Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on ...convergent biological, epidemiological, and clinical data.
To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.
Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.
Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.
The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.
Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 95% CI, 9.7-12.6 points per year) and placebo (MDS-UPDRS score, 9.9 95% CI, 8.4-11.3 points per year; difference, 1.26 95% CI, -0.59 to 3.11 points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL 95% CI, 1.85-2.19 mg/dL; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).
Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.
ClinicalTrials.gov Identifier: NCT02642393.
Background
Bismuth quadruple therapy is the treatment of choice for the first‐line therapy of Helicobacter pylori infection in areas of high clarithromycin resistance. Currently, the impact of the ...promising treatment on gut microbiota remains unclear.
Aim
To investigate the short‐term and long‐term impacts of bismuth quadruple therapy on gut microbiota.
Methods
Adult patients with H. pylori‐related gastritis were treated with 14‐day bismuth quadruple therapy. Fecal samples were collected before treatment at week 2, week 8, and week 48. Nucleic acid extraction from fecal samples was performed. The V3‐V4 region of the bacterial 16S rRNA gene was amplified by polymerase chain reaction and sequenced with the MiSeq followed by data analysis using Qiime pipeline.
Results
Eleven patients received complete follow‐up. Before treatment, the most abundant phyla were Firmicutes (45.3%), Bacteroidetes (24.3%), Proteobacteria (9.9%), and Actinobacteria (5.0%). At the end of bismuth therapy, the relative abundances of Bacteroidetes and Actinobacteria decreased to 0.5% (P < .001) and 1.3% (P = .038), respectively. Additionally, the relative abundance of Verrucomicrobia also decreased from 3.2% to 1.11E−3% (P = .034). In contrast, the relative abundances of Proteobacteria and Cyanobacteria increased (P < .001 and P = .003, respectively). At week 8, the relative abundances of all phyla restored to the levels at baseline. The relative abundances of all phyla at week 48 also did not significantly differ from those at baseline. During eradication therapy, 6 patients (55%) reported at least 1 adverse event. The relative abundance of phylum Proteobacteria in patients with adverse effects was more than that in patients without adverse effects (68.7% ± 8.8% vs 43.4% ± 25.5%; P = .048).
Conclusions
Bismuth quadruple therapy for H. pylori eradication can lead to short‐term dysbiosis of gut microbiota. The increase in Proteobacteria in gut microbiota may attribute to the development of adverse effects during bismuth quadruple therapy.
We tested the hypothesis that overexpression of cellular-prion-protein in adipose-derived mesenchymal stem cells (PrPC
-ADMSCs) effectively protected the kidney against ischemia-reperfusion (IR) ...injury in rat.
Part I of cell culture was categorized into A1(ADMSCs)/A2(ADMSCs+p-Cresol)/A3(PrPC
in ADMSCs)/A4 (PrPC
in ADMSCs+p-Cresol). Part II of cell culture was divided into B1(ADMSCs)/B2ADMSCs+lipopolysaccharide (LPS)/B3(PrPC
in ADMSCs)/B4(PrPC
in ADMSCs+LPS). Sprague-Dawley (SD) rats (n = 50) were equally categorized into groups 1 (sham-operated-control)/2 (IR)/3 (IR+ADMSCs/6.0 × 10
equally divided into bilateral-renal arteries and 6.0 × 10
intravenous administration by 1 h after IR)/4 IR+PrPC
-ADMSCs (identical dosage administered as group 3)/5 IR+silencing PRNP -ADMSCs (identical dosage administered as group 3), and kidneys were harvested post-day 3 IR injury.
Part I results demonstrated that the cell viability at 24/48/72 h, BrdU uptake/number of mitDNA/APT concentration/mitochondrial-cytochrome-C+ cells and the protein expressions of ki67/PrPC at 72 h-cell culturing were significantly higher in PrPC
-ADMSCs than in ADMSCs (all
< 0.001). The protein expressions of oxidative-stress (NOX-1/NOX2/NOX4/oxidized protein)/mitochondrial-damaged (p22-phox/cytosolic-cytochrome-C)/inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers were lowest in A1/A3 and significantly higher in A2 than in A4 (all
< 0.001). Part II result showed that the protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers exhibited an identical pattern of part I among the groups (all
< 0.001). The protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized-protein)/mitochondrial-damaged (cytosolic-cytochrome-C/p22-phox)/apoptotic (cleaved caspase-3/cleaved-PARP/mitochondrial-Bx)/autophagic (beclin-1/ratio of LC3B-II/LC3B-I)/fibrotic (Smad3/TGF-ß) biomarkers and kidney-injury-score/creatinine level were lowest in group 1, highest in group 2, significantly higher in group 5 than in groups 3/4 (all
< 0.0001).
PrPC
in ADMSCs rejuvenated these cells and played a cardinal role on protecting the kidney against IR injury.
Traumatic spinal cord injury (SCI) is a highly destructive disease in human neurological functions. Adipose‐derived mesenchymal stem cells (ADMSCs) have tissue regenerations and anti‐inflammations, ...especially with prion protein overexpression (PrPcOE). Therefore, this study tested whether PrPcOE‐ADMSCs therapy offered benefits in improving outcomes via regulating nod‐like‐receptor‐protein‐3 (NLRP3) inflammasome/DAMP signalling after acute SCI in rats. Compared with ADMSCs only, the capabilities of PrPcOE‐ADMSCs were significantly enhanced in cellular viability, anti‐oxidative stress and migration against H2O2 and lipopolysaccharide damages. Similarly, PrPcOE‐ADMSCs significantly inhibited the inflammatory patterns of Raw264.7 cells. The SD rats (n = 32) were categorized into group 1 (Sham‐operated‐control), group 2 (SCI), group 3 (SCI + ADMSCs) and group 4 (SCI + PrPcOE‐ADMSCs). Compared with SCI group 2, both ADMSCs and PrPcOE‐ADMSCs significantly improved neurological functions. Additionally, the circulatory inflammatory cytokines levels (TNF‐α/IL‐6) and inflammatory cells (CD11b/c+/MPO+/Ly6G+) were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4. By Day 3 after SCI induction, the protein expressions of inflammasome signalling (HGMB1/TLR4/MyD88/TRIF/c‐caspase8/FADD/p‐NF‐κB/NEK7/NRLP3/ASC/c‐caspase1/IL‐ß) and by Day 42 the protein expressions of DAMP‐inflammatory signalling (HGMB1/TLR‐4/MyD88/TRIF/TRAF6/p‐NF‐κB/TNF‐α/IL‐1ß) in spinal cord tissues displayed an identical pattern as the inflammatory patterns. In conclusion, PrPcOE‐ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling.
Commercial virtual visits are an increasingly popular model of health care for the management of common acute illnesses. In commercial virtual visits, patients access a website to be connected ...synchronously-via videoconference, telephone, or webchat-to a physician with whom they have no prior relationship. To date, whether the care delivered through those websites is similar or quality varies among the sites has not been assessed.
To assess the variation in the quality of urgent health care among virtual visit companies.
This audit study used 67 trained standardized patients who presented to commercial virtual visit companies with the following 6 common acute illnesses: ankle pain, streptococcal pharyngitis, viral pharyngitis, acute rhinosinusitis, low back pain, and recurrent female urinary tract infection. The 8 commercial virtual visit websites with the highest web traffic were selected for audit, for a total of 599 visits. Data were collected from May 1, 2013, to July 30, 2014, and analyzed from July 1, 2014, to September 1, 2015.
Completeness of histories and physical examinations, the correct diagnosis (vs an incorrect or no diagnosis), and adherence to guidelines of key management decisions.
Sixty-seven standardized patients completed 599 commercial virtual visits during the study period. Histories and physical examinations were complete in 417 visits (69.6%; 95% CI, 67.7%-71.6%); diagnoses were correctly named in 458 visits (76.5%; 95% CI, 72.9%-79.9%), and key management decisions were adherent to guidelines in 325 visits (54.3%; 95% CI, 50.2%-58.3%). Rates of guideline-adherent care ranged from 206 visits (34.4%) to 396 visits (66.1%) across the 8 websites. Variation across websites was significantly greater for viral pharyngitis and acute rhinosinusitis (adjusted rates, 12.8% to 82.1%) than for streptococcal pharyngitis and low back pain (adjusted rates, 74.6% to 96.5%) or ankle pain and recurrent urinary tract infection (adjusted rates, 3.4% to 40.4%). No statistically significant variation in guideline adherence by mode of communication (videoconference vs telephone vs webchat) was found.
Significant variation in quality was found among companies providing virtual visits for management of common acute illnesses. More variation was found in performance for some conditions than for others, but no variation by mode of communication.
This study tested whether human umbilical cord–derived mesenchymal stem cells (HUCDMSCs) treatment effectively protected the rat lung against acute respiratory distress syndrome (ARDS) injury, and ...benefits of early and dose-dependent treatment. Rat pulmonary epithelial cell line L2 (PECL2) were categorized into G1 (PECL2), G2 (PECL2 + healthy rat lung-derived extraction/50 mg/ml co-cultured for 24 h), G3 (PECL2 + ARDS rat lung-derived extraction/50 mg/ml co-cultured for 24 h), and G4 (condition as G3 + HUCDMSCs/1 × 10
5
/co-cultured for 24 h). The result showed that the protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IkB/NF-κB/IL-1β/TNF-α), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/JNKs/JUN/cytosolic-cytochrome-C/cyclophilin-D/DRP1), and cell-apoptotic/fibrotic (cleaved-caspase 3/cleaved-PARP/TGF-β/p-Smad3) biomarkers were significantly increased in G3 than in G1/G2 and were significantly reversed in G4 (all P < 0.001), but they were similar between G1/G2. Adult male rats ( n = 42) were equally categorized into group 1 (normal control), group 2 (ARDS only), group 3 ARDS + HUCDMSCs/1.2 × 10
6
cells intravenous administration at 3 h after 48 h ARDS induction (i.e., early treatment), group 4 ARDS + HUCDMSCs/1.2 × 10
6
cells intravenous administration at 24 h after 48 h ARDS induction (late treatment), and group 5 ARDS + HUCDMSCs/1.2 × 10
6
cells intravenous administration at 3 h/24 h after-48 h ARDS induction (dose-dependent treatment). By day 5 after ARDS induction, the SaO
2
%/immune regulatory T cells were highest in group 1, lowest in group 2, significantly lower in group 4 than in groups 3/5, and significantly lower in group 3 than in group 5, whereas the circulatory/bronchioalveolar lavage fluid inflammatory cells (CD11b-c+/LyG6+/MPO+)/circulatory immune cells (CD3-C4+/CD3-CD8+)/lung-leakage-albumin level/lung injury score/lung protein expressions of inflammatory (HMGB-1/TLR-2/TLR-4/MAL/TRAM/MyD88/TRIF/TRAF6/IκB-β/p-NF-κB/IL-1β/TNF-α)/fibrotic (p-SMad3/TGF-β), apoptosis (mitochondrial-Bax/cleaved-caspase-3)/oxidative-cell-stress (NOX-1/NOX-2/ASK1/p-MKK4/p-MKK7/p-JNKs/p-cJUN)/mitochondrial damaged (cyclophilin-D/DRP1/cytosolic-cytochrome-C) biomarkers displayed an opposite pattern of SaO
2
% among the groups (all P < 0.0001). Early administration was superior to and two-dose counterpart was even more superior to late HUCDMSCs treatment for protecting the lung against ARDS injury.
This study tested the hypothesis that combined therapy with human umbilical cord‐derived mesenchymal stem cells (HUCDMSCs) and hyperbaric oxygen (HBO) was superior to either one on preserving ...neurological function and reducing brain haemorrhagic volume (BHV) in rat after acute intracerebral haemorrhage (ICH) induced by intracranial injection of collagenase. Adult male SD rats (n = 30) were equally divided into group 1 (sham‐operated control), group 2 (ICH), group 3 (ICH +HUCDMSCs/1.2 × 106 cells/intravenous injection at 3h and days 1 and 2 after ICH), group 4 (ICH +HBO/at 3 hours and days 1 and 2 after ICH) and group 5 (ICH +HUCDMSCs‐HBO), and killed by day 28 after ICH. By day 1, the neurological function was significantly impaired in groups 2‐5 than in group 1 (P < .001), but it did not differ among groups 2 to 5. By days 7, 14 and 28, the integrity of neurological function was highest in group 1, lowest in group 2 and significantly progressively improved from groups 3 to 5 (all P < .001). By day 28, the BHV was lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3/4 (all P < .0001). The protein expressions of inflammation (HMGB1/TLR‐2/TLR‐4/MyD88/TRAF6/p‐NF‐κB/IFN‐γ/IL‐1ß/TNF‐α), oxidative stress/autophagy (NOX‐1/NOX‐2/oxidized protein/ratio of LC3B‐II/LC3B‐I) and apoptosis (cleaved‐capspase3/PARP), and cellular expressions of inflammation (CD14+, F4/80+) in brain tissues exhibited an identical pattern, whereas cellular levels of angiogenesis (CD31+/vWF+/small‐vessel number) and number of neurons (NeuN+) exhibited an opposite pattern of BHV among the groups (all P < .0001). These results indicate that combined HUCDMSC‐HBO therapy offered better outcomes after rat ICH.
Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms ...leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE–expressing cells reduced T231M-RhoE–mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.
Intracranial hemorrhage from stroke and head trauma elicits a cascade of inflammatory and immune reactions detrimental to neurological integrity and function at cellular and molecular levels. This ...study tested the hypothesis that human umbilical cord–derived mesenchymal stem cell (HUCDMSC) therapy effectively protected the brain integrity and neurological function in rat after acute traumatic brain injury (TBI). Adult male Sprague-Dawley rats (n = 30) were equally divided into group 1 (sham-operated control), group 2 (TBI), and group 3 TBI + HUCDMSC (1.2 × 106 cells/intravenous injection at 3 h after TBI) and euthanized by day 28 after TBI procedure. The results of corner test and inclined plane test showed the neurological function was significantly progressively improved from days 3, 7, 14, and 28 in groups 1 and 3 than in group 2, and group 1 than in group 3 (all P < 0.001). By day 28, brain magnetic resonance imaging brain ischemic volume was significantly increased in group 2 than in group 3 (P < 0.001). The protein expressions of apoptosis mitochondrial-bax positive cells (Bax)/cleaved-caspase3/cleaved-poly(adenosine diphosphate (ADP)-ribose) polymerase, fibrosis (Smad3 positive cells (Smad3)/transforming growth factor-β), oxidative stress (NADPH Oxidase 1 (NOX-1)/NADPH Oxidase 2 (NOX-2)/oxidized-protein/cytochrome b-245 alpha chain (p22phox)), and brain-edema/deoxyribonucleic acid (DNA)–damaged biomarkers (Aquaporin-4/gamma H2A histone family member X ( (γ-H2AX)) displayed an identical pattern to neurological function among the three groups (all P < 0.0001), whereas the protein expressions of angiogenesis biomarkers (vascular endothelial growth factor/stromal cell–derived factor-1α/C-X-C chemokine receptor type 4 (CXCR4)) significantly increased from groups 1 to 3 (all P < 0.0001). The cellular expressions of inflammatory biomarkers (cluster of differentiation 14 (+) cells (CD14+)/glial fibrillary acidic protein positive cells (GFAP+)/ a member of a new family of EGF-TM7 molecules positive cells (F4/80+)) and DNA-damaged parameter (γ-H2AX) exhibited an identical pattern, whereas cellular expressions of neural integrity (hexaribonucleotide Binding Protein-3 positive cells (NeuN+)/nestin+/doublecortin+) exhibited an opposite pattern of neurological function among the three groups (all P < 0.0001). Xenogeneic HUCDMSC therapy was safe and it significantly preserved neurological function and brain architecture in rat after TBI.
This study tested the hypothesis that preactivated and disaggregated shape‐changed platelet (PreD‐SCP) therapy significantly protected rat kidney from ischemia‐reperfusion (IR) injury. Adult‐male ...Sprague–Dawley rats (n = 24) were equally categorized into Groups 1 (sham‐operated control SC), 2 (SC + PreD‐SCP), 3 (IR only), and 4 (IR + PreD‐SCP). By 72 hr after IR procedure, the circulatory levels of creatinine, blood urine nitrogen and inflammatory biomarkers (interleukin IL‐6/tumor necrosis factor TNF‐α), and ratio of urine protein to urine creatinine were significantly higher in Group 3 than in other groups and significantly higher in Group 4 than in Groups 1 and 2, but they showed no different between Groups 1 and 2 (all p < .001). The microscopic findings showed that the expressions of kidney injury score, cellular inflammation (MMP‐9/CD14//F4/80), and fibrotic area were identical to the circulatory inflammation, whereas the integrity of podocyte components (ZO‐1/synaptopodin/podocin) exhibited an opposite to circulatory inflammation among the four groups (all p < .0001). The protein expressions of inflammatory (TNF‐α/IL‐1ß/NF‐κB/iNOS/TRAF6/MyD88/TLR‐4), apoptotic/cell death (mitochondrial Bax/cleaved caspase‐3/p‐53), oxidized protein, mitogen‐activated protein kinase family (p‐38/p‐JNK/p‐c‐JUN), and mitochondrial‐damaged biomarkers displayed a similar pattern, whereas the antiapoptotic (Bcl‐2/Bcl‐XL) and integrity of mitochondrial biomarkers followed an opposite trend to circulatory inflammation among the four groups (all p < .001). PreD‐SCP therapy effectively protected the kidney against IR injury.
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