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Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an ‘intersectional short pulse’ stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than those used in conventional protocols. Though transcranial electric stimulation has been used to influence brain activity, it is debated whether neuronal spiking activity is directly affected by commonly-used protocols. Here, the authors quantify the voltage gradients necessary to instantaneously affect neuronal spiking and show that they are higher than commonly-used protocols.

The clinicopathological and molecular features of synchronous parathyroid carcinoma (PC) and thyroid carcinoma in a male patient are presented. At 11, he received mantle field radiotherapy for Hodgkin lymphoma. He had a 26-year adulthood history of recurrent nephrolithiasis treated five times with lithotripsy. At 52, he was referred to our clinic for hypercalcemia. Primary hyperparathyroidism was diagnosed (calcium: 3.46 mmol/L, parathormone: 150 pmol/L, preserved renal function, nephrolithiasis, and osteoporosis). Neck ultrasound revealed a 41 × 31 × 37 mm nodule in the left thyroid and smaller nodules in the right thyroid. Enlarged cervical lymph nodes were not observed. The large nodule was interpreted as parathyroid adenoma on 99Tc-pertechnetate scintigraphy/99Tc-MIBI scintigraphy with SPECT/CT. Total left-sided and subtotal right-sided thyroidectomy were performed. Histopathology confirmed locally invasive, low-grade PC (pT2; positive for parafibromin and E-cadherin, negative for galectin-3 and PGP9.5; wild-type expression for p53 and retinoblastoma protein; Ki-67 index 10%) and incidental papillary thyroid carcinoma (pT1b). Genetic profiling revealed no loss in CDC73, MEN1, CCND1, PIK3CA, CDH1, RB1, and TP53 genes. Deletions in CDKN2A, LATS1, ARID1A, ARID1B, RAD54L, and MUTYH genes and monosomies in nine chromosomes were identified. The tumor mutational burden and genomic instability score were low, and the tumor was microsatellite-stable. The thyroid carcinoma exhibited a TRIM24::BRAF fusion. Following surgery, the parathormone and calcium levels had normalized, and the patient underwent radioiodine treatment for thyroid cancer. The follow-up of 14 months was eventless. In summary, the clinical, laboratory, and imaging features of hyperparathyroidism taken together could have suggested malignancy, then confirmed histologically. The synchronous carcinomas were most likely caused by irradiation treatment diagnosed 41 years after exposure. It seems that the radiation injury initially induced parathyroid adenoma in young adulthood, which underwent a malignant transformation around age fifty.

The cause of nephrotic–nephritic syndrome and elevated blood pressure values was investigated by renal biopsy in a 72-year-old Caucasian male with B-cell chronic lymphocytic leukemia (B-CLL) and a low level of IgG/lambda paraprotein. Double-contoured glomerular capillaries, glomerular thrombi, interstitial B-CLL infiltrates, and normal-looking arteries and arterioles were observed histologically. The glomerular capillaries displayed nonspecific entrapment of IgM and C3 and pseudolinear C4d positivity immunohistochemically. With electron microscopy, diffusely effaced foot processes, widened and duplicated glomerular basement membrane (BM), mesangial cell interposition, and thickened, non-fenestrated, and serrated endothelial cells located on subendothelial BM layer(s) were seen. The peritubular capillaries lacked any significant BM multilayering. Chronic glomerular thrombotic microangiopathy (TMA) was diagnosed; the C4d positivity result indicated structural remodeling of glomerular capillary walls. Laboratory features of microangiopathic hemolytic anemia were absent. The functional complement assay found selective classical pathway activation and the consumption of early complement components. The components of the alternative pathway were not consumed. A disease-causing variant in the coding region of the complement C2 gene was screened, with negative results. The kidney function gradually deteriorated to stage 4 chronic kidney disease over a period of six months. Second-line treatment with ibrutinib markedly decreased the leukemic symptoms, stopped the production of paraprotein, and eliminated the nephrotic syndrome; the kidney function improved. The decreased activity of the classical pathway remained unchanged. The culprit of glomerular anomalies seemed to be the paraprotein, which acted as a nephrotoxic mediator and triggered glomerular TMA. A hypothetical pathophysiologic explanation of TMA is presented. The paraneoplastic classical pathway activation of complement did not play any role in the development of glomerular TMA.

With primary membranous nephropathy (pMN), the genetic background is not precisely known. Certain HLA-DQ serotypes however like HLA-DQ 2.5, and single-nucleotide polymorphisms (SNPs) in the phospholipase A2 receptor 1 (PLA2R1) gene pose a risk for the development of pMN. As antigen presentation is linked to a 3-dimensional conformation of the HLA-DQA/DQB dimer, we thought that the specific HLA-DQ haplotype combinations might also be risk factors in the evolution of MN. The HLA-DQ haplotype combinations and the PLA2R1 gene risk variant (rs4664308) genotypes were examined in 67 patients with MN (52 primary, 15 secondary [sMN]) and 77 controls. Based on the presence or absence of PLA2R1 risk alleles, we used a scoring system to assess the risk and to identify protective HLA-DQ haplotype combinations. The HLA-DQ 2.5 serotype was significantly enriched in both pMN and sMN patients compared to the controls. The pMN group had a significantly higher frequency of the PLA2R1 risk allele compared to the sMN group and the controls. HLA-DQ 2.5 appeared to carry the highest risk for the development of pMN, while HLA-DQ 7.5 and 6.2 seemed to be protective. Our results indicate that the HLA-DQ 2.5 probably carries the highest risk in both pMN and sMN, suggesting that this serotype has less specificity for antigens, and it induces an autoimmune response. Here, PLA2R1 played a role in the development of pMN but not in sMN.

Animal models are ideal to study the pathomechanism and therapy of acute pancreatitis (AP). The use of L-arginine-induced AP model is nowadays becoming increasingly popular in mice. However, carefully looking through the literature, marked differences in disease severity could be observed. In fact, while setting up the L-arginine (2×4 g/kg i.p.)-induced AP model in BALB/c mice, we found a relatively low rate (around 15%) of pancreatic necrosis, whereas others have detected much higher rates (up to 55%). We suspected that this may be due to differences between mouse strains. We administered various concentrations (5-30%, pH = 7.4) and doses (2×4, 3×3, or 4×2.5 g/kg) of L-arginine-HCl in BALB/c, FVB/n and C57BL/6 mice. The potential gender-specific effect of L-arginine was investigated in C57BL/6 mice. The fate of mice in response to the i.p. injections of L arginine followed one of three courses. Some mice (1) developed severe AP or (2) remained AP-free by 72 h, whereas others (3) had to be euthanized (to avoid their death, which was caused by the high dose of L-arginine and not AP) within 12 h., In FVB/n and C57BL/6 mice, the pancreatic necrosis rate (about 50%) was significantly higher than that observed in BALB/c mice using 2×4 g/kg 10% L-arginine, but euthanasia was necessary in a large proportion of animals, The i.p. injection of lower L-arginine concentrations (e.g. 5-8%) in case of the 2×4 g/kg dose, or other L-arginine doses (3×3 or 4×2.5 g/kg, 10%) were better for inducing AP. We could not detect any significant differences between the AP severity of male and female mice. Taken together, when setting up the L-arginine-induced AP model, there are several important factors that are worth consideration such as the dose and concentration of the administered L arginine-HCl solution and also the strain of mice.

The morphotype and grade of renal cell carcinoma (RCC) in 928 nephrectomies were reclassified according to the 2016 WHO classification in order to analyze the distribution and outcomes of RCC subtypes in Hungary, to assess whether microscopic tumor necrosis is an independent prognostic factor in clear cell RCC, and to study whether a two-tiered grading (low/high) for clear cell and papillary RCC provides similar prognostic information to that of the four-tiered ISUP grading system. 83.4% of the cohort were clear cell, 6.9% papillary, 4.5% chromophobe, 2.3% unclassified, 1.1% Xp11 translocation, 1.1% clear cell papillary, 0.3% collecting duct and 0.1% mucinous tubular and spindle cell RCCs. RCC occurred in 16 patients with end-stage kidney disease and none of them displayed features of acquired cystic kidney disease-associated RCC. The 5-year survival rates were as follows: chromophobe 100%, clear cell papillary 100%, clear cell low-grade 96%, papillary type 1 92%, clear cell high-grade 63%, papillary type 2 65%, unclassified 46%, Xp11 translocation 20%, and collecting duct 0%. The 5-year survival rates in low-grade and high-grade papillary RCC were 95% and 59%, respectively. In clear cell RCC, only the grade, the stage and the positive surgical margin proved to be independent prognostic factors statistically. Overall, papillary RCC occurred relatively infrequently; microscopic tumor necrosis in clear cell RCC did not predict the outcome independently of the tumor grading; and the assignment of clear cell and papillary RCCs into low-grade or high-grade tumors was in terms of survival no worse than the ISUP grading.

Background The diagnostic performance of PLA2R and IgG subclass staining of kidney biopsies relative to anti-PLA2R seropositivity in the differentiation of primary and secondary membranous nephropathy (pMN, sMN) was examined. Besides PLA2R staining – which has a lower specificity than anti-PLA2R antibody serology – there is insufficient knowledge to decide which IgG1-4 subtype immunohistological patterns (IgG4-dominance, IgG4-dominance/IgG1-IgG4-codominance or IgG4-dominance/IgG4-codominance with any IgG subtype) could be used to distinguish between pMN and sMN. Methods 87 consecutive Hungarian patients (84 Caucasians, 3 Romas) with the biopsy diagnosis of MN were classified clinically as pMN (n = 63) or sMN (n = 24). The PLA2R and IgG subclass staining was part of the diagnostic protocol. Anti-PLA2R antibodies were determined by an indirect immunofluorescence test in 74 patients with disease activity. Results For pMN, the sensitivity of anti-PLA2R seropositivity was 61.1%, and the specificity was 90.0%; and similar values for PLA2R staining were 81.0%, and 66.7%, respectively. In all stages of pMN, IgG4-dominance was the dominant subclass pattern, while the second most frequent was IgG3/IgG4-codominance. The sensitivity and specificity scores were: IgG4-dominance 52.2% and 91.7%, IgG4-dominance/IgG3-IgG4-codominance 76.2% and 87.5%, IgG4-dominance/IgG1-IgG4-codominance 64.2% and 75%, and IgG4-dominance/codominance with any IgG subclass 92.1% and 70.8%, respectively. Anti-PLA2R seropositivity, glomerular PLA2R, and IgG4-dominance/codominance significantly correlated with each other. The IgG4 subclass was rarely encountered in sMN. Conclusion In our series, IgG4-dominance had the highest specificity in the differentiation of MN, just as high as that for anti-PLA2R seropositivity. The specificity values of PLA2R staining and IgG4-dominance/codominance with any IgG subclass or IgG4-dominance/IgG1-IgG4 codominance were ≤ 75%. Apart from IgG4 dominance, IgG4-dominance/IgG3-IgG4-codominance also had good statistical value in differentiating pMN from sMN. As IgG subclass switching during the progression of pMN was not the feature of our cohort, pMN in Hungarian patients is presumed to be an IgG4-related disorder right from the start. Although anti-PLA2R seropositivity has become the cornerstone for diagnosing pMN, if a kidney biopsy evaluation is conducted, besides the staining of PLA2R antigen, the evaluation of IgG subclasses provides relevant information for a differential diagnosis. Even in cases with IgG4-dominance, however, malignancy should be thoroughly checked.

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 (FN1) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice.

Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic–genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous FAN1 mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous FAN1 mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for FAN1 mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history.

This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.