Enhanced Resistance to Viruses in Nicotiana edwardsonii 'Columbia' Is Dependent on Salicylic Acid, Correlates with High Glutathione Levels, and Extends to Plant-Pathogenic Bacteria and Abiotic Stress.

Our earlier research showed that an interspecific tobacco hybrid (Nicotiana edwardsonii 'Columbia' [NEC]) displays elevated levels of salicylic acid (SA) and enhanced resistance to localized necrotic symptoms (hypersensitive response [HR]) caused by tobacco mosaic virus (TMV) and tobacco necrosis virus (TNV), as compared with another interspecific hybrid (Nicotiana edwardsonii [NE]) derived from the same parents. In the present study, we investigated whether symptomatic resistance in NEC is indeed associated with the inhibition of TMV and TNV and whether SA plays a role in this process. We demonstrated that enhanced viral resistance in NEC is manifested as both milder local necrotic (HR) symptoms and reduced levels of TMV and TNV. The presence of an adequate amount of SA contributes to the enhanced defense response of NEC to TMV and TNV, as the absence of SA resulted in seriously impaired viral resistance. Elevated levels of subcellular tripeptide glutathione (GSH) in NEC plants in response to viral infection suggest that in addition to SA, GSH may also contribute to the elevated viral resistance of NEC. Furthermore, we found that NEC displays an enhanced resistance not only to viral pathogens but also to bacterial infections and abiotic oxidative stress induced by paraquat treatments. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Heat Treatments at Varying Ambient Temperatures and Durations Differentially Affect Plant Defense to Blumeria hordei in a Resistant and a Susceptible Hordeum vulgare Line.

Our previous research showed that a powdery mildew resistant barley line (MvHV07-17) maintains its resistance to Blumeria hordei (Bh) even if plants are exposed to a long-term high temperature of 35°C for 120 h before Bh inoculation, whereas such high temperature pretreatment further increases susceptibility to infection in the susceptible barley line MvHV118-17. In the present study, we extended this approach using short-term high-temperature water treatment (49°C for 30 s) to determine how it affects powdery mildew resistance in these barley lines. We found that this short-term heat shock (HS) impaired plant defense responses, as reflected by development of Bh colonies and visible necrotic spots on leaves of MvHV07-17, which does not develop visible symptoms upon Bh inoculation under optimal growth conditions. In contrast, both HS and long-term heat stress enhanced susceptibility to Bh in MvHV118-17 plants. These results were supported by the measurement of Bh biomass using a qPCR method. Furthermore, microscopic examinations showed that HS elevated the rate of successful Bh penetration events and the spread of cell death in the surrounding mesophyll area and allowed for colony formation and sporulation in resistant barley, whereas early and effective plant defense responses, such as papilla formation and single-cell epidermal hypersensitive response, were significantly reduced. Furthermore, we found that the accumulation of hydrogen peroxide in both resistant and susceptible barley was correlated with susceptibility induced by HS and long-term heat-stress. This study may contribute to a better understanding of plant defense responses to Bh in barley exposed to heat. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Relationship between arterial stiffness, left ventricular diastolic function, and renal function in chronic kidney disease.

AIM: In chronic kidney disease, IgA nephropathy, and left ventricular diastolic dysfunction have prognostic significance as well. However, the relationship between diastolic dysfunction, arterial stiffness, and renal function has not been fully elucidated. METHODS: 79 IgA nephropathy patients (aged 46 ± 11 years) and 50 controls were investigated. Tissue Doppler imaging was used to measure early (Ea) and late (Aa) diastolic velocities. Arterial stiffness was measured by a photoplethysmographic (stiffness index (SI)) and an oscillometric method (aortic pulse wave velocity (PWVao)). RESULTS: We compared the IgAN patients to a similar cardiovascular risk group with a preserved eGFR. A strong correlation was found between Ea/Aa and SI (p < 0.001), also with PWVao (p < 0.001), just in IgAN, and with eGFR (p < 0.001) in both groups. IgAN patients were divided into groups CKD1-2 vs. CKD3-5. In the CKD 3-5 group, the incidence of diastolic dysfunction increased significantly: 39% vs. 72% (p = 0.003). Left ventricle rigidity (LVR) was calculated, which showed a close correlation with SI (p = 0.009) and eGFR (p = 0.038). By linear regression analysis, the independent predictors of SI were age, E/A, and E/Ea; SI was the predictor of LVR; and E/A and hypertension were the predictors of eGFR. CONCLUSION: In chronic kidney disease, increased cardiac rigidity and vascular stiffness coexist with decreased renal function, which is directly connected to diastolic dysfunction and vascular stiffness. On the basis of comparing the CKD group to the control group, vascular alterations in very early CKD can be identified.

The Role of Two Heart Biomarkers in IgA Nephropathy.

Cardiovascular mortality is a leading cause of death in chronic kidney disease (CKD), as is IgA nephropathy (IgAN). The purpose of this study is to find different biomarkers to estimate the outcome of the disease, which is significantly influenced by the changes in vessels (characterized by arterial stiffness) and the heart. In our cross-sectional study, 90 patients with IgAN were examined. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was measured as a heart failure biomarker by an automated immonoassay method, while the carboxy-terminal telopeptide of collagen type I (CITP) as a fibrosis marker was determined using ELISA kits. Arterial stiffness was determined by measuring carotid-femoral pulse wave velocity (cfPWV). Renal function and routine echocardiography examinations were performed as well. Based on eGFR, patients were separated into two categories, CKD 1-2 and CKD 3-5. There were significantly higher NT-proBNP (p = 0.035), cfPWV (p = 0.004), and central aortic systolic pressure (p = 0.037), but not CITP, in the CKD 3-5 group. Both biomarker positivities were significantly higher in the CKD 3-5 group (p = 0.035) compared to the CKD 1-2 group. The central aortic systolic pressure was significantly higher in the diastolic dysfunction group (p = 0.034), while the systolic blood pressure was not. eGFR and hemoglobin levels showed a strong negative correlation, while left ventricular mass index (LVMI), aortic pulse pressure, central aortic systolic pressure, and cfPWV showed a positive correlation with NT-proBNP. cfPWV, aortic pulse pressure, and LVMI showed a strong positive correlation with CITP. Only eGFR was an independent predictor of NT-proBNP by linear regression analysis. NT-proBNP and CITP biomarkers may help to identify IgAN patients at high risk for subclinical heart failure and further atherosclerotic disease.

Antimicrobial Diterpenes from Rough Goldenrod (Solidago rugosa Mill.).

Solidago rugosa is one of the goldenrod species native to North America but has sporadically naturalized as an alien plant in Europe. The investigation of the root and leaf ethanol extracts of the plant using a bioassay-guided process with an anti-Bacillus assay resulted in the isolation of two antimicrobial components. Structure elucidation was performed based on high-resolution tandem mass spectrometric and one- and two-dimensional NMR spectroscopic analyses that revealed (-)-hardwickiic acid (Compound 1) and (-)-abietic acid (Compound 2). The isolates were evaluated for their antimicrobial properties against several plant pathogenic bacterial and fungal strains. Both compounds demonstrated an antibacterial effect, especially against Gram-positive bacterial strains (Bacillus spizizenii, Clavibacter michiganensis subsp. michiganensis, and Curtobacterium flaccumfaciens pv. flaccumfaciens) with half maximal inhibitory concentration (IC50) between 1 and 5.1 µg/mL (5-20 times higher than that of the positive control gentamicin). In the used concentrations, minimal bactericidal concentration (MBC) was reached only against the non-pathogen B. spizizenii. Besides their activity against Fusarium avenaceum, the highest antifungal activity was observed for Compound 1 against Bipolaris sorokiniana with an IC50 of 3.8 µg/mL.

Left ventricular myocardial mass index associated with cardiovascular and renal prognosis in IgA nephropathy.

INTRODUCTION: In chronic kidney disease (CKD), like in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and left ventricular hypertrophy (LVH) is an independent risk factor for CV disease. This follow-up study investigated the association between left ventricular mass index (LVMI) and renal or cardiovascular outcomes. METHODS: We examined 118 IgAN patients prospectively. LVMI and LV geometry was investigated using echocardiography. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease. Secondary endpoints, i.e.-cardiovascular or renal endpoints,-were also examined separately. RESULTS: Sixty seven percent were males, mean age 53.5 ± 13.5. Mean follow-up time: 184 months. LVMI inversely correlated with eGFR (corr. coefficient: -0.365; p < 0.01). We divided the patients into two groups based on the LVMI cut-off suggested by the literature. The presence of LVH caused a worse prognosis in primary (p < 0.001), renal endpoints (p = 0.01), and also in CV endpoints (p = 0.001). The higher LVMI in men significantly worsened the prognosis in all endpoints. Concentric hypertrophy meant a worse prognosis. Independent predictors of LVMI were gender and eGFR in uni- and multivariate regression and hemoglobin levels only in logistic regression. Independent predictors of the primary endpoint were LVMI, eGFR, gender, obesity, HT, DM, and metabolic syndrome in Cox regression analysis. CONCLUSION: Increased LVMI may predict the progression to end-stage renal disease and CV events in IgAN. Determining LVMI may be a useful parameter not only in CV risk but also in the stratification of renal risk in CKD.

A pattern-triggered immunity-related phenolic, acetosyringone, boosts rapid inhibition of a diverse set of plant pathogenic bacteria.

BACKGROUND: Acetosyringone (3,5-dimethoxy-4-hydroxyacetophenone, AS) is a syringyl-type phenolic compound rarely found in plants in free form. It has been shown earlier to inhibit the growth of Pseudomonas bacteria in the presence of hydrogen peroxide and peroxidase (AS mix). RESULTS: We detected elevated levels of free AS in Nicotiana tabacum and N. benthamiana plants after inducing pattern-triggered immunity (PTI) by injecting bacterial elicitor flg22, or pathogenicity-mutant Pseudomonas syringae pv. syringae 61 hrcC- bacteria; but not after inoculations with compatible or incompatible pathogens at the time of PTI onset. In this study, we demonstrate that the antibacterial effect of the AS mix is general, as growth of several Gram-negative and -positive phytopathogenic bacteria was characteristically inhibited. The inhibition of bacterial metabolism by the AS mix was rapid, shown by the immediate drop of luminescence intensity of P. syringae pv. tomato DC3000 lx strain after addition of AS mix. The mechanism of the bacteriostatic effect was investigated using fluorescent reporter dye assays. SYTOX Green experiments supported others' previous findings that the AS mix does not result in membrane permeabilization. Moreover, we observed that the mode of action could be depolarization of the bacterial cell membrane, as shown by assays carried out with the voltage sensitive dye DIBAC4(3). CONCLUSIONS: Level of free acetosyringone is elevated during plant PTI responses in tobacco leaves (N. tabacum and N. benthamiana). When combined with hydrogen peroxide and peroxidase (AS mix), components of the mix act synergistically to inhibit bacterial metabolism and proliferation rapidly in a wide range of plant pathogens. This effect is related to depolarization rather than to permeabilization of the bacterial cell membrane. Similar AS mixture to the in vivo model might form locally at sites of invading bacterial attachment to the plant cells and the presence of acetosyringone might have an important role in the inhibition of bacterial proliferation during PTI.

The prognostic role of heart rate recovery after exercise and metabolic syndrome in IgA nephropathy.

BACKGROUND: Cardiovascular (CV) morbidity and mortality are higher in chronic kidney disease (CKD) than in the general population. Reduced heart rate recovery (HRR) is an independent risk factor for CV disease. The aim of the study was to determine the prognostic role of HRR in a homogenous group of CKD patients. METHODS: One hundred and twenty-five IgA nephropathy patients (82 male, 43 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for average 70 months. We performed a graded exercise treadmill stress test. HRR was derived from the difference of the peak heart rate and the heart rate at 1 min after exercise. Patients were divided into two groups by the mean HRR value (22.9 beats/min). The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularisation (CV) and end-stage renal disease, renal replacement therapy (renal). RESULTS: Patients with reduced HRR (< 23 bpm) had significantly more end point events (22/62 patients vs. 9/53 patients, p = 0.013) compared to the higher HRR (≥23 bpm). Of the secondary the endpoints (CV or renal separately) rate of the renal endpoint was significantly higher in the lower HRR group (p = 0.029), while there was no significant difference in the CV endpoint between the two HRR groups (p = 0.285). Independent predictors of survival were eGFR and diabetes mellitus by using Cox regression analysis. Kaplan-Meier curves showed significant differences in metabolic syndrome and non-metabolic syndrome when examined at the combined endpoints (cardiovascular and renal) or at each endpoint separately. The primary endpoint rate was increased significantly with the increased number of metabolic syndrome component (Met.sy. comp. 0 vs. Met. sy. comp. 2+, primary endpoints, p = 0.012). CONCLUSION: Our results showed that reduced HRR measured by treadmill exercise test has a predictive value for the prognosis of IgA nephropathy. The presence of metabolic syndrome may worsen the prognosis of IgA nephropathy.

Present Status of Musculoskeletal Radiology in Europe: International Survey by the European Society of Musculoskeletal Radiology.

No official data exist on the status of musculoskeletal (MSK) radiology in Europe. The Committee for National Societies conducted an international survey to understand the status of training, subspecialization, and local practice among the European Society of Musculoskeletal Radiology (ESSR) partner societies. This article reports the results of that survey. An online questionnaire was distributed to all 26 European national associations that act as official partner societies of the ESSR. The 24 questions were subdivided into six sections: society structure, relationship with the national radiological society, subspecialization, present radiology practice, MSK interventional procedures, and MSK ultrasound. The findings of our study show a lack of standardized training and/or accreditation methods in the field of MSK radiology at a national level. The European diploma in musculoskeletal radiology is directed to partly overcome this problem; however, this certification is still underrecognized. Using certification methods, a more homogeneous European landscape could be created in the future with a view to subspecialist training. MSK ultrasound and MSK interventional procedures should be performed by a health professional with a solid knowledge of the relevant imaging modalities and sufficient training in MSK radiology. Recognition of MSK radiology as an official subspecialty would make the field more attractive for younger colleagues as well as attracting the brightest and best, an important key to further development of both clinical and academic radiology. KEY POINTS: · Standardized training and/or accreditation methods in the field of MSK radiology is lacking at a national level.. · With certification methods, such as the European diploma in musculoskeletal radiology, a more homogeneous European landscape could be created in the future with a view to subspecialist training.. · Recognition of MSK radiology as an official subspecialty would make the field more attractive for younger colleagues as well as attracting the brightest and best, an important key to further development of both clinical and academic radiology..

Effect of Inflammatory Mediators Lipopolysaccharide and Lipoteichoic Acid on Iron Metabolism of Differentiated SH-SY5Y Cells Alters in the Presence of BV-2 Microglia.

Lipopolysaccharide (LPS) and lipoteichoic acid (LTA), the Gram-negative and the Gram-positive bacterial cell wall components are important mediators of neuroinflammation in sepsis. LPS and LTA are potent activators of microglial cells which induce the production of various pro-inflammatory cytokines. It has been demonstrated that disturbance of iron homeostasis of the brain is one of the underlying causes of neuronal cell death but the mechanisms contributing to this process are still questionable. In the present study, we established monocultures of differentiated SH-SY5Y cells and co-cultures of differentiated SH-SY5Y cells and BV-2 microglia as neuronal model systems to selectively examine the effect of inflammatory mediators LPS and LTA on iron homeostasis of SH-SY5Y cells both in mono- and co-cultures. We monitored the IL-6 and TNFα secretions of the treated cells and determined the mRNA and protein levels of iron importers (transferrin receptor-1 and divalent metal transporter-1), and iron storing genes (ferritin heavy chain and mitochondrial ferritin). Moreover, we examined the relation between hepcidin secretion and intracellular iron content. Our data revealed that LPS and LTA triggered distinct responses in SH-SY5Y cells by differently changing the expressions of iron uptake, as well as cytosolic and mitochondrial iron storage proteins. Moreover, they increased the total iron contents of the cells but at different rates. The presence of BV-2 microglial cells influenced the reactions of SH-SY5Y cells on both LPS and LTA treatments: iron uptake and iron storage, as well as the neuronal cytokine production have been modulated. Our results demonstrate that BV-2 cells alter the iron metabolism of SH-SY5Y cells, they contribute to the iron accumulation of SH-SY5Y cells by manipulating the effects of LTA and LPS proving that microglia are important regulators of neuronal iron metabolism at neuroinflammation.

[Considerations on the treatment of IgA nephropathy on the basis of the results of the latest studies (STOP-IgAN, TESTING, NEFIGAN)]. / Terápiás megfontolások IgA-nephropathiában a legutolsó vizsgálatok (STOP-IgAN, TESTING, NEFIGAN) eredményei alapján.

IgA nephropathy is an immune-mediated chronic glomerulonephritis with a great variability in clinical presentation and outcome. The disease can progress to end-stage renal failure in 25% of patients. For this reason we should identify patients with potential to progress. Most important risk factors for progression are persistent proteinuria, hypertension, decreased renal function and some histological lesions. The actually suggested treatment is summarized in KDIGO Clinical Practice Guideline from 2012. They suggest to give firstly non-specific supportive treatment (especially renin-angiotensin system blocking agents). Recommendation about steroid/immunosuppression treatment is based on low level of evidence. Recently three studies were organised concerning benefits and risk of steroid/immunosuppressive treatment added together with specific supportive treatment. In the STOP-IgAN study, systemic steroid/immunosuppressive treatment significantly decreased proteinuria but did not stop progression. In the TESTING study, systemic steroid treatment significantly decreased proteinuria and progression. However, the study was recently discontinued due to several severe side effects of steroid treatment. Involvement of intestinal mucosal immunity in the pathogenesis of IgA nephropathy suggested the NEFIGAN study with budesonide treatment. Budesonide releases corticosteroid in distal small intestine and colon. Proteinuria was significantly decreased and renal function remained stabile. High number of withdrawals owing to adverse effects is a major concern implying a substantial systemic effect of budesonide. We need further information on the characteristics of patients who most likely benefit from steroid/immunosuppressive treatment given after or together with specific supportive treatment. Orv Hetil. 2017; 158(49): 1946-1952.

[The effect of smoking on the quality of life enhancement following prosthetic rehabilitation in head and neck cancer patients who underwent surgical treatment]. / A dohányzás hatása a fej-nyak régió daganata miatt sebészi terápiában részesült betegek protetikai rehabilitációt követo életminoség-javulására.

INTRODUCTION: It is known that the quality of life (QoL) of patients surgically treated for head and neck cancer (HNC) is significantly enhanced by rehabilitation. It is also known that some of these patients will not quit smoking. AIM: To assess if smoking hampers rehabilitation-related QoL enhancement after surgery. METHOD: Applying the H&N 35 questionnaire of EORTC, we assessed the QoL of 38 smoking and non-smoking patients who underwent surgical therapy for HNC and subsequent rehabilitation. QoL was assessed after surgery (after the healing period) and 6 months after rehabilitation. RESULTS: While the QoL enhancement of nonsmokers was significant in almost all aspects, that of smoking patients did not reach the level of significance on a number of scales. The results suggest that smoking does not hamper rehabilitation directly, rather, it prevents rehabilitation from exerting its beneficial effects through its own effects. CONCLUSIONS: Smoking is a factor that measurably acts against the efforts to enhance the QoL of the surgically treated HNC patient. Therefore, it is essential that emphasis is put on smoking cessation right from the cancer diagnosis also for this reason. Orv. Hetil., 2017, 158(5), 172-177.

Hepcidin and its potential clinical utility.

A number of pathophysiological conditions are related to iron metabolism disturbances. Some of them are well known, others are newly discovered or special. Hepcidin is a newly identified iron metabolism regulating hormone, which could be a promising biomarker for many disorders. In this review, we provide background information about mammalian iron metabolism, cellular iron trafficking, and the regulation of expression of hepcidin. Beside these molecular biological processes, we summarize the methods that have been used to determine blood and urine hepcidin levels and present those pathological conditions (cancer, inflammation, neurological disorders) when hepcidin measurement may have clinical relevance.

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹°), with heterogeneity detected only at the PSMB9/TAP1 locus (I²â€Š= 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²8). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

Application of a vibrating device for the prevention of flexion contracture after total knee arthroplasty.

Our research team developed a new, heel support-based static and vibrating complementary treatment method for the prevention of flexion contractures often arising after total knee arthroplasty. We examined the efficiency of the method performing a randomized clinical trial with 144 patients undergoing total knee replacement. Seventy-nine patients were treated for 1 week with a generally used continuous passive motion (CPM) device complemented with our new method, which was based on the application of a static and an alternating heel support. The 65 patients in the control group were treated with only a CPM device as in usual clinical practice. The femoro-tibial angle was measured immediately following surgery, and after 1 week of treatment. At the end of the 1 week treatment, the target extension angle (0° ± 5°) was achieved by significantly more patients with the new combined method. This way the elevated heel rest and the vibrating device proved to be a good adjunct treatment along with the CPM used in routine clinical practice in the first place for the prevention of flexion contractures.

Quality of life in head and neck cancer patients after tumor therapy and subsequent rehabilitation: an exploratory study.

PURPOSE: The aim of the study was to evaluate patient-reported quality of life effects of post-treatment intraoral and extraoral rehabilitation in head and neck cancer by repeated measures. METHODS: Fifty-nine patients were involved. Basic socio-demographic, oncological and epidemiological data were gathered, and the type of rehabilitation was recorded. For the assessment of quality of life changes, two widely used brief questionnaires, the University of Washington Quality of Life Questionnaire and the Head and Neck module of the European Organization of Research and Treatment for Cancer Quality of Life Questionnaire, were used. The questionnaires were administered to patients two times: the first time after tumor therapy, but before rehabilitation (upon arriving for rehabilitation) and the second time 6 months after the application of any particular method of rehabilitation. Quality of life data were gathered prospectively, while socio-demographic data were gathered from patient files. RESULTS: Quality of life after rehabilitation was significantly enhanced as compared to the post-treatment status, in all domains of both questionnaires (p < 0.05 and p < 0.01, Mann-Whitney U). CONCLUSIONS: The results support the hypothesis that post-treatment maxillofacial rehabilitation in head and neck cancer does not only restore lost physical capabilities, but also brings about profound changes in patients' quality of life in general.

Prohepcidin binds to the HAMP promoter and autoregulates its own expression.

Hepcidin is the major regulatory peptide hormone of iron metabolism, encoded by the HAMP (hepcidin antimicrobial peptide) gene. Hepcidin is expressed mainly in hepatocytes, but is also found in the blood in both a mature and prohormone form. Although, the function of mature hepcidin and the regulation of the HAMP gene have been extensively studied, the intracellular localization and the fate of prohepcidin remains controversial. In the present study, we propose a novel role for prohepcidin in the regulation of its own transcription. Using indirect immunofluorescence and mCherry tagging, a portion of prohepcidin was detected in the nucleus of hepatocytes. Prohepcidin was found to specifically bind to the STAT3 (signal transducer and activator of transcription 3) site in the promoter of HAMP. Overexpression of prohepcidin in WRL68 cells decreased HAMP promoter activity, whereas decreasing the amount of prohepcidin caused increased promoter activity measured by a luciferase reporter-gene assay. Moreover, overexpression of the known prohepcidin-binding partner, α-1 antitrypsin caused increased HAMP promoter activity, suggesting that only the non-α-1 antitrypsin-bound prohepcidin affects the expression of its own gene. The results of the present study indicate that prohepcidin can bind to and transcriptionally regulate the expression of HAMP, suggesting a novel autoregulatory pathway of hepcidin gene expression in hepatocytes.

Renal and cardiovascular prognostic significance of echocardiographic early diastolic mitral annular velocity in IgA nephropathy.

In chronic kidney disease (CKD), as in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and diastolic dysfunction (LVDD) has prognostic significance as well. Tissue Doppler Echocardiography (TDI) is another method for measuring myocardial contractility and determining diastolic dysfunction. 79 IgAN patients (age 46 ± 11 years) with CKD stages 1-3 were investigated and followed for 70 ± 28.7 months. Doppler echocardiography was used to measure the E (early) and A (late) waves, as well as the E wave deceleration time (EDT) during mitral inflow. TDI was used to measure early (Ea) and late (Aa) diastolic velocities (lateral and septal basal wall fragment average). From these, we calculated the E/Ea and Ea/Aa ratios. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease, and the secondary endpoints were cardiovascular or renal (eGFR decreased below 15 ml/min/1.73 m2 or renal replacement therapy was started). Patients with decreased Ea (< 13 cm/s) had significantly more endpoints (20/42 vs. 3/37; p = 0.001) than patients with higher Ea (≥ 13 cm/s). The secondary renal endpoints were also significantly higher (p = 0.004). In a multivariate model, the eGFR showed independent correlation with the E/A ratio (r = 0.466; p < 0.01), EDT (r = - 0.270; p < 0.01), Ea/Aa ratio (r = 0.455; p < 0.01), and decreased Ea (r = 0.544; p < 0.01). Independent factors influencing Ea were only EDT by uni- and multivariate regression but age and albuminuria by logistic regression. Decreased Ea measured by TDI seems to be an eligible factor to predict the prognosis of IgA nephropathy. The decreased Ea may be a helpful parameter to identify high-risk CKD patients.

Does Metabolic Syndrome and Its Components Have Prognostic Significance for Renal and Cardiovascular Outcomes in IgA Nephropathy?

BACKGROUND: Patients with IgA nephropathy (IgAN), a chronic kidney disease (CKD), are significantly more likely to have cardiovascular (CV) mortality and morbidity than the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease and renal progression. The purpose of this study was to determine how metabolic characteristics in a homogeneous population of CKD patients relate to prognosis. METHODS: A total of 145 patients with CKD stages 1-4 diagnosed with IgA nephropathy (92 men and 53 women, aged 54.7 ± 13 years) were examined and monitored for a median of 190 months. All-cause mortality and any CV event, such as stroke, myocardial infarction, revascularization (CV), end-stage renal disease, and renal replacement therapy (renal), have been included in the composite endpoints (CV and renal). RESULTS: Patients with MetS had significantly more primary endpoint events (23/65 patients vs. 15/60 patients, p < 0.001) compared to the non-MetS group. The MetS group had a statistically significant increase in both primary renal and CV endpoints (18/65 vs. 10/60, p = 0.001), and in CV endpoint events (7/65 vs. 6/60, p = 0.029) among the secondary endpoints (CV and renal separately). Based on Cox regression analysis, the main endpoint independent predictors of survival were dyslipidemia, eGFR, hemoglobin, urine albuminuria, and diabetes mellitus. Independent predictors of secondary renal endpoints were dyslipidemia, hemoglobin, urine albumin, and eGFR. Predictors of secondary cardiovascular endpoints were gender, BMI, and diabetes. When Kaplan-Meier curves were analyzed at the combined endpoints (CV and renal) or each endpoint independently, significant differences were seen between MetS and non-MetS. With more MetS components, the primary endpoint rate increased significantly (MetS comp. 0 vs. MetS comp. 2+, primary endpoints, p = 0.012). CONCLUSIONS: Our results show that the metabolic profile has a prognostic role not only for renal endpoints but also for CV endpoints in IgAN. BMI, hyperuricemia, hypertension, and diabetes have a predictive value for the prognosis of IgA nephropathy.