vs. 10%, p  = 1.00). Our results showed that a higher Hb decrease in GIB is associated with an increased untoward outcome rate even when the lowest hemoglobin exceeds the recommended transfusion thresholds. New randomized controlled trials investigating transfusion thresholds should consider ΔHb% as a potential key variable and risk factor.

Calprotectin, a heterodimer of the S100A8 and S100A9 proteins, has been implicated in cancer-related inflammation and metastasis. Its role in melanoma progression, particularly in organ-specific metastasis, remains underexplored. In this retrospective study, plasma calprotectin levels were measured in 201 individuals, including healthy controls (n = 22), melanoma patients without evidence of metastasis (n = 71), and patients with metastatic melanoma (n = 108). Calprotectin concentrations were determined using the ELISA assay. Receiver operating characteristic (ROC) curve analyses were used to evaluate its diagnostic value, both alone and in combination with established biomarkers S100B and LDH. Plasma calprotectin levels were significantly elevated in patients with metastatic melanoma compared to non-metastatic patients (p < 0.001). Calprotectin showed moderate diagnostic value (AUC = 0.672), which improved to 0.755 when combined with S100B and LDH. Organ-specific analysis revealed that patients with liver metastases exhibited the highest calprotectin concentrations, with good discriminatory power (AUC = 0.710). No significant association was found between calprotectin levels and the type of metastasis identified (lymphatic vs. hematogenous). Logistic regression analysis showed that calprotectin levels above 2728 ng/mL were associated with a 7.4-fold increased risk of liver metastasis. Calprotectin is a promising blood-based biomarker that may enhance the detection of metastatic melanoma, particularly in cases with liver involvement. These findings suggest that calprotectin could be integrated into multivariable prediction models to improve risk stratification in clinical practice.

The molecular landscape of cutaneous melanoma is complex and heterogeneous, and a deeper understanding of the genesis and progression of the tumor driven by genetic alterations is essential for the development of effective diagnostic and therapeutic strategies. Molecular diagnostics and the use of biomarkers are increasingly playing a role in treatment decisions. However, further research is urgently needed to elucidate the relationships between complex genetic alterations and the effectiveness of target therapies (although BRAF mutation is still the only targeted genetic alteration). Further research is required to exploit other targetable genetic alterations such as NRAS, KIT or rare mutations. Treatment guidelines for cutaneous melanoma are continually evolving based on data from recent and ongoing clinical trials. These advancements reflect changes mainly in the optimal timing of systemic therapy and the choice of combination therapies increasingly tailored to molecular profiles of individual tumors. Mono- or combination immunotherapies demonstrated unprecedented success of melanoma treatment; still, there is room for improvement: though several factors of primary or acquired resistance are known, they are not part of patient management as biomarkers. The novel developments of cancer vaccines to treat melanoma (melanoma-marker-based or personalized neoantigen-based) are encouraging; introduction of them into clinical practice without proper biomarkers would be the same mistake made in the case of first-generation immunotherapies.