The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis.

Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.

Multiple Kidney Infarctions Due to COVID-19 Infection in a Patient with Repeatedly Negative RT-PCR Tests-A Case Report.

Since the outbreak of novel coronavirus in 2019, SARS-CoV-2 has spread worldwide at an unexpected rate, becoming a major global health concern. Although respiratory tract infections represent typical clinical presentation, recently, numerous cases of acute arterial thrombosis and thromboembolic disease have been reported due to COVID-19 infection. Renal artery embolism is a condition that is easily missed due to its infrequent and nonspecific presentation. In this paper, we reported a case of a 63-year-old, previously healthy, male patient who has developed multiple right kidney infarctions due to COVID-19 infection without any respiratory or other typical clinical manifestations. Consecutive RT-PCR tests were negative and the diagnosis was set finally by serological screening. Our presentation has emphasized the necessity of clinical, laboratory, microbiological, and radiological integration in diagnostic approach to this novel and challenging disease with often unusual clinical presentations to avoid false negative discrimination.

Expression of Connexins 37, 40 and 45, Pannexin 1 and Vimentin in Laryngeal Squamous Cell Carcinomas.

Approximately 60% of patients with squamous cell carcinoma (LSCC) have regional occult metastatic disease/distant metastases at the time of diagnosis, putting them at higher risk for disease progression. Therefore, biomarkers are needed for early prognostic purpose. The aim of this study was to analyze the expression pattern of connexins (Cx) 37, 40 and 45, pannexin1 (Panx1) and vimentin in LSCC and correlate with tumor grade (G) and outcome. METHODS: Thirty-four patients who underwent (hemi-)laryngectomy and regional lymphadenectomy due to LSCC from 2017 to 2018 in University Hospital Split, Croatia, were studied. Samples of tumor tissue and adjacent normal mucosa embedded in paraffin blocks were stained using the immunofluorescence method and were semi-quantitatively analyzed. RESULTS: The expression of Cx37, Cx40, and Panx1 differed between cancer and adjacent normal mucosa and between histological grades, being the highest in well-differentiated (G1) cancer and low/absent in poorly differentiated (G3) cancer (all p < 0.05). The expression of vimentin was the highest in G3 cancer. Expression of Cx45 was generally weak/absent, with no significant difference between cancer and the controls or between grades. Lower Panx1 and higher vimentin expression were found to be prognostic factors for regional metastatic disease. Lower Cx37 and 40 expressions were present in patients with disease recurrence after the three-year follow-up period. CONCLUSION: Cx37 and Cx40, Panx1, and vimentin have the potential to be used as prognostic biomarkers for LSCC.

Emerging Biomarkers for Early Detection of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major and serious global health problem that leads to kidney damage as well as multiple systemic diseases. Early diagnosis and treatment are two major measures to prevent further deterioration of kidney function and to delay adverse outcomes. However, the paucity of early, predictive and noninvasive biomarkers has undermined our ability to promptly detect and treat this common clinical condition which affects more than 10% of the population worldwide. Despite all limitations, kidney function is still measured by serum creatinine, cystatin C, and albuminuria, as well as estimating glomerular filtration rate using different equations. This review aims to provide comprehensive insight into diagnostic methods available for early detection of CKD. In the review, we discuss the following topics: (i) markers of glomerular injury; (ii) markers of tubulointerstitial injury; (iii) the role of omics; (iv) the role of microbiota; (v) and finally, the role of microRNA in the early detection of CKD. Despite all novel findings, none of these biomarkers have met the criteria of an ideal early marker. Since the central role in CKD progression is the proximal tubule (PT), most data from the literature have analyzed biomarkers of PT injury, such as KIM-1 (kidney injury molecule-1), NGAL (neutrophil gelatinase-associated lipocalin), and L-FABP (liver fatty acid-binding protein).

Knowledge, Attitudes, and Screening for Obstructive Sleep Apnea and Diabetes Mellitus among War Veterans Seeking Treatment of Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric disorders. However, we should not neglect the somatic aspects of PTSD. Associations with cardiovascular diseases (CVD) are particularly concerning because PTSD was associated with an even 53% higher risk for CVD. This study aimed to analyze the prevalence of several CVD risk factors, especially diabetes mellitus among PTSD patients divided into three groups according to obstructive sleep apnea (OSA) risk stratification (low, intermediate, and high). This cross-sectional study included one hundred male PTSD veterans. The mean age was 53 (40-67) years. The estimated OSA risk was 95% for the whole cohort, and 53% were in the high-risk group. Median HbA1c was 5.6 (4.6-10)%. The hemoglobin A1c (HbA1c) levels showed that 34 patients were in the prediabetes group, and 20 of them fulfilled the criteria for diabetes. However, only 13 of them were aware of their previous diagnosis of diabetes mellitus. In testing knowledge about diabetes, 62% and only 23% of patients knew the correct definition of HbA1c and level of fasting plasma glucose, respectively. Diabetic patients had insufficient knowledge about diabetic complications and treatment. A higher level of PTSD symptoms in veterans was associated with a higher prevalence of OSA. The results strongly support further research and education into early detection of CVD risk factors associated with PTSD.

Plasma Catestatin Levels and Advanced Glycation End Products in Patients on Hemodialysis.

Catestatin (CST) is a pleiotropic peptide involved in cardiovascular protection with its antihypertensive and angiogenic effects. Considering that patients with end-stage renal disease (ESRD) who are undergoing hemodialysis (HD) are associated with higher cardiovascular risk, the aim of this study was to investigate plasma CST levels in HD patients, compare them to healthy controls and evaluate possible CST associations with advanced glycation end products (AGEs) and laboratory, anthropometric and clinical parameters. The study included 91 patients on HD and 70 healthy controls. Plasma CST levels were determined by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit, while AGEs were determined using skin autofluorescence. Plasma CST levels were significantly higher in the HD group compared to the controls (32.85 ± 20.18 vs. 5.39 ± 1.24 ng/mL, p < 0.001) and there was a significant positive correlation between CST and AGEs (r = 0.492, p < 0.001). Furthermore, there was a significant positive correlation between plasma CST levels with both the Dialysis Malnutrition Score (r = 0.295, p = 0.004) and Malnutrition-Inflammation Score (r = 0.290, p = 0.005). These results suggest that CST could be playing a role in the complex pathophysiology of ESRD/HD and that it could affect the higher cardiovascular risk of patients on HD.

Serum Adropin Levels in Patients on Hemodialysis.

Adropin is a novel pleotropic peptide involved in energy homeostasis, with possible contribution to cardiovascular protection through production of nitric oxide and subsequent blood pressure regulation. Given that patients undergoing hemodialysis (HD) are related with high cardiovascular risk, hyperlipidemia, chronic low-grade inflammation, and malnutrition the aim of our study was to investigate serum adropin levels in HD patients to evaluate possible associations with nutritional status and other relevant clinical and laboratory parameters. The study included 70 patients on HD and 60 healthy controls. Serum adropin levels were determined by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit. Serum adropin levels were significantly lower in the HD group compared to the control group (2.20 ± 0.72 vs. 4.05 ± 0.93 ng/mL, p < 0.001). Moreover, there was a significant negative correlation with malnutrition-inflammation score (r = -0.476, p < 0.001), dialysis malnutrition score (r = -0.350, p = 0.003), HD duration (r = -0.305, p = 0.010), and high sensitivity C-reactive protein (hsCRP) (r = -0.646, p < 0.001). Additionally, there was a significant negative correlation between adropin levels and pre-dialysis systolic (r = -0.301, p = 0.011) and diastolic blood pressure (r = -0.299, p = 0.011). These results are implying that adropin is potentially involved in the pathophysiological mechanisms of chronic kidney disease (CKD)/HD and its complications. However, future larger scale longitudinal studies need to further address it.

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy arising from the adrenal cortex often with unexpected biological behavior. It can occur at any age, with two peaks of incidence: in the first and between fifth and seventh decades of life. Although ACC are mostly hormonally active, precursors and metabolites, rather than end products of steroidogenesis are produced by dedifferentiated and immature malignant cells. Distinguishing the etiology of adrenal mass, between benign adenomas, which are quite frequent in general population, and malignant carcinomas with dismal prognosis is often unfeasible. Even after pathohistological analysis, diagnosis of adrenocortical carcinomas is not always straightforward and represents a great challenge for experienced and multidisciplinary expert teams. No single imaging method, hormonal work-up or immunohistochemical labelling can definitively prove the diagnosis of ACC. Over several decades' great efforts have been made in finding novel reliable and available diagnostic and prognostic factors including steroid metabolome profiling or target gene identification. Despite these achievements, the 5-year mortality rate still accounts for approximately 75% to 90%, ACC is frequently diagnosed in advanced stages and therapeutic options are unfortunately limited. Therefore, imperative is to identify new biological markers that can predict patient prognosis and provide new therapeutic options.

SATB1 and PTEN expression patterns in biopsy proven kidney diseases.

BACKGROUND: In present study we investigated expression pattern of the special tissue markers. SATB1 and PTEN to evaluate possible influence in pathophysiology and development of various biopsy proven kidney diseases. METHODS: The 32 kidney biopsy samples were analysed using light, immunofluorescence and electron microscopy. There were 19 samples in proliferative and 13 samples in non- proliferative group of renal diseases. As control group, 9 specimens of healthy kidney tissue taken after surgery of kidney tumour were used. SATB1 and PTEN markers were used for immunofluorescence staining. Analysed tissue structures were glomeruli, proximal convoluted tubules (PCT) and distal convoluted tubules (DCT). The number of SATB1 and PTEN cells were calculated and the data compared between kidney structures, disease groups and control specimens. RESULTS: Both markers were positive in all investigated kidney structures, with expression generally, more prominent in tubular epithelial cells than in glomeruli, with the highest staining intensity rate as well as highest rate of both markers in DCT of proliferative diseases group (SATB1 64.5 %, PTEN 52 %). There was statistically significant difference in SATB1 expression in all tissue structures of interest in proliferative as well as non- proliferative group compared to control group (p < 0.01-p < 0.0001). PTEN expression were found significantly decreased in PCT of both disease groups in regard to control (PTEN 25.3 % and 23.8 % vs. 41.1 % (p < 0.01 and p < 0.001 respectively). CONCLUSION: SATB1 and PTEN could be considered as markers influenced in kidney disease development. SATB1/PTEN expression should be further investigated as useful markers of kidney disease activity as well as potential therapeutic target.

Prognostic value of connective tissue growth factor and c-Myb expression in IgA nephropathy and Henoch-Schönlein purpura-A pilot immunohistochemical study.

AIM: Adverse and advanced prognostic signs in IgA nephropathy (IgAN) are interstitial fibrosis and tubular atrophy, but early predictors of bad outcome are still lacking. We investigated expression of connective tissue growth factor (CTGF) and c-Myb in renal biopsies of IgAN and Henoch-Schönlein purpura (HSP), because these gene products are indirectly included in fibrosis and epithelial-mesenchymal transition (EMT). METHODS: The sample included 23 patients and 8 controls who underwent nephrectomy due to renal cancer. The slides cut from the paraffin blocks were prepared for standard indirect immunoflourescence, using antibodies to CTGF and c-Myb. Ten high-power non-overlapping fields were photographed on Olympus IX51 microscope. Average percent of positive tubular cells, as well as number of positive cells per glomerulus were calculated. RESULTS: The cytoplasmic tubular CTGF expression was higher in IgAN/HSP than in controls (P < 0.001), whereas no difference was found in glomeruli (P = 0.437). The nuclear c-Myb expresssion in glomeruli and tubules was higher in IgAN/HSP than in controls (P < 0.05). In the follow-up, decline in renal function correlated with glomerular and tubular c-Myb, as well as tubular CTGF expression (all P < 0.05). CONCLUSION: Our results proposed c-Myb and CTGF as novel, early and sensitive markers of chronic kidney disease and worse renal outcome, but larger series are needed.

Expression of DENDRIN in several glomerular diseases and correlation to pathological parameters and renal failure - preliminary study.

BACKGROUND: In glomerular injury dendrin translocates from the slit diaphragm to the podocyte nucleus, inducing apoptosis. We analyzed dendrin expression in IgA glomerulonephritis and Henoch Schönlein purpura (IgAN/HSP) versus in podocytopathies minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), and compared it to pathohistological findings and renal function at the time of biopsy and the last follow-up. METHODS: Twenty males and 13 females with median of age 35 years (min-max: 3-76) who underwent percutaneous renal biopsy and had diagnosis of glomerular disease (GD) were included in this retrospective study. Fifteen patients had IgAN/HSP and eighteen podocytopathy. Control group consisted of ten patients who underwent nephrectomy due to renal cancer. Dendrin expression pattern (membranous, dual, nuclear or negative), number of dendrin positive nuclei and proportion of dendrin negative glomeruli were analyzed. RESULTS: In GD and the control group significant differences in number of dendrin positive nuclei and proportion of dendrin negative glomeruli were found (P = 0.004 and P = 0.003, respectively). Number of dendrin positive nuclei was higher in podocytopathies than in IgAN/HSP, 3.90 versus 1.67 (P = 0.028). Proportion of dendrin negative glomeruli correlated to higher rates of interstitial fibrosis (P = 0.038), tubular atrophy (P = 0.011) and globally sclerotic glomeruli (P = 0.008). Dual and nuclear dendrin expression pattern were connected with lower rate of interstitial fibrosis and tubular atrophy than negative dendrin expression pattern (P = 0.024 and P = 0.017, respectively). Proportion of dendrin negative glomeruli correlated with lower creatinine clearance (CC) at the time of biopsy and the last follow-up (P = 0.010 and P < 0.001, respectively). Dendrin expression pattern correlated to CC at the last follow-up (P = 0.009), being lower in patients with negative than nuclear or dual dendrin expression (P = 0.034 and P = 0.004, respectively). CONCLUSION: In this pilot study the number of dendrin positive nuclei was higher in podocytopathies than in inflammatory GD. Negative dendrin expression pattern correlated to chronic tubulointerstitial changes and lower CC, which needs to be confirmed in a larger series.

Incidence of Central Nervous System Tumors in Patients Hospitalized at Split University Hospital Centre During a Ten-Year Period (January 1, 2004 - December 31, 2013).

The aim was to evaluate the incidence and characteristics of central nervous system tumors in patients hospitalized at the Department of Neurology, Split University Hospital Centre, during a 10-year period. The study included data on 859 patients with the diagnosis of central nervous system (CNS) tumor. Diagnosis was based on the routine CNS neuroimaging methods (computed tomography/magnetic resonance imaging). Access to patient medical records provided demographic and clinical data, continued by collection of data on potential lethal outcome of patients at the Registrar's Office. The study was conducted at the Department of Neurology, Split University Hospital Centre, from January 1, 2004 to December 31, 2013. There were 448 male and 411 female patients. Median age at the diagnosis was 65 (range, 18-95) years. Primary CNS tumors were diagnosed in 527 patients, including 30 primary recurrent tumors, whereas 328 patients had metastatic tumors; in 4 cases, it was impossible to determine whether the tumor was a primary one or metastasis based on CNS neuroimaging. The primary tumors proved to be more common than the metastatic ones (χ2-test, p<0.05). Multiple tumor transplants were more common than solitary (211 vs. 117; the conclusion was made at a 95% level of confidence; χ2-test, p<0.05). The majority of metastases originated from the lung (bronchus and pleura cancer; 46.41%; χ2-test, p<0.05; 95% CI). The most common localization of CNS tumors was supratentorial. Based on the double-logarithmic model, we proved with statistical significance that there was an increase in the incidence of CNS tumors (p=0.001). The most common tumors studied were supratentorially localized meningiomas.