Retinal laser photocoagulation and intravitreal injection of anti-VEGF for hemorrhagic retinal arterial microaneurysm.

AIM: To evaluate the efficacy of retinal laser photocoagulation and intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) for hemorrhagic retinal arterial macroaneurysm (RAM). METHODS: This was a retrospective clinical study. Patients with hemorrhagic RAM were divided into 4 groups defined by different treatments: a retinal laser photocoagulation therapy monotherapy group, an anti-VEGF intravitreal injection monotherapy group, a laser and anti-VEGF combination therapy group, and an observation group. Visual acuity (VA), central macular thickness (CMT), and retinal hemorrhage area (RHA) were collected. RESULTS: Forty-seven eyes of 47 patients were enrolled. VA improved and had a significant difference between baseline and final in each treatment group (logMAR; laser group: 1.90±0.53 vs 1.05±0.63, P<0.001; anti-VEGF group: 1.75±0.63 vs 1.12±0.54, P=0.009; combination group: 1.76±0.38 vs 1.01±0.52, P<0.001); however, VA decreased and had no significant difference in observation group (1.63±0.51 vs 1.76±0.61, P=0.660). CMT decreased and had a significant difference between baseline and final in each group (laser group: 815.16±310.83 vs 252.05±83.90 µm, P<0.001; anti-VEGF group: 725.00±290.79 vs 203.56±69.89 µm, P=0.001; combination group: 595.50±186.51 vs 253.13±55.06 µm, P=0.001; observation group: 758.88±195.65 vs 267.00±120.90 µm, P=0.001). RHA were 28.99±28.15, 25.94±11.58, 19.64±8.97, and 27.45±13.76 mm2 in laser group, anti-VEGF group, combination group and observation group, respectively. RHA was statistically correlated with final VA (P=0.032) in the observation group. CONCLUSION: Both laser and anti-VEGF treatments are effective for hemorrhagic RAM. Combination therapy reduces the number of injections of anti-VEGF. RHA is a visual prognosis predictor in the natural history of hemorrhagic RAM.

[Analyzing the Chinese medicine pathogenesis of stroke].

Both ischemic and hemorrhage stroke pertain to the category of wind stroke in Chinese medicine (CM). Up to date, it is deemed that the etiology and pathogenesis of wind stroke are wind, fire, sputum, qi, stasis, and deficiency. Among them, it is regarded that wind and fire are the key factors triggering wind stroke. By analyzing the time order and causality, it is found that wind stroke is prior to the onset of wind and fire, wind and fire are the secondary outcomes of wind stroke. By parallel comparing stroke with thromboembolism and hemorrhagic diseases in other Zang-organs, it can be comprehended that the reason why wind symptoms appear in stroke is due to its physiological feature of brain itself. Based on Neijing, the pathogenesis of wind stroke is proposed as follows. Tunnels of viscera (vessels) get lesions. The old pathogenic factors of sputum and stasis or the stasis formed by bleeding inside viscera consume qi, and blood of viscera and damage the spirits hidden in them. The damage of Gan-spirit causes symptoms of stroke, such as hemiplegia, deviation of eyes and mouth, and so on. Wind and fire symptoms are caused by the injury of Gan blood and yin, and/or the stagnation of fire in pericardium (the pathway organ) due to obstruction by old pathogenic factors and stasis (formed by bleeding).

Clinicopathologic and Genomic Features in Triple-Negative Breast Cancer Between Special and No-Special Morphologic Pattern.

Background: Triple-negative breast cancer (TNBC) is refractory and heterogeneous, comprising various entities with divergent phenotype, biology, and clinical presentation. As an aggressive subtype, Chinese TNBC patients with special morphologic patterns (STs) were restricted to its incidence of 10-15% in total TNBC population. Methods: We recruited 89 patients with TNBC at Guangdong Provincial People's Hospital (GDPH) from October 2014 to May 2021, comprising 72 cases of invasive ductal carcinoma of no-special type (NSTs) and 17 cases of STs. The clinical data of these patients was collected and statistically analyzed. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) with cancer-related, 520- or 33-gene assay. Immunohistochemical analysis of FFPE tissue sections was performed using anti-programmed cell death-ligand 1(PD-L1) and anti-androgen receptor antibodies. Results: Cases with NSTs presented with higher histologic grade and Ki-67 index rate than ST patients (NSTs to STs: grade I/II/III 1.4%, 16.7%,81.9% vs 0%, 29.4%, 58.8%; p<0.05; Ki-67 ≥30%: 83.3% vs. 58.8%, p<0.05), while androgen receptor (AR) and PD-L1 positive (combined positive score≥10) rates were lower than of STs cases (AR: 11.1% vs. 47.1%; PD-L1: 9.6% vs. 33.3%, p<0.05). The most commonly altered genes were TP53 (88.7%), PIK3CA (26.8%), MYC (18.3%) in NSTs, and TP53 (68.8%), PIK3CA (50%), JAK3 (18.8%), KMT2C (18.8%) in STs respectively. Compared with NSTs, PIK3CA and TP53 mutation frequency showed difference in STs (47.1% vs 19.4%, p=0.039; 64.7% vs 87.5%, p=0.035). Conclusions: In TNBC patients with STs, decrease in histologic grade and ki-67 index, as well as increase in PD-L1 and AR expression were observed when compared to those with NSTs, suggesting that TNBC patients with STs may better benefit from immune checkpoint inhibitors and/or AR inhibitors. Additionally, lower TP53 and higher PIK3CA mutation rates were also found in STs patients, providing genetic evidence for deciphering at least partly potential mechanism of action.

A Low-Producing Haplotype of Interleukin-6 Disrupting CTCF Binding Is Protective against Severe COVID-19.

Interleukin6 (IL-6) is a key driver of hyperinflammation in COVID-19, and its level strongly correlates with disease progression. To investigate whether variability in COVID-19 severity partially results from differential IL-6 expression, functional single-nucleotide polymorphisms (SNPs) of IL-6 were determined in Chinese COVID-19 patients with mild or severe illness. An Asian-common IL-6 haplotype defined by promoter SNP rs1800796 and intronic SNPs rs1524107 and rs2066992 correlated with COVID-19 severity. Homozygote carriers of C-T-T variant haplotype were at lower risk of developing severe symptoms (odds ratio, 0.256; 95% confidence interval, 0.088 to 0.739; P = 0.007). This protective haplotype was associated with lower levels of IL-6 and its antisense long noncoding RNA IL-6-AS1 by cis-expression quantitative trait loci analysis. The differences in expression resulted from the disturbance of stimulus-dependent bidirectional transcription of the IL-6/IL-6-AS1 locus by the polymorphisms. The protective rs2066992-T allele disrupted a conserved CTCF-binding locus at the enhancer elements of IL-6-AS1, which transcribed antisense to IL-6 and induces IL-6 expression in inflammatory responses. As a result, carriers of the protective allele had significantly reduced IL-6-AS1 expression and attenuated IL-6 induction in response to acute inflammatory stimuli and viral infection. Intriguingly, this low-producing variant that is endemic to present-day Asia was found in early humans who had inhabited mainland Asia since ∼40,000 years ago but not in other ancient humans, such as Neanderthals and Denisovans. The present study suggests that an individual's IL-6 genotype underlies COVID-19 outcome and may be used to guide IL-6 blockade therapy in Asian patients. IMPORTANCE Overproduction of cytokine interleukin-6 (IL-6) is a hallmark of severe COVID-19 and is believed to play a critical role in exacerbating the excessive inflammatory response. Polymorphisms in IL-6 account for the variability of IL-6 expression and disparities in infectious diseases, but its contribution to the clinical presentation of COVID-19 has not been reported. Here, we investigated IL-6 polymorphisms in severe and mild cases of COVID-19 in a Chinese population. The variant haplotype C-T-T, represented by rs1800796, rs1524107, and rs2066992 at the IL-6 locus, was reduced in patients with severe illness; in contrast, carriers of the wild-type haplotype G-C-G had higher risk of severe illness. Mechanistically, the protective variant haplotype lost CTCF binding at the IL-6 intron and responded poorly to inflammatory stimuli, which may protect the carriers from hyperinflammation in response to acute SARS-CoV-2 infection. These results point out the possibility that IL-6 genotypes underlie the differential viral virulence during the outbreak of COVID-19. The risk loci we identified may serve as a genetic marker to screen high-risk COVID-19 patients.

Identification of an immune-related signature for the prognosis of uveal melanoma.

AIM: To construct an immune-related prognostic signature (IPS) that can distinguish and predict prognosis in uveal melanoma (UM). METHODS: The transcriptomic data and clinicopathological information of 80 UM patients were extracted from the TCGA database. These patients were randomly assigned to a training and a testing set. RESULTS: Lasso Cox analysis was performed for the prognostic immune-related genes to develop an IPS for UM in the training set. The signature was validated in both the testing set and entire cohort. We confirmed the prognostic value of our IPS in distinct subgroups and found its association with the T stage and basal diameter of the tumor. Tumor Immune Estimation Resource database analysis revealed that the IPS was negatively correlated with the infiltration of neutrophils and dendritic cells, but positively correlated with the infiltration level of CD8+ T cells. In addition, we demonstrated that immune checkpoints containing PD-1, CTLA-4, IDO, and TIGIT were moderately associated with the IPS. CONCLUSION: This is the first study to develop and validate an immune-related signature with the ability of predicting prognosis for UM patients. Further studies are needed to validate its prediction accuracy.

Melanin change of retinal pigment epithelium and choroid in the convalescent stage of Vogt-Koyanagi-Harada disease.

AIM: To observe the melanin change of the retinal pigment epithelium (RPE) and choroid in the convalescent stage of Vogt-Koyanagi-Harada (VKH). METHODS: A retrospective study was performed on 40 eyes of 20 patients in the convalescent stage of VKH. Fundus photography (FP), multi-spectral imaging (MSI), and optical coherence tomography (OCT) were performed. RESULTS: In the VKH convalescent stage, focal RPE melanin accumulation (FRMA) was detected in 34 eyes (85%) on MSI and in 7 eyes (17.5%) on FP. FRMA was limited to the previous retinal detachment area in all 28 eyes (FRMA was detected in 34 eyes on MSI, which were enrolled, and 6 eyes lacked data in the acute stage). Sunset-glow fundus was detected in 20 eyes (50%) on FP. The mean density of FRMA in a 1-mm-diameter circular area of the fovea was 0.04±0.07 on MSI, which was significantly correlated with sunset-glow fundus (ρ=0.467, P=0.02). CONCLUSION: In the VKH convalescent stage, FRMA is derived from the RPE melanin change, and sunset-glow fundus is derived from the choroid melanin change. A higher density of FRMA in the fovea and sunset-glow fundus represents more serious depigmentation of melanin.

Clinical characteristics of acute zonal occult outer retinopathy in Chinese patients.

PURPOSE: To review the clinical features of acute zonal occult outer retinopathy (AZOOR) in Chinese patients. METHODS: All patients with AZOOR during 2002-2004 in our hospitals were reviewed retrospectively. RESULTS: Seven consecutive Chinese patients with AZOOR were recruited and followed up for 4-18 months. Their age ranged from 26 to 47 years and all were affected bilaterally. They were from the cities near the Pacific Ocean and were used to eating seafood. The common complaints were slightly reduced visual acuity and photopsia. At least one eye of each patient had a visual field defect or decreased local area sensitivity and one patient had bilateral blind spot enlargement. Ten in 14 eyes showed increased numbers of vitreous cells and 4 eyes had anterior chamber inflammatory cells and a keratic precipitate. In their initial examination, minimal or no fundus changes were found, only yellow-white dots or gray dots presented on the deep retina or outer retinal layer. Fundus fluorescent angiography showed large-area depigmentation and hyperfluorescein spots corresponding to fundus findings. Electroretinogram (ERG) or multifocal ERG was abnormal in all eyes with no changes in their follow-up examination. Not all of the initial diagnoses of these patients were consistent with the final ones. CONCLUSIONS: AZOOR is not a common disease in China, but easy to misdiagnose. Female predilection, photopsia, visual field defect, ERG abnormality and minimal ophthalmoscopic changes are the common characteristics of AZOOR in Chinese patients. Living habits may play a role in the development of AZOOR.

[Diagnosis and differential diagnosis of acute zonal occult outer retinopathy].

OBJECTIVE: To study the clinical manifestations of acute zonal occult outer retinopathy (AZOOR) and to differentiate it from other retinal diseases. METHODS: Six patients diagnosed AZOOR had complete eye examinations including fundus photography, fundus fluorescein angiography (FFA), electroretinography (ERG), visual evoked potentials and visual field examination. Medical consultation and neurological consultation were performed in those patients. All patients were followed up and the data were collected for analysis, discussion, diagnosis and differential diagnosis. RESULTS: Six patients (five female and one male) aged 26 - 42 years (mean 35 years) with AZOOR were followed up for 4 - 18 months [mean (7.5 +/- 3.2) months]. All of them were affected bilaterally and their visual acuity were slightly reduced except one eye was CF/40 cm. Half of them had photopsia. At least one eye of each patient had visual field defect or decreased sensitivity in local area or blind-spot enlargement. Biomicroscopic examination revealed vitreous cells in 10/12 eyes and anterior chamber inflammatory cells and keratic precipitate in 4/12 eyes. Minimal (10/12 eyes) or no (2/12 eyes) fundus changes were found in their initial examination. Funduscopic examination revealed yellow-white dots (4/12 eyes) and gray dots (6/12 eyes) at the posterior pole of deep retina or retinal pigment epithelium-Bruch membrane-choroid capillary complex layer. FFA showed depigmentation (2/12 eyes) or hyperfluorescein spots (10/12 eyes) that identical to the retinal lesions. In the follow-up examination, the visual acuity was reduced in one eye and visual field defect enlarged in both eyes of one patient; the number of retinal dots increased in one eye, decreased in one eye and extinguished in one eye. ERG or mERG revealed abnormal in all of their eyes with no changes in their follow-up examination. All of the initial diagnoses of six patients were not consistent with final diagnosis. CONCLUSIONS: AZOOR is a rare eye disease, usually occurs in young females, with the characteristics of photopsia, visual field defects, abnormal ERG and slight changes in the fundus. The differential diagnosis of this disease is relatively complicate and is easily to be misdiagnosed.

Application of MPVR and TL-VR with 64-row MDCT in neonates with congenital EA and distal TEF.

AIM: To assess the application of multiple planar volume reconstruction (MPVR) and three-dimensional (3D) transparency lung volume rendering (TL-VR) with 64-row multidetector-row computed tomography (MDCT) in neonates with congenital esophageal atresia (EA) and distal tracheoesophageal fistula (TEF). METHODS: Twenty neonates (17 boys, 3 girls) with EA and distal TEF at a mean age of 4.6 d (range 1-16 d) were enrolled in this study. A helical scan of 64-row MDCT was performed at the 64 mm × 0.625 mm collimation. EA and TEF were reconstructed with MPVR and TL-VR, respectively. Initial diagnosis of EA was made by chest radiography showing the inserted catheter in the proximal blind-ended esophageal pouch. Manifestations of MDCT images were compared with the findings at surgery. RESULTS: MDCT showed the proximal and distal esophageal pouches in 20 cases. No significant difference was observed in gaps between the proximal and distal esophageal pouches detected by MPVR and TL-VR. The lengths of gaps between the proximal and distal esophageal pouches detected by MPVR and TL-VR correlated well with the findings at surgery (R = 0.87, P < 0.001). The images of MPVR revealed the orifice of TEF in 13 cases, while TL-VR images showed the orifice of TEF in 4 cases. CONCLUSION: EA and distal TEF can be reconstructed using MPVR and TL-VR of 64-row MDCT, which is a noninvasive technique to demonstrate the distal esophageal pouches and inter-pouch distance in neonates with EA and distal TEF.

Identification, expression and tissue distribution of a renalase homologue from mouse.

FAD (flavin adenine dinucleotide)-dependent monoamine oxidases play very important roles in many biological processes. A novel monoamine oxidase, named renalase, has been identified in human kidney recently and is found to be markedly reduced in patients with end-stage renal disease (ESRD). Here, we reported the identification of a renalase homologue from mouse, termed mMAO-C (mouse monoamine oxidase-C) after the monoamine oxidase-A and -B (MAO-A and -B). This gene locates on the mouse chromosome 19C1 and its coding region spans 7 exons. The deuced amino acid sequences were predicted to contain a typical secretive signal peptide and a conserved amine oxidase domain. Phylogenetic analysis and multiple sequences alignment indicated that mMAO-C-like sequences exist in all examined species and share significant similarities. This gene has been submitted to the NCBI GenBank database (Accession number: DQ788834). With expression vectors generated from the cloned mMAO-C gene, exogenous protein was effectively expressed in both prokaryotic and eukaryotic cells. Recombinant mMAO-C protein was secreted out of human cell lines, indicating the biological function of its signal peptide. Moreover, tissue expression pattern analysis revealed that mMAO-C gene is predominantly expressed in the mouse kidney and testicle, which implies that kidney and testicle are the main sources of renalase secretion. Shortly, this study provides an insight into understanding the physiological and biological functions of mMAO-C and its homologues in endocrine.