Etiologic Relationship Research Articles

Subacute Thyroiditis Exacerbated by the COVID-19 Pandemic

Objective: It was aimed to evaluate the etiological relationship between the SARS-CoV-2 virus and subacute thyroiditis (SAT). We also wanted to point out the fact that these two entities may have similar clinical features. Materials and Methods: During the 4th month of the Coronavirus disease-19 (COVID-19) pandemic in our country; five patients were referred to our clinic for neck ultrasonography (USG) with a suspected diagnosis of SAT based on clinical and laboratory features. Past medical history, contact history, and COVID-19 Polyerase Chain Reaction (PCR) test results of these cases were evaluated. Results: Subfebrile fever, sore throat, burning sensation in the throat, difficulty in swallowing were the presenting symptoms of the patients. All cases had abnormal thyroid hormone values and elevated erythrocyte sedimentation rate/C-Reactive Protein (CRP) values. USG showed increased thyroid gland volume in four patients. Hypovascularized heterogeneous hypoechoic patchy areas in thyroid parenchyma were observed in all patients without discrete nodules. Ultrasound elastography revealed parenchymal heterogeneity and stiffness. Low-dose non-contrast chest computerized tomography (CT) findings was normal with negative Polymerase chain reaction (PCR) test results in patients. Conclusion: Subacute thyroiditis, which is often accused by viral agents in etiology, may also be associated with SARS-CoV-2. The similarity of clinical and laboratory findings between subacute thyroiditis and COVID-19 infection may pose diagnostic challenges.

Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

ObjectiveThis study aimed to explore shared genetic etiology and the causality between smoking status and type 2 diabetes (T2D), cardiovascular diseases (CVDs), and related metabolic traits.MethodsUsing summary statistics from publicly available genome-wide association studies (GWASs), we estimated genetic correlations between smoking status and T2D, 6 major CVDs, and 8 related metabolic traits with linkage disequilibrium score regression (LDSC) analysis; identified shared genetic loci with large-scale genome-wide cross-trait meta-analysis; explored potential shared biological mechanisms with a series of post-GWAS analyses; and determined causality with Mendelian randomization (MR).ResultsWe found significant positive genetic associations with smoking status for T2D (Rg = 0.170, p = 9.39 × 10−22), coronary artery disease (CAD) (Rg = 0.234, p = 1.96 × 10−27), myocardial infarction (MI) (Rg = 0.226, p = 1.08 × 10−17), and heart failure (HF) (Rg = 0.276, p = 8.43 × 10−20). Cross-trait meta-analysis and transcriptome-wide association analysis of smoking status identified 210 loci (32 novel loci) and 354 gene–tissue pairs jointly associated with T2D, 63 loci (12 novel loci) and 37 gene–tissue pairs with CAD, 38 loci (6 novel loci) and 17 gene–tissue pairs with MI, and 28 loci (3 novel loci) and one gene–tissue pair with HF. The shared loci were enriched in the exo-/endocrine, cardiovascular, nervous, digestive, and genital systems. Furthermore, we observed that smoking status was causally related to a higher risk of T2D (β = 0.385, p = 3.31 × 10−3), CAD (β = 0.670, p = 7.86 × 10−11), MI (β = 0.725, p = 2.32 × 10−9), and HF (β = 0.520, p = 1.53 × 10−6).ConclusionsOur findings provide strong evidence on shared genetic etiology and causal associations between smoking status and T2D, CAD, MI, and HF, underscoring the potential shared biological mechanisms underlying the link between smoking and T2D and CVDs. This work opens up a new way of more effective and timely prevention of smoking-related T2D and CVDs.

Rare Occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers.

Simple SummaryAristolochic acids (AAs) are a family of carcinogenic phytochemical compounds commonly found in plants of the Aristolochia and Asarum genera. Comprehensive genomic profiling of genitourinary and hepatobiliary cancers has highlighted the widespread prevalence of Aristolochic acid (AA) signatures in cancer patients across parts of Asia, particularly in Taiwan. The aim of our study was to determine in oro-gastrointestinal tract cancers (OGITCs), the prevalence, role and significance that AA plays as a driver of tumorigenesis as AA-containing products are commonly administered orally. This suggests a possible etiological relationship between OGITCs. However, in this study, the rarity of AA mutational signatures in OGITCs suggests that AA is unlikely to drive carcinogenesis in OGITCs through direct exposure. Our study is valuable because it shows that AA exposure is not an equal driver of tumorigenesis in different organs and represents an important piece of information in the field.Background: Aristolochic acids (AAs) are potent mutagens commonly found in herbal plant-based remedies widely used throughout Asian countries. Patients and Methods: To understand whether AA is involved in the tumorigenesis of the oro-gastrointestinal tract, we used whole-exome sequencing to profile 54 cases of four distinct types of oro-gastrointestinal tract cancer (OGITC) from Taiwan. Results: A diverse landscape of mutational signatures including those from DNA mismatch repair and reactive oxygen species was observed. APOBEC mutational signatures were observed in 60% of oral squamous cell carcinomas. Only one sample harbored AA mutational signatures, contradictory to prior reports of cancers from Taiwan. The metabolism of AA in the liver and urinary tract, transient exposure time, and high cell turnover rates at OGITC sites may explain our findings. Conclusion: AA signatures in OGITCs are rare and unlikely to be a major contributing factor in oro-gastrointestinal tract tumorigenesis.

Epstein-Barr Virus Infection in Lung Cancer: Insights and Perspectives.

Lung cancer (LC) is the leading cause of cancer death worldwide. Tobacco smoke is the most frequent risk factor etiologically associated with LC, although exposures to other environmental factors such as arsenic, radon or asbestos are also involved. Additionally, the involvement of some viral infections such as high-risk human papillomaviruses (HR-HPVs), Merkel cell polyomavirus (MCPyV), Jaagsiekte Sheep Retrovirus (JSRV), John Cunningham Virus (JCV), and Epstein–Barr virus (EBV) has been suggested in LC, though an etiological relationship has not yet been established. EBV is a ubiquitous gamma herpesvirus causing persistent infections and some lymphoid and epithelial tumors. Since EBV is heterogeneously detected in LCs from different parts of the world, in this review we address the epidemiological and experimental evidence of a potential role of EBV. Considering this evidence, we propose mechanisms potentially involved in EBV-associated lung carcinogenesis. Additional studies are warranted to dissect the role of EBV in this very frequent malignancy.

Studies on Relationship Between Bacterial and Fungal Infections in Some Freshwater Fish

This study aimed to, spotlight on, isolation and identification of the most common Bacterial and systemic Mycotic agent from cultured Oreochromis niloticus, study the incidence, prevalence and organs distributions of the isolated Bacteria and Fungi among the examined diseased fish, investigated the effect of different water quality parameters on the incidence such etiological agents and relationship studies between Bacterial and Mycotic diseases in examined fish. A total number of 100 diseased O. niloticus that, weighed 80 ±mg and 18 ± 0.2 cm in length were randomly collected from earthen ponds in Alexandria private cultured freshwater farms in January 2021. A bacteriological analysis of naturally 400 samples isolated from 100 infected fishes confirmed 400 positive samples and mycological analysis of 400 samples confirmed 214 positive samples. Morphologically, isolated bacteria were Gram –ve represented by Pseudomonas fluorescence, Schwenellea spp, Pseudomonas putediae, Pseudomonas aeruoginosa and Gram +ve bacteria represented by Streptococcus agalactia. Fungal isolates are represented by Aspergillus niger, Asp. flavus, Asp. fumigatus, Asp. parasiticus, Geotrichum spp., Candida spp. and Torulopsis spp. Combination between bacteria and fungi in fish ponds agreviates the morbidity and mortality rates.

MALT-лимфома желудка у пациентки с хроническим гастритом, ассоциированным с Helicobacter pylori

Objective of the Paper: To analyze the development and course of gastric MALT-lymphoma in a patient with chronic gastritis associated with Helicobacter pylori. Key points. Regression of gastric MALT-lymphoma, diagnosed in a 68-year-old patient at stage IE2, was achieved by a combination of 6 courses of immunochemotherapy according to the R-B protocol (rituximab and bendamustine) and H. pylori eradication. Conclusion. Clinical observation demonstrates the etiological relationship between gastric MALT-lymphoma and the H. pylori infection in the upper digestive tract, as well as the positive effect of immunochemotherapy and persistent eradication therapy, which contributed to the regression of gastric MALT-lymphoma itself and affected intra-abdominal lymph nodes. Keywords: gastric MALT-lymphoma, regressive course, Helicobacter pylori, eradication therapy, immunochemotherapy.

Взаємозв’язок патології серцево-судинної системи і захворювань тканин пародонта

У статті наведений сучасний погляд на етіологічний і патогенетичний взаємозв’язок між станом пародонтопатогенної мікрофлори ротової порожнини у хворих на генералізований пародонтит і розвитком серцево-судинних захворювань. Подані дані літератури та власних досліджень про прямий вплив пародонтопатогенів на етіологію захворювань серця в результаті виникнення транзиторної бактеріємії. Наведено патогенетичний взаємозв’язок і вплив інфекційно-запальних захворювань у порожнині рота шляхом стимулювання продукції прозапальних цитокінів у тканинах пародонта і С-реактивного білка організмом на розвиток серцево-судинних захворювань.

ИНФЕКЦИОННЫЙ ЭНДОКАРДИТ АОРТАЛЬНОГО И МИТРАЛЬНОГО КЛАПАНОВ СЕРДЦА ПРИ ХРОНИЧЕСКОМ УРОСЕПСИСЕ

Infective endocarditis (IE) is a multisystem disease that results from an infection, usually a bacterial one, on the endocardial heart surface. A clinical case of a patient admitted to the department of cardiovascular surgery with a diagnosis of active infectious endocarditis of the aortic and mitral valves with concomitant chronic urosepsis is described. According to the bacteriological study an etiological relationship between the origin of heart pathology and chronic urosepsis was established. The results of current methods of visual diagnostics on the basis of which the preoperative diagnosis was formed are also described. Prosthetics of the On-X 19 aortic valve and On-X 27/29 mitral valve was performed. The postoperative period and the features of its course were assessed, taking into account the etiological nature of infective endocarditis. This clinical case clearly shows that any chronic infectious process can cause damage to the endocardium, even with slowly developing processes of atypical origin, for example, the urinary system. Thus, this case indicates that it is necessary to examine a patient with acute and chronic infectious processes carefully and comprehensively for infective endocarditis, since in the early stages the disease manifests itself gradually; and this helps prevent serious complications in the future.

Proving Etiologic Relationships to Disease: Another Look at the Common Cold Coronaviruses.

Proving Etiologic Relationships to Disease: Another Look at the Common Cold Coronaviruses.

Clinical characteristics of odontogenic sinusitis with periapical lesions

IntroductionAlthough the symptoms and radiographic signs may mimic rhinogenic sinusitis, odontogenic sinusitis (OS) with periapical lesions (PALs) is fundamentally an endodontic infection. It is considered to be one of the main causes of OS, especially when presented unilaterally. Despite this routine dental examination is not performed and periapical infection frequently remains undiagnosed by otolaryngologists and radiologists. Material and methodsThis prospective observational study covered a group of 61 patients with symptomatic OS with PAL. Assessment of quality of life was done using the 22-item Sino-Nasal Outcome Test-22 (SNOT-22) and Oral Health-Impact Profile-14 (OHIP-14). Temporal and etiological relationship between the dental cause and sinonasal complication was established among the otolaryngologist and dental specialist based on the clinical symptoms, nasal endoscopy described according to the modified Lund-MacKay scale, computed tomography (CT) scans measured and scored in compliance with Lund- Kennedy, Zinreich and Estrela scales. ResultsOut of 61 patients, 28 (46%) were women and 33 (54%) men. Group median age 49.1 years, ranged from 22.8 to 78.9 years.Total OHIP-14 score was 12.7 ± 11.3, with the highest value obtained in domains describing physical pain (mean 2.9 ± 2.4, median 3) in which the highest score was obtained in item 3 – painful aching in mouth and/or teeth – scored ≥2 by 52.5% of participants. Concerning dental symptoms 11.5% of patients were asymptomatic.Total SNOT-22 score was 40.7 ± 21.1, with the highest value in domains describing nasal symptoms. 23% of patients reported mild, 44.3% moderate and 32.7% severe symptoms.In the endoscopic evaluation 86.8% of cases presented discharge, 73.8% mucosal edema. In 11.5% of cases the polypoid tissues was observed in nasal cavities.The first molar tooth was the most frequently affected with an incidence of 42.6%, followed by the second molar (27.9%).In 33 (48.5%) of cases the inflammatory process caused the discontinuity of the sinus floor, which in 51.5% coexisted with total maxillary sinus opacification.10 teeth (14.7%) had the periapical lesions with a diameter exceeding 8 mm. In case of the multi-rooted teeth, PALs were usually encountered at more than one root (57.4%). Maxillary and ethmoid sinus were affected in 54% of cases and additional frontal sinus involvement in 32.8%. In 69.6% patients, ostiomeatal complex was obstructed. ConclusionsPersistent sinonasal symptoms such as rhinorrhea, post-nasal drip and nose congestion along with dental pain may suggest endodontic nature of OS, especially after previous root-canal treatment. The bigger the PAL is in diameter and the closer to the maxillary sinus, the greater effect on its mucosal involvement and obstruction of ostiomeatal complex is observed. PALs around molar or premolar tooth apexes with coexistence of unilateral sinus opacifications should be noticed and mentioned by radiologists and evaluated by dental specialists in order to refer the patient to further treatment.

Vascular involvement in chronic thromboembolic pulmonary hypertension is associated with spirometry obstructive impairment

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension caused by persistent thromboembolism of the pulmonary arteries. In clinical practice, CTEPH patients often show obstructive ventilatory impairment, even in the absence of a smoking history. Recent reports imply a tendency for CTEPH patients to have a lower FEV1.0; however, the mechanism underlying obstructive impairment remains unknown.MethodsWe retrospectively analyzed CTEPH patients who underwent a pulmonary function test and respiratory impedance test to evaluate their exertional dyspnea during admission for right heart catheterization from January 2000 to December 2019. We excluded patients with a smoking history to rule out the effect of smoking on obstructive impairment.ResultsA total of 135 CTEPH patients were analyzed. The median FEV1.0/FVC was 76.0%, %FEV 1.0 had a negative correlation with the mean pulmonary artery pressure and pulmonary vascular resistance and the CT Angiogram (CTA) obstruction score. A multivariate regression analysis revealed that the CTA obstruction score was an independent factor of a lower %FEV1.0. In the 54 patients who underwent pulmonary endarterectomy, %FEV1.0 was improved in some cases and was not in some. Mean PAP largely decreased after PEA in the better %FEV1.0 improved cases, suggesting that vascular involvement in CTEPH could be associated with spirometry obstructive impairment.Conclusion%FEV1.0 had a significant correlation with the CTA obstruction score. Obstructive impairment might have an etiological relationship with vascular involvement. Further investigations could shed new light on the etiology of CTEPH.

Gambling fallacies: Predicting problem gambling in a national sample.

Objective: The relationship between the level of gambling fallacy endorsement and type of gambler (nongambler, recreational gambler, at-risk gambler, and problem/pathological gambler) was assessed both concurrently and prospectively in a large national cohort of Canadian adults. Method: This cohort (n = 10,199 at baseline; 18-24 years, n = 481, 43% female; 25-34 years, n = 1,335, 62% female; 35-44 years, n = 1,543, 55% female, 45-54 years, n = 1,985, 58% female; 55-64 years, n = 2,459, 55% female; 65-74 years, n = 1,865, 44% female, 75+ years, n = 531, 43% female) was recruited from LEO, Leger Opinion's registered online panelists. The follow-up survey was completed by 55.9% of the cohort, 1 year after baseline. The full survey can be viewed at https://www.ucalgary.ca/research/national-gambling-study/. For the current study, scores on the Gambling Fallacies Measure, the Problem and Pathological Gambling Measure, Gambling Participation Instrument, and Impulsivity were analyzed. Results: There were three main findings. The first is that gambling fallacies are common in all categories of gamblers but somewhat more prevalent in problem and pathological gamblers. Second, the multivariate analysis determined that gambling fallacies are significant concurrent and prospective predictors of the problem/pathological gambling category, but not strong predictors relative to other variables. Third, problem gambling and heavier gambling involvement are also predictors of a future higher level of gambling fallacies. Conclusions: Collectively, these results show that gambling fallacies have some etiological relationship to problem gambling but are not the main cause of problem gambling and should not be the exclusive focus of problem gambling treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Abstract 12089: Dual Actions of β 2 AR-Agonism Confer Protection Against Heart Failure and Renal Dysfunction via Inotropic and Lusitropic Effects and Normalized Cholesterol Homeostasis in a Mouse Model of Alport Syndrome

Introduction: Col4a3-/- Alport mice present a model of heart failure with preserved ejection fraction (HFpEF) secondary to chronic kidney disease(CKD) wherein etiological relationships have been established between hypertension, pulmonary edema, inflammation, cardiac hypertrophy and fibrosis, diastolic dysfunction and underlying abnormalities of elevated low-density lipoprotein receptor (LDLR) expression, excess LDL-cholesterol(LDL-C) accumulation, and mitochondrial dysfunction in renal tubules. Hypothesis: We tested the hypothesis that selective β2-Adrenoceptor (β2AR) modulation with salbutamol, a short-acting β2AR agonist, could alleviate symptoms of CKD and simultaneously augment cardiac function. Methods: Alport mice were injected i.p.with salbutamol or DMSO vehicle as a single bolus of 200μg/dose in short-term studies or daily with 100 μg/dose for 2 wks long-term. Cardiac and renal functions, cAMP levels, in vivo renal tubular LDL-C uptake and renal histology were evaluated post-injection. N=3-8 for all experiments. Results: Short-term, salbutamol improved renal function in parallel with decreased LDLR levels and reduced uptake of LDL-C into renal tubules. Long-term, cardiac diastolic function assessed by isovolumetric relaxation time, filling pressures, and myocardial performance index, and systolic function reflected by ejection fraction, stroke volume and cardiac output improved significantly in parallel with increased cardiac cAMP (p<.05). Mechanistically, in the kidney, salbutamol activated IDOL and hence lysosomal ubiquitination and degradation of LDLR via a novel β2AR-mediated, cAMP-independent pathway involving the Rac1/Cdc42 β1PixGEF. β1Pix reversibly sequesters IDOL into a complex with LDLR, thereby blocking the degradation pathway. β2AR stimulation dissipates the complex reactivating IDOL-mediated LDLR degradation thereby re-establishing LDL-C homeostasis and renal function. Using flow cytometry in 293T cells, ectopic expression of bPix stabilized membrane LDLR, sensitive to IDOL- but not PCSK-mediated degradation. Conclusions: β2AR agonism represents a potential treatment strategy to alleviate progression of CKD and HF associated with HFpEF phenogroup 3.

Abstract 13169: Serum Calcium is Positively Associated With Right Ventricular Function as Assessed by Hemodynamics and Echocardiography

Introduction: The physiologic role of calcium for cardiomyocyte contractility is well established. Post cardiac surgery, maintaining normocalcemia is associated with improved right ventricular (RV) function as compared to hypocalcemia. Hypothesis: We hypothesize that lower serum ionized calcium (iCa) is associated with RV dysfunction in non-surgical subjects. Methods: From a de-identified electronic health record, we extracted demographic, laboratory, echocardiographic, and first right heart catheterization (RHC) data to perform a cross-sectional analysis. iCa, obtained within 2 days of RHC, was tested for association with hemodynamics and pulmonary artery pulsatility index (PAPI; pulmonary artery pulse pressure / right atrial pressure) as a measure of RV function. We tested the association of iCa with reader-assessed RV dysfunction by echocardiography. RV dysfunction was coded as 0=none, 1=mild, 2=moderate, and 3=severe. All analyses were performed using ordinal regression adjusted for age, sex, and self-declared race. Results: From the 1,658 participants identified: median age 61 years, 42% female, 76% white, 18% black, 82% with mean pulmonary artery pressure ≥20mmHg, and 28% with pulmonary vascular resistance ≥3 Wood units. We observed a positive association between iCa and PAPI (Figure 1A, P<0.0001, n=1,658). Higher iCa was positively associated with systemic pressures and negatively associated with pulmonary pressures (P<0.01). By echocardiography, lower iCa was associated with higher prevalence of RV dysfunction (Figure 1B, P<0.0001, n=1,355). Conclusion: In a clinical population referred for RHC, we concluded that higher iCa was associated with better RV function assessed by invasive hemodynamics and echocardiography. Further studies are needed to assess whether there is an etiologic relationship between iCa and RV function.

Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain.

Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (rg = 0.299 ± 0.026, p = 9.10 × 10–31), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (βOA→MD = 0.09, SE = 0.02, z-score p-value < 1.02 × 10–5; βMD→OA = 0.19, SE = 0.026, p < 2.67 × 10–13), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (Pmeta ≤ 5 × 10–8), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted “mechanosensory behavior” genes (GO:0007638; Pgene_set = 2.45 × 10–8) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.

Association of Oral Health Literacy Level and Periodontal Health Status: A Contributory Step Towards Prevention of Periodontal Diseases

OBJECTIVE: To Evaluate the level of oral health literacy (OHL) among new patients seeking care at the private teaching dental hospital. METHODOLOGY: A cross-sectional study conducted at Department of Oral Diagnosis &amp; Periodontology at Private Teaching Dental Hospital. Adults (&gt;18years) was recruited in the study using non-probability convenient sampling technique. Participants verbally consented to participate, then interview based validated questionnaire was administered. Data collected from April 2019 to August 2019. The study was approved by Scientific Review Committee of Private Teaching Dental Hospital. OHL was measured by REALD-20. Clinical assessment was performed using periodontal index. Two investigators and 2 house surgeons were trained for increasing inter-examiner reliability. Demographic variables were examined as exploratory covariates. Statistical analysis was performed using SPSS 21.Fisher’s exact test used to determine bivariate association and Multivariate regression analysis showed the relationship. RESULTS: The total sample size was n=236 out of which 100 (42.6%) were male and 136 (57.6%) were female. Mean age of the sample was 36 years (±13.6) and majority 150(64%) had 12 years of education completed. Smokers were 50 (21%) were smokers. Respondents 173(73.3%) brush at least once in a day and 93% used toothpaste as dentifrice. Respondents belong to low-OHL had moderate 84 (36%) and severe periodontal 72 (31%) diseases. The mean Periodontal Index Score: 2± 0.54. OHL was significantly associated with periodontal disease (p 0.01). Smokers showing significant association (p 0.04) with periodontal disease. Multivariate regression analysis revealed that for one- point decrease in OHL score, the occurrence of periodontal disease reduced by 25% (Adjusted OR=0.75). CONCLUSION:This has been concluded that oral health literacy associated with periodontal health status. Understanding of periodontal health knowledge and its implication is vital for prevention of periodontal diseases. Future intervention researches are required to develop etiological relationship between oral health literacy and periodontal health status. KEYWORDS: Periodontal disease, dental oral health, smokes adults

Abstract MP257: Dual Actions Of β 2 Ar-agonism Confer Protection Against Heart Failure And Renal Dysfunction Via Inotropic And Lusitropic Effects And Normalized Cholesterol Homeostasis In A Mouse Model Of Alport Syndrome

Background: Col4a3 -/- Alport mice present a model of heart failure with preserved ejection fraction (HFpEF) secondary to chronic kidney disease (CKD) wherein etiological relationships have been established between hypertension, pulmonary edema, inflammation, cardiac hypertrophy and fibrosis, diastolic dysfunction and underlying abnormalities of elevated low-density lipoprotein receptor (LDLR) expression, excess LDL-cholesterol (LDL-C) accumulation, and mitochondrial dysfunction in renal tubules. HFpEF is characteristically unresponsive to pharmacological intervention. Here, we tested the hypothesis that selective β 2 -Adrenoceptor (β 2 AR) modulation with salbutamol, a short-acting β 2 AR agonist, could alleviate symptoms of CKD and simultaneously augment cardiac function. Secondarily, we investigated the mechanism of actions of such β 2 AR-mediated therapeutics on cardiac and renal functions. Methods: Alport mice were injected intraperitoneally with salbutamol or DMSO vehicle as a single bolus of 200μg/dose in short-term studies or daily with 100 μg/dose for 2 weeks long-term. Cardiac and renal functions, cAMP levels, in vivo renal tubular LDL-C uptake and renal histology were evaluated post-injection. In vitro mechanistic studies were performed in HK-2, Alport dog smooth muscle and tubular epithelial cells differentiated from Alport patient-derived iPSCs. Protein-protein interactions were studied using co-immunoprecipitation experiments and LDL-C uptake was measured by live-cell imaging. Results: Short-term, salbutamol improved renal function in parallel with decreased LDLR levels and reduced uptake of LDL-C into renal tubules. Long-term, cardiac diastolic function assessed by isovolumetric relaxation time (IVRT), filling pressures (E/E’), and myocardial performance index, and systolic function reflected by ejection fraction, stroke volume and cardiac output improved significantly in parallel with increased cardiac cAMP. Mechanistically, in the kidney, salbutamol activated IDOL and hence lysosomal ubiquitination and degradation of LDLR via a novel β 2 AR-mediated, cAMP-independent pathway involving the Rac1/Cdc42 β 1 PixGEF. β 1 Pix reversibly sequesters IDOL into a complex with LDLR, thereby blocking the degradation pathway. β 2 AR stimulation dissipates the complex reactivating IDOL-mediated LDLR degradation thereby re-establishing LDL-C homeostasis and renal function. Using flow cytometry in HEK293T cells, ectopic expression of bPix stabilized membrane LDLR, sensitive to IDOL- but not PCSK-mediated degradation. Conclusions: β 2 AR agonism represents a potential treatment strategy to alleviate progression of CKD and heart failure associated with HFpEF phenogroup 3.

Perivascular (Virchow–Robin) spaces

Perivascular spaces; also known as the Virchow-Robin Spaces, they are pleurally lined, interstitial fluid-filled areas that surround certain blood vessels in various organs, especially the perforating arteries in the brain, with an immunological function. Dilated perivascular spaces are divided into three types. The first of these is on the lenticulostriate artery, the second is in the cortex following the path of the medullary artery, and the third is in the midbrain. Perivascular spaces can be detected as areas of dilatation on MR images. Although a limited number of perivascular spaces can be seen in a normal brain, the increase in the number of these spaces has been associated with the incidence of various neurodegenerative diseases. Different theories have been suggested about the tendency of the perivascular spaces to expand. Current theories include mechanical trauma due to cerebrospinal fluid pulsing, elongation of penetrating blood vessels, unusual vascular permeability, and increased fluid exudation. In addition, the brain tissue atrophy that occurs with aging; It is thought to contribute to the widening of perivascular spaces by causing shrinkage of arteries, altered arterial wall permeability, obstruction of lymphatic drainage pathways and vascular demyelination. It is assumed that the clinical significance of the dilation tendencies of the perivascular spaces is based on shape change rather than size. These spaces have been mostly observed in brain regions such as corpus callosum, cingulate gyrus, dentate nucleus, substantia nigra and various arterial basins including lenticulostriate artery and mesencephalothalamic artery. In conclusion, when sections are taken on MR imaging, it is possible that perivascular spaces may be confused with microvascular diseases and some neurodegenerative changes. In addition, perivascular spaces can be seen without pathological significance. Therefore, it would be appropriate to investigate the etiological relationship by evaluating the radiological findings and clinical picture together.

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next-generation sequencing analysis.

BackgroundThe present study aimed to explore the etiological relationship between miscarriage and stillbirth and copy number variations (CNVs), as well as provide useful genetic guidance for high‐risk pregnancy.MethodsIn total, 659 fetal samples were recruited and subjected to DNA extraction and CNV sequencing (CNV‐seq), relevant medical records were collected.ResultsThere were 322 cases (48.86%) with chromosomal abnormalities, including 230 with numerical abnormalities and 92 with structural abnormalities. Chromosomal monosomy variations mainly occurred on sex chromosomes and trisomy variations mainly occurred on chromosomes 16, 22, 21, 18, 13 and 15. In total, 41 pathogenic CNVs (23 microdeletions and 18 microduplications) were detected in 27 fetal tissues. The rates of numerical chromosomal abnormalities were 29.30% (109/372), 32.39% (57/176) and 57.66% (64/111) in < 30‐year‐old, 30–34‐year‐old and ≥ 35‐year‐old age pregnant women, respectively, and increased with an increasing age (p < 0.001). There was statistically significant difference (χ2 = 7.595, p = 0.022) in the rates of structural chromosomal abnormalities in these groups (13.71%, 18.75% and 7.21%, respectively). The rates of numerical chromosomal abnormalities were 45.44% (219/482), 7.80% (11/141) and 0% (0/36) in the ≤ 13 gestational weeks, 14–27 weeks and ≥ 28 weeks groups, respectively, and decreased with respect to the increasing gestational age of the fetuses (p < 0.001).ConclusionsThe present study has obtained useful and accurate genetic etiology information that will provide useful genetic guidance for high‐risk pregnancies.

Labor activity of a woman and uterine fibroids

As you know, the question of the etiological relationship between a woman's labor and fibroids has long been a subject of controversy among gynecologists.