Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/ß-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/ß-dependent antiviral immunity.

Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.

Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we delineated the BP-ACC segments of all human introns and found extreme depletion of AG/YAG in the [BP+8, ACC-4] high-risk region. We developed AGAIN as a genome-wide computational approach to systematically and precisely pinpoint intronic AG-gain variants within the BP-ACC regions. AGAIN identified 350 AG-gain variants from the Human Gene Mutation Database, all of which alter splicing and cause disease. Among them, 74% created new acceptor sites, whereas 31% resulted in complete exon skipping. AGAIN also predicts the protein-level products resulting from these two consequences. We performed AGAIN on our exome/genomes database of patients with severe infectious diseases but without known genetic etiology and identified a private homozygous intronic AG-gain variant in the antimycobacterial gene SPPL2A in a patient with mycobacterial disease. AGAIN also predicts a retention of six intronic nucleotides that encode an in-frame stop codon, turning AG-gain into stop-gain. This allele was then confirmed experimentally to lead to loss of function by disrupting splicing. We further showed that AG-gain variants inside the high-risk region led to misspliced products, while those outside the region did not, by two case studies in genes STAT1 and IRF7. We finally evaluated AGAIN on our 14 paired exome-RNAseq samples and found that 82% of AG-gain variants in high-risk regions showed evidence of missplicing. AGAIN is publicly available from https://hgidsoft.rockefeller.edu/AGAIN and https://github.com/casanova-lab/AGAIN.

Comparison of specificity and sensitivity of diagnostic methods for Enteromyxum leei and Enteromyxum fugu detected from cultured tiger puffer, Takifugu rubripes in Korea.

Enteromyxum leei and Enteromyxum fugu, which are myxosporean parasites, were first found in cultured tiger puffer Takifugu rubripes in Korea. We collected four tiger puffers that showed severe emaciation signs for our experiments. DNA sequencing was confirmed that the tiger puffers were coinfected with E. leei and E. fugu. Furthermore, similar amounts of E. leei and E. fugu were confirmed using real-time PCR in the intestine. To the best of our knowledge, there have been no reports of E. fugu infection in the olive flounder Paralichthys olivaceus. However, the diagnosis of inflowing water, discharged water and olive flounder samples using highly sensitive diagnostic methods confirmed the presence of E. fugu in water and fish samples from olive flounder farms near the tiger puffer farm. Therefore, the present study aimed to develop highly sensitive diagnostic methods such as real-time and two-step PCR for early diagnosis and follow-up of the emaciation disease and multiplex PCR for rapid diagnosis. The multiplex PCR method exhibited the same sensitivity as the one-step PCR method developed in this study, demonstrating its efficacy for rapid diagnosis. Therefore, the suggested methods can be utilized for the early diagnosis and rapid diagnosis of emaciation diseases and reduction of economic losses through rapid disease control.

Long-term prognosis after decoronation of avulsed teeth with replacement resorption: a report of three cases.

The complications of replacement resorption following tooth injury in growing children include infrapositioning of the tooth, tilting of the adjacent teeth, and alveolar ridge deformity. Decoronation is a conservative treatment method that facilitates bone preservation. The current case report focuses on the long-term preservation of alveolar ridge dimension following decoronation in three patients. Decoronation was performed prior to occurrence of the pubertal growth spurt, and the patients' ridge width and vertical apposition were monitored for at least 4 years. Timely intervention and regular monitoring are essential for maximization of the benefits of decoronation, a simple procedure that preserves esthetics and minimizes the need for further treatments. The importance of space management for prosthetic treatment has also been highlighted. The findings of this study show that infrapositioned teeth in growing children can be treated successfully using decoronation.

PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.

Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones with the α-crystalline domain that is critical to their chaperone activity. Within the sHSP family, three (HSPB1, HSPB3, and HSPB8) proteins are linked with inherited peripheral neuropathies, including distal hereditary motor neuropathy (dHMN) and Charco-Marie-Tooth disease (CMT). In this study, we introduced the HSPB3 Y118H (HSPB3Y118H) mutant gene identified from the CMT2 family in Drosophila. With a missense mutation on its α-crystalline domain, this human HSPB3 mutant gene induced a loss of motor activity accompanied by reduced mitochondrial membrane potential in fly neuronal tissues. Moreover, mitophagy, a critical mechanism of mitochondrial quality control, is downregulated in fly motor neurons expressing HSPB3Y118H. Surprisingly, PINK1 and Parkin, the core regulators of mitophagy, successfully rescued these motor and mitochondrial abnormalities in HSPB3 mutant flies. Results from the first animal model of HSPB3 mutations suggest that mitochondrial dysfunction plays a critical role in HSPB3-associated human pathology.

Multibatch Cytometry Data Integration for Optimal Immunophenotyping.

High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).

Aberrantly Expressed MicroRNAs in Cancer-Associated Fibroblasts and Their Target Oncogenic Signatures in Hepatocellular Carcinoma.

Cancer-associated fibroblasts (CAFs) contribute to tumor progression, and microRNAs (miRs) play an important role in regulating the tumor-promoting properties of CAFs. The objectives of this study were to clarify the specific miR expression profile in CAFs of hepatocellular carcinoma (HCC) and identify its target gene signatures. Small-RNA-sequencing data were generated from nine pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively. Bioinformatic analyses were performed to identify the HCC-CAF-specific miR expression profile and the target gene signatures of the deregulated miRs in CAFs. Clinical and immunological implications of the target gene signatures were evaluated in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA_LIHC) database using Cox regression and TIMER analysis. The expressions of hsa-miR-101-3p and hsa-miR-490-3p were significantly downregulated in HCC-CAFs. Their expression in HCC tissue gradually decreased as HCC stage progressed in the clinical staging analysis. Bioinformatic network analysis using miRWalks, miRDB, and miRTarBase databases pointed to TGFBR1 as a common target gene of hsa-miR-101-3p and hsa-miR-490-3p. TGFBR1 expression was negatively correlated with miR-101-3p and miR-490-3p expression in HCC tissues and was also decreased by ectopic miR-101-3p and miR-490-3p expression. HCC patients with TGFBR1 overexpression and downregulated hsa-miR-101-3p and hsa-miR-490-3p demonstrated a significantly poorer prognosis in TCGA_LIHC. TGFBR1 expression was positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages in a TIMER analysis. In conclusion, hsa-miR-101-3p and hsa-miR-490-3p were substantially downregulated miRs in CAFs of HCC, and their common target gene was TGFBR1. The downregulation of hsa-miR-101-3p and hsa-miR-490-3p, as well as high TGFBR1 expression, was associated with poor clinical outcome in HCC patients. In addition, TGFBR1 expression was correlated with the infiltration of immunosuppressive immune cells.

Chromatographic Method for Monitoring of Pesticide Residues and Risk Assessment for Herbal Decoctions Used in Traditional Korean Medicine Clinics.

The presence of pesticide residues in herbs and the herbal products derived from them raises serious health concerns. This study was conducted to investigate the residual pesticide concentrations and assess potential human health risks from herbal medicines used in traditional Korean medicine clinics. A total of 40 samples of herbal decoctions were collected from 10 external herbal dispensaries. The pesticide residues were analyzed by the multiresidue method for 320 different pesticides using liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS). As a result of the monitoring, carbendazim was detected at 0.01 and 0.03 µg/g in eight samples and no pesticide was detected in the other herbal decoctions. Carbendazim was set for each individual item as less than 0.05 µg/g in Paeoniae radix, less than 0.05 µg/g in Cassiae semen, less than 2.0 µg/g in Lycii fructus, and less than 10 µg/g in Schisandrae fructus (dried). Therefore, the results of this study suggested that the detected pesticide residues in herbal decoctions could not be considered as posing a serious health risk.

Human HSPB1 mutation recapitulates features of distal hereditary motor neuropathy (dHMN) in Drosophila.

Distal hereditary motor neuropathies (dHMN) are a group of inherited peripheral nerve disorders characterized by length-dependent motor neuron weakness and subsequent muscle atrophy. Missense mutations in the gene encoding small heat shock protein HSPB1 (HSP27) have been associated with hereditary neuropathies including dHMN. HSPB1 is a member of the small heat shock protein (sHSP) family characterized by a highly conserved α-crystallin domain that is critical to their chaperone activity. In this study, we modeled HSPB1 mutant-induced neuropathies in Drosophila using a human HSPB1S135F mutant that has a missense mutation in its α-crystallin domain. Overexpression of the HSPB1 mutant produced no significant defect in the Drosophila development, however, a partial reduction in the life span was observed. Further, the HSPB1 mutant gene induced an obvious loss of motor activity when expressed in Drosophila neurons. Moreover, suppression of histone deacetylase 6 (HDAC6) expression, which has critical roles in HSPB1 mutant-induced axonal defects, successfully rescued the motor defects in the HSPB1 mutant Drosophila model.

Endoscopic Vacuum Therapy in the Management of Postoperative Leakage After Esophagectomy.

BACKGROUND: Postoperative leakage after esophagectomy is associated with significant life-threatening complications. Recently, endoscopic vacuum therapy (EVT) was introduced and has been successfully used as a new treatment option. The purpose of this study was to evaluate the safety and efficacy of EVT for the management of postoperative leakage after esophagectomy. METHODS: A total of 22 patients were treated with either intraluminal or intracavitary EVT for the management of postoperative leakage from May 2012 to April 2018. The location of leakage was intrathoracic in 17 patients and cervical in five patients. The outcomes of EVT were analyzed retrospectively. RESULTS: Complete postoperative leakage closure was achieved in 19 of 22 patients. The median duration of EVT application was 14 days (range 2-103), and a median number of three EVT systems (range 1-14) were used. In 19 patients who were successfully managed with EVT, oral feeding was possible a median of 15 days after the first day of treatment. There were no cases of mortality related to postoperative leakage. CONCLUSIONS: EVT is a well-tolerated and effective therapeutic option for the treatment of various types of postoperative leakage after esophagectomy.

Left Hepatic Artery Pseudoaneurysm Caused by Acute Pancreatitis.

OBJECTIVE: The aim of this work was to report a case of left hepatic artery pseudoaneurysm due to acute pancreatitis following endoscopic papillectomy. CLINICAL PRESENTATION AND INTERVENTION: A 74-year-old female with an ampullary adenoma underwent papillectomy, which was complicated by acute pancreatitis. Computed tomography showed aneurysmal dilatation of the proximal left hepatic artery. An angiography with coli embolization was performed and was successful. The patient was doing well at the 1-year follow-up. CONCLUSION: This patient with left hepatic artery pseudoaneurysm following severe acute pancreatitis was successfully treated with coil embolization.

Adverse events of herbal decoction: A systematic review and meta-analysis over past 10 years.

BACKGROUND: Herbal decoctions (HDs) are the oldest and most common herbal medicine formulations. Different HDs exist, and some consumers are concerned that they may become contaminated during manufacturing. Therefore, the need for a safety assessment of HDs has been raised. This study aimed to investigate the adverse events (AEs) associated with HDs by comprehensively analyzing randomized controlled trials (RCTs) using systematic reviews and meta-analyses. METHODS: A systematic search was conducted on PubMed, Embase, and the Cochrane Library for articles published up to November 2022. The included RCTs compared HDs with other treatments published between 2013 and 2022, and the risk of bias was assessed using RevMan 5.4. Meta-analyses of the number of AEs associated with HDs reported in the included RCTs were also performed. RESULTS: The systematic review included 26 RCTs, and the meta-analysis included 17 RCTs that reported AEs. The meta-analysis comparing HDs with active controls showed that both the number of AEs (14 studies; risk ratio (RR)= 0.50 cases, 95 % confidence interval (CI) [0.29, 0.88]; I2 = 42 %) and the number of patients who complained of AEs (seven studies; RR=0.51 patients, 95 % CI [0.28, 0.94]; I2 =9 %) were fewer in the HDs group than in the active control groups. CONCLUSION: This study showed that HDs are safer than other conventional medications based on the results of qualitative and quantitative syntheses of RCTs.

Association of sildenafil use with age-related macular degeneration: a retrospective cohort study.

OBJECTIVE: Despite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)-a major cause of global blindness-lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data. METHODS AND ANALYSIS: Using the UK's IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years. RESULTS: The primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes. CONCLUSION: The study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil's protective effect on AMD is likely insignificant.

The Impact of Statins on the Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib or Lenvatinib.

We aimed to evaluate the survival benefits of coadministering statins and multityrosine kinase inhibitors (TKIs) in patients with advanced hepatocellular carcinoma (HCC). Data from the Health Insurance Review and Assessment Service in Korea (2010-2020) were utilized. Statin use (≥28 cumulative defined daily doses) was analyzed, with 1534 statin users matched to 6136 non-users (1:4 ratio) using propensity scores. Primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS). Statin use significantly improved OS (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.72-0.82, p < 0.001) and PFS (HR 0.78, 95% CI 0.74-0.84, p < 0.001). Continuous or post-TKI statin users had better OS, while discontinuation after TKI use led to poorer OS. Both lipophilic and hydrophilic statins improved OS and PFS, particularly with ≥730 cumulative defined daily doses. In conclusion, combining statins and TKIs in patients with advanced HCC yielded significant survival benefits, influenced by statin dosage and duration. Continuous statin administration post-TKI treatment is crucial for improving outcomes in patients with HCC.

Term delivery following tuboovarian abscess after in vitro fertilization and embryo transfer.

A tuboovarian abscess (TOA) during pregnancy following oocyte retrieval is extremely rare. We report a rare case of pregnancy complicated by the development of a TOA following in vitro fertilization-embryo transfer that was treated successfully with laparoscopy. We also review all similar cases reported in the English-language literature.

Analysis of histone deacetylase inhibitor-induced responses in human periodontal ligament fibroblasts.

Periodontal ligament (PDL) fibroblasts play critical roles in the regeneration of periodontal tissues damaged by periodontitis. Histone deacetylase inhibitors (HDIs) have been suggested to be potential tools in tissue engineering. The feasibility of using the HDI, sodium butyrate (NaB) for periodontal regeneration was examined by evaluating its effect on the osteogenic differentiation of human PDL fibroblasts and its modulation of the inflammatory responses to lipopolysaccharide (LPS). NaB did not cause significant cell death at 100 µM but promoted the expression of the osteoblast phenotype (Runx2, osterix, osteocalcin, and bone sialoprotein). NaB significantly inhibited the LPS-induced production of reactive oxygen species and the expression of pro-inflammatory cytokines (IL-1ß and TNF-α). These results suggest that HDIs can offer a potential therapeutic agent for periodontal regeneration.

Bee Venom Acupuncture for Neck Pain: A Review of the Korean Literature.

Bee venom is a natural toxin that is effective in treating various types of pain. The purpose of this paper was to review all the features of clinical studies conducted on bee venom acupuncture (BVA) for the treatment of neck pain in Korean publications. Six Korean databases and 16 Korean journals were searched in August 2022 for clinical studies on BVA for neck pain. We identified 24 trials that met our inclusion criteria, of which 316 patients with neck pain were treated with BVA. The most common diagnosis in the patients with neck pain was herniated intervertebral discs (HIVDs) of the cervical spine (C-spine) (29.2%), and the concentration and dosage per session were 0.05-0.5 mg/mL and 0.1-1.5 mL, respectively. The visual analog scale was most often measured for neck pain severity (62.5%), and all clinical research reported improvements in 16 outcome measures. This study shows that BVA could be recommended for the treatment of neck pain, especially HIVD of the C-spine; however, the adverse effects of BVA must be examined in future studies.