Current knowledge on Rickettsia felis infection in humans is based on sporadic case reports. Here we conducted a retrospective seroepidemiological survey of R. felis infection among febrile patients ...visiting a medical center in Taipei.
A total of 122 patients with suspected rickettsioses presenting with fever of unknown origin (FUO) but tested negative for scrub typhus, murine typhus, or Q fever were retrospectively identified during 2009 to 2010. The archived serum samples were examined for the presence of antibodies against R. felis, Rickettsia japonica, and Rickettsia typhi using microimmunofluorescence (MIF) assay. Serological evidence of Rickettsia exposure was found in 23 (19%, 23/122) patients. Eight patients had antibodies reactive to R. felis, including four with current infection (a ≥4-fold increase in IgG titer between acute and convalescent sera). The clinical presentations of these four patients included fever, skin rash, lymphadenopathy, as well as more severe conditions such as pancytopenia, hepatomegaly, elevated liver enzymes/bilirubin, and life-threatening acute respiratory distress syndrome. One of the patients died after doxycycline was stopped after being tested negative for scrub typhus, Q fever, and murine typhus.
Rickettsia felis is a neglected flea-borne pathogen in Taiwan, and its infection can be life-threatening. Further prospective studies of the prevalence of R. felis among patients with FUO and compatible clinical manifestations are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Locally advanced oral squamous cell carcinoma (OSCC) requires multimodal therapy, including surgery and concurrent chemoradiotherapy (CCRT). CCRT-resistant and recurrent cancer has a poor prognosis. ...We investigated the effects of Bruton's tyrosine kinase (BTK) on CCRT-resistant OSCC tissues. The effect of ibrutinib, a first-in-class BTK inhibitor, was tested on stem cell-like OSCC tumorspheres. A tissue array was constructed using tissue samples from 70 patients with OSCC. Human OSCC cell lines, SAS, TW2.6 and HSC-3, were examined. Wound healing, Matrigel invasion, and tumorsphere formation assays, as well as immunofluorescence analysis and flow cytometry, were used to investigate the effects of BTK knockdown (shBTK), ibrutinib, cisplatin, and ibrutinib/cisplatin combination on OSCC cells. We demonstrated that BTK was aberrantly highly expressed in the clinical CCRT-resistant OSCC tissue array, which resulted in poor overall survival in our local Tri-Service General Hospital and freely accessible TCGA OSCC cohorts. shBTK significantly downregulated the stemness markers Nanog, CD133, T cell immunoglobulin-3 (TIM-3), and Krüppel-like factor 4 (KLF4) in SAS tumorspheres and attenuated OSCC cell migration and colony formation. Ibrutinib reduced the number of aldehyde dehydrogenase (ALDH)-rich OSCC cells and reduced tumorsphere formation, migration, and invasion in a dose-dependent manner. Compared with ibrutinib or cisplatin monotherapy, the ibrutinib/cisplatin combination significantly reduced the formation of ALDH + OSCC tumorspheres and enhanced apoptosis. These results demonstrate that ibrutinib effectively inhibits the CSCs-like phenotype of OSCC cells through dysregulation of BTK/CD133 signaling. The ibrutinib/cisplatin combination may be considered for future clinical use.
Fuzi, Aconiti Lateralis Radix Praeparata, is widely used in Traditional Chinese Medicine (TCM) for the treatment of acute heart failure (HF) for 2000 years. However, the clinical evidence of Fuzi in ...the treatment of chronic HF is limited, especially when used in combination with Western medications.
This population-based propensity score (PS)-matched cohort study aimed to evaluate the effectiveness of Fuzi on the chronic HF. From 4753 chronic HF patients who had used TCM herbal medicine, we performed 1:1 PS matching and selected target patients with (n = 921) and without (n = 921) Fuzi use for further analysis. The primary outcomes were all-cause mortality and composite cardiovascular (CV) outcomes. Hazard ratio (HR) was calculated by Cox proportional hazard regression and the competing risk analysis. The dose-response relationship and the association between the initiation of TCM herbal medicine and the primary outcomes were evaluated by restricted cubic spline (RCS) functions.
There was no difference in all-cause mortality (HR, 0.99; 95% confidence interval CI, 0.76–1.27) and composite CV outcomes (HR, 0.96; 95% CI, 0.84–1.11) between the Fuzi user and non-user groups. For CV safety issue, the result showed that Fuzi use was not associated with a higher risk of cardiac arrhythmias (HR, 1.03; 95% CI, 0.83–1.29). The dose-response relationship showed that Fuzi cumulative dose (≥150g) was associated with lower composite CV risk (HR, 0.76; 95% CI, 0.59–0.99). In addition, the RCS model showed that late initiation (≥2.5 years) of TCM herbal drugs in chronic HF patients had a higher risk of all-cause mortality (HR, 1.81; 95%CI, 1.07–3.08).
This study is the first real-world evidence to demonstrate the effect of Fuzi combined with routine HF treatment. Importantly, the result indicated that long-term Fuzi use had a significant benefit in preventing cardiovascular events. The late initiation of TCM herbal drugs was associated with a higher risk of all-cause mortality. Further clinical trials are needed to support or undermine the assumption of using Fuzi and current Western medications to treat chronic HF.
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•Fuzi use (cumulative dose >150 g) had benefit in preventing cardiovascular events.•Fuzi use was not associated with a higher risk of cardiac arrhythmias.•Late initiation of TCM herbal drugs was associated with increased all-cause mortality.
Background
Endoscopic therapy combined with vasoconstrictor was generally recommended to treat acute variceal bleeding. However, up to 30% of patients may still encounter treatment failure.
...Objectives
This trial was to evaluate the efficacy of combination with endoscopic variceal ligation (EVL) and proton pump inhibitor (PPI) infusion in patients with acute variceal bleeding.
Methods
Cirrhotic patients presenting with acute esophageal variceal bleeding were rescued by emergency EVL. Soon after arresting of bleeding varices, eligible subjects were randomized to two groups. Vasoconstrictor group received either somatostatin or terlipressin infusion. PPI group received either omeprazole or pantoprazole. End points were initial hemostasis, very early rebleeding rate, and adverse events.
Results
Sixty patients were enrolled in vasoconstrictor group and 58 patients in PPI group. Both groups were comparable in baseline data. Initial hemostasis was achieved in 98% in vasoconstrictor group and 100% in PPI group (P = 1.0). Very early rebleeding within 48–120 h occurred in one patient (2%) in vasoconstrictor group and one patient (2%) in the PPI group (P = 1.0). Treatment failure was 4% in vasoconstrictor group and 2% in PPI group (P = 0.95). Adverse events occurred in 33 patients (55%) in vasoconstrictor group and three patients (6%) in PPI group (P < 0.001). Two patients in vasoconstrictor group and one patient in PPI group encountered esophageal ulcer bleeding.
Conclusions
After successful control of acute variceal bleeding by EVL, adjuvant therapy with PPI infusion was similar to combination with vasoconstrictor infusion in terms of initial hemostasis, very early rebleeding rate, and associated with fewer adverse events.
Summary
Aims
Amyloid beta‐peptide (Aβ), the main component of senile plaques in the Alzheimer's disease (AD) brains, is generated from sequential cleavage of amyloid precursor protein (APP) by β‐ and ...γ‐secretase. Hyperglycemia in diabetes may compromise barrier integrity in endothelial cells (ECs). However, the roles of endothelial APP in response to high glucose (HG) remain to be delineated. The aims of this study were to test whether HG may increase Aβ secretion, thereby leading to heightened paracellular permeability in ECs.
Methods
We determined the effects of HG on production of Aβ, expression of full‐length APP, intercellular permeability, and expression levels of specific junctional proteins in human umbilical vein endothelial cells (HUVECs).
Results
HG at 30 mM significantly stimulated expression of full‐length APP accompanied by heightened secretion of Aβ1‐42, increased paracellular permeability, and attenuated expression of zona occluden‐1 (ZO‐1), claudin‐5, occludin, and junctional adhesion molecule (JAM)‐C in HUVECs; all of which were abolished by the γ‐secretase inhibitor BMS299897. Exogenous application of Aβ1‐42, but not the reverse peptide Aβ42‐1, was sufficient to downregulate the expression of the same junction proteins.
Conclusion
Hyperglycemia enhances APP expression with increased Aβ production, which downregulates junctional proteins causing increased intercellular permeability in ECs.
Abstract
The mutations in the genes encoding the subunits of complex I of the mitochondrial electron transport chain are the most common cause of Leber’s hereditary optic neuropathy (LHON), a ...maternal hereditary disease characterized by retinal ganglion cell (RGC) degeneration. The characteristics of incomplete penetrance indicate that nuclear genetic and environmental factors also determine phenotypic expression of LHON. Therefore, further understanding of the role of mutant mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit proteins and nuclear genetic factors/environmental effects in the etiology of LHON is needed. In this study, we generated human-induced pluripotent stem cells (hiPSCs) from healthy control, unaffected LHON mutation carrier, and affected LHON patient. hiPSC-derived RGCs were used to study the differences between affected and unaffected carriers of mitochondrial DNA point mutation m.11778G > A in the MT-ND4 gene. We found that both mutated cell lines were characterized by increase in reactive oxygen species production, however, only affected cell line had increased levels of apoptotic cells. We found a significant increase in retrograde mitochondria and a decrease in stationary mitochondria in the affected RGC axons. In addition, the messenger RNA and protein levels of KIF5A in the LHON-affected RGCs were significantly reduced. Antioxidant N-acetyl-L-cysteine could restore the expression of KIF5A and the normal pattern of mitochondrial movement in the affected RGCs. To conclude, we found essential differences in the mutually dependent processes of oxidative stress, mitochondrial transport and apoptosis between two LHON-specific mutation carrier RGC cell lines, asymptomatic carrier and disease-affected, and identified KIF5A as a central modulator of these differences.
Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among ...individuals with DM and CHC after successful antiviral therapy.
Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases.
Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio aHR 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications.
Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR.
The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.
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•Diabetes mellitus is associated with an increased risk of HCC in individuals with CHC.•Diabetes mellitus still increases the risk of HCC after successful antiviral therapy.•Use of metformin for DM greatly reduces HCC risk after successful antiviral therapy.•A simple risk stratification model could predict the risk of HCC and other major liver-related complications.
Despite current guidelines for tuberculosis (TB) control in health care settings, which focused on smear-positive cases, prevention of nosocomial TB transmission continues to be a challenge. Here, we ...report the results of the first hospital-wide prospective study applying interferon-gamma release assay to investigate the role of smear-negative, culture-positive index cases in nosocomial TB transmission.
We prospectively identified cases of culture-confirmed smear-negative pulmonary TB receiving aerosol-generating procedures (AGPs) and cases of culture-confirmed smear-positive pulmonary TB admitted at a medical center. Nosocomial transmission was evaluated by screening their close contacts for latent TB infection (LTBI) using an interferon-gamma release assay.
A total of 93 smear-negative index receiving AGP and 122 smear-positive index were enrolled. Among them, 13 (14.0%) and 43 (35.2%) index cases, respectively, had secondary cases of LTBI (P < .001). Sputum smear negativity (adjusted odds ratio: 0.20 0.08-0.48) and AGP (sputum suction; adjusted odds ratio: 3.48 1.34-9.05) are independent factors of transmission. A similar proportion in the close contacts of the 2 index groups had LTBI (17 15.3% and 63 16.0%, respectively), and the former index group contributed to 21.3% of the nosocomial transmission.
Smear-negative, culture-positive index cases receiving AGPs could be as infectious as smear-positive index cases. Hospital TB control policy should also focus on the former group.
•The role of smear-negative index cases in nosocomial transmission remains unknown.•Smear-negative cases receiving AGPs could be as infectious as smear-positive cases.•Smear-negative cases may be responsible for 21.3% nosocomial TB transmissions.•Ongoing physician education to optimize the utilization of TB-NAAT is imperative.•Hospital TB control should also focus on smear-negative index receiving AGPs.
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells ...(CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored.
In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, Western blot, real-time polymerase chain reaction (RT-PCR), and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2.
This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-acetylantroquinonol B (4-AAQB), as evidenced by inhibited cell viability and proliferation, as well as attenuated migration, invasion, and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. Interestingly, 4-AAQB did not affect the viability and proliferation of normal colon cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates the FOLFOX (folinate (leucovorin), fluorouracil (5FU), and oxaliplatin) anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324, and inhibiting SOD2-mediated tumorigenicity.
Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.
Pseudophakic pupillary block (PPB) was rare in patients who undergo phacoemulsification and posterior chamber intraocular lens (PCIOL) implantation. Laser peripheral iridotomy was the most reported ...but ineffective treatment in the literature.
Retrospective, interventional case series of patients who developed PPB in Taipei Veterans General Hospital from 2017 to 2021. Clinical course, diagnostic methods, treatment and outcomes were recorded and discussed.
Four eyes of three patients were documented. All of them had diabetes and diabetic retinopathy. Anterior segment Optical coherence tomography (OCT) of these patients showed an exudative membrane at the peripapillary area while slit lamp image could not provide a clear view due to the severely edematous corneal condition. Laser peripheral iridotomy and yttrium aluminum garnet (YAG) laser aiming to the peripapillary exudation were applied to break the PPB successfully.
Diabetes mellitus, intravitreal injection and inflammation are crucial risk factors for PPB. Anterior segment OCT can be a useful diagnostic tool for the detection of the peripapillary exudative membrane while corneal clarity is compromised due to high intraocular pressure. In addition to peripheral laser iridotomy, an effective approach to resolve PPB may be the use of the YAG laser to break the exudative membrane.
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