Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.     

Microsatellite Instability in Russian Patients with Colorectal Cancer

The aim of this study was to determine the characteristics of Russian patients with microsatellite instability (MSI) tumors. MSI in the tumor was determined in 514 patients with colon cancer using PCR and subsequent fragment analysis for five markers (NR21, NR24, BAT25, BAT26, and NR27). In the presence of microsatellite instability, the mismatch repair (MMR) system genes were examined using the NGS and MLPA methods to establish the diagnosis of Lynch syndrome. The overall frequency of MSI tumors was 15%: at stage I—19% (9/48), at stage II—21% (44/213), at stage III—16% (26/160), and at stage IV—2% (2/93). Patients with MSI tumors differed in the age of diagnosis, tumor localization, time of cancer recurrence, and stage of the disease. The overall and disease-free survival of patients whose tumors had MSI status was higher than that of patients with microsatellite-stable status, p = 0.04 and p = 0.02, respectively. Analysis of overall and disease-free survival of patients with Lynch syndrome and patients with sporadic colon cancer, but with MSI status, did not reveal significant differences, p = 0.52 and p = 0.24, respectively. The age of patients with Lynch syndrome was significantly younger than that of patients with sporadic colon cancer whose tumors had MSI status (p < 0.001).     

Identification of Spliceogenic Variants beyond Canonical GT-AG Splice Sites in Hereditary Cancer Genes

Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.     

微胶囊化儿茶素对阿霉素肾病大鼠总抗氧化能力的影响

目的:探讨微胶囊化儿茶素对阿霉素肾病大鼠总抗氧化能力的影响。方法:将60只雌性SD大鼠随机分为对照组、肾病组、激素组、VE组、儿茶素组和微胶囊组共六组,尾静脉一次性注射阿霉素(5mg/kg)制备肾病模型;实验第六周末杀鼠取尿、血、肾及肝脏,利用生化法测定血、肾及肝脏总抗氧化能力和·OH,利用考马斯亮蓝法测定24h尿蛋白的排泄量。结果:微胶囊组大鼠血、肾及肝脏中总抗氧化能力显著高于儿茶素组(p<0.01);微胶囊组大鼠·OH的浓度在肾与肝脏中显著低于儿茶素组(p分别<0.05,0.01),在血清中无显著性差异;微胶囊化儿茶素治疗组24h尿蛋白排泄量显著低于儿茶素治疗组(p>0.05)。结论:微胶囊化儿茶素可能是通过提高肾病大鼠总抗氧化能力,有效清除·OH,达到降低肾病大鼠尿蛋白排泄的目的。     

Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging

Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 μm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint.     

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3^-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3^-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3^-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3^-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3^-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.     

中国大陆进口冷链食品关联新型冠状病毒疫情调查

目的 新型冠状病毒（SARS-CoV-2）全球大流行以来,中国大陆报道了多起SARS-CoV-2污染进口冷链食品引起的本土新冠疫情,分析此类疫情的特点和传播概况,可以为今后类似疫情防控提出相应建议。方法 收集SARS-CoV-2污染进口冷链食品引起本土新冠疫情文献、官方新闻报道等信息,整理和分析相应数据。结果 2020年6月至2022年11月,共检索到此类疫情20起,包含1 646例病例,涉及9个省（自治区、直辖市）。其中,2020年10起,2021年3起,2022年7起;病例数规模在200例及以上共3起。结论 新冠全球大流行以来中国大陆检索到的20起进口冷链食品相关本土新冠疫情均为冷链从业人员接触进口冷链食品或其外包装感染引起,且大部分（75%）引起了后续社区传播,但是在中国大陆集中监管仓建设等各种有力控制措施下,此类疫情数量和持续时间均呈下降趋势。     

Closed-loop control of extracorporeal oxygen and carbon dioxide gas transfer

Additional extracorporeal gas transfer facilitates ultra-protective mechanical ventilation during treatment of severe lung disease. The proposed automation contributes to both patient safety and therapeutic success. A decentralized control system set the oxygen and carbon dioxide gas transfer rates. The controlled variables are estimated using standard measurement devices without direct blood contact. To reduce patient stress, an outer-loop integral controller adjusts the extracorporeal blood flow. The control system was first evaluated in silico and then in vivo using an animal model. Finally, the method is shown to be feasible and its response time is sufficient to meet patients' clinical needs.     

The Health Benefits of Selected Culinary Herbs and Spices Found in the Traditional Mediterranean Diet

The Mediterranean diet is considered one of the healthiest diets in the world. This is often attributed to low saturated fat consumption, moderate wine consumption, and high vegetable consumption. However, herbs and spices associated with these diets may also play an important role in the quality of this diet. This review summarizes the most recent research regarding the anti-diabetic, anti-inflammatory, anti-hyperlipidemic and anti-hypertensive properties of this collection of culinary species. Additionally, this review briefly summarizes studies performed on lesser known herbs from around the world, with the goal of identifying new culinary species that may be useful in the treatment or prevention of diseases.     

Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high‐dose cinacalcet exposure

We are reporting on a series of two patients with end‐stage renal disease on hemodialysis, presented for surgical parathyroidectomy secondary refractory hyperparathyroidism. Both patients had failed maximized medical managements, including higher‐than‐usual doses of the calcimimetic cinacalcet (270 and 180 mg/day, respectively). On physical exam, both patients had marked symmetrical craniofacial hypertrophy with coarse distortion of facial features, similar in appearance to past reports of Sagliker syndrome. On X‐ray and computed tomographic exam, they had peculiar areas of bone absorption on the skull, imitating the radiologic appearance of multiple myeloma. Bone biopsy of the maxilla, however, did not show the expected brown tumor, but rather described only fibrosis and reactive bone formations. This phenotype developed while being on cinacalcet, progressed despite escalation of therapy, and improved only after parathyroidectomy. Both patients developed massive “hungry bone syndrome” after parathyroidectomy necessitating prolonged IV calcium infusion. This pattern of severe facial distortion likely represented an adverse consequence of severe tertiary hyperparathyroidism, along with supraphysiologic dose of cinacalcet administration and 25‐hydroxy vitamin D deficiency in sensitive individuals. The genetic base of this observation remained unexplained.