EarlyTect BCD, a Streamlined PENK Methylation Test in Urine DNA, Effectively Detects Bladder Cancer in Patients with Hematuria.

The current noninvasive diagnostic approaches for detecting bladder cancer (BC) often exhibit limited clinical performance, especially for the initial diagnosis. This study aims to evaluate the validity of a streamlined urine-based PENK methylation test called EarlyTect BCD in detecting BC in patients with hematuria scheduled for cystoscopy in Korean and American populations. The test seamlessly integrates two steps, linear target enrichment and quantitative methylation-specific PCR within a single closed tube. The detection limitation of the test was approximately two genome copies of methylated PENK per milliliter of urine. In the retrospective training set (n = 105), an optimal cutoff value was determined to distinguish BC from non-BC, resulting in a sensitivity of 87.3% and a specificity of 95.2%. In the prospective validation set (n = 210, 122 Korean and 88 American patients), the overall sensitivity for detecting all stages of BC was 81.0%, with a specificity of 91.5% and an area under the curve value of 0.889. There was no significant difference between the two groups. The test achieved a sensitivity of 100% in detecting high-grade Ta and higher stages of BC. The negative predictive value of the test was 97.7%, and the positive predictive value was 51.5%. The findings of this study demonstrate that EarlyTect BCD is a highly effective noninvasive diagnostic tool for identifying BC among patients with hematuria.

The Effects of an App-Based Physical Activity Program on Colorectal Cancer Patients Undergoing Chemotherapy: A Randomized Controlled Trial.

BACKGROUND: Colorectal cancer is one of the most common malignancies worldwide. Oxaliplatin, which is used as adjuvant chemotherapy, affects quality of life by causing oxaliplatin-induced peripheral neuropathy in colorectal cancer patients. OBJECTIVES: This study examined the effects of an application (app)-based physical activity program for alleviating peripheral neuropathy symptoms in colorectal cancer patients undergoing chemotherapy. METHODS: This was a randomized controlled study that included 34 patients undergoing chemotherapy after being diagnosed with colorectal cancer. Outcomes were compared between patients who participated in a 6-week app-based physical activity program (experimental group; n = 17) and who received standard booklet education (control group; n = 17). Data were collected using questionnaires, and exercise time was recorded to evaluate intervention adherence. RESULTS: Significant differences were observed between the groups in peripheral neuropathy symptoms (F = 8.93, P = .002), interference with activities (Z = -2.55, P = .011), and quality of life (F = 7.65, P = .003). The experimental group showed significantly higher average exercise times at 1 to 4 weeks (Z = -2.10, P = .026), 5 to 6 weeks (Z = -4.02, P < .001), and 1 to 6 weeks (Z = -3.40, P = .001) than the control group. CONCLUSIONS: The app-based physical activity program had a positive effect on participants' exercise adherence and reduced peripheral neuropathy symptoms. Thus, we propose the adoption of a mobile health app that can be used at any time or place as an intervention for preventing or alleviating adverse effects during the treatment of cancer patients. IMPLICATIONS FOR PRACTICE: An app-based physical activity program using the mobile health app can be used as a nursing intervention to manage symptoms and increase the health behavior adherence in cancer patients.

A Novel Incisionless Disposable Vaginal Device for Female Stress Urinary Incontinence: Efficacy and Quality of Life.

PURPOSE: This clinical study sought to evaluate the possible clinical effectiveness and practicality of URINO, an innovative, incisionless, and disposable intravaginal device, designed for patients suffering from stress urinary incontinence. METHODS: A prospective, multicenter, single-arm clinical trial was carried out, involving women diagnosed with stress urinary incontinence who used a self-inserted, disposable intravaginal pessary device. Comparisons were made between the results of the 20-minute pad-weight gain (PWG) test at baseline and visit 3, where the device was applied. After 1 week of device usage, compliance, satisfaction, the sensation of a foreign body, and adverse events were assessed. RESULTS: Out of 45 participants, 39 completed the trial and expressed satisfaction within the modified intention-to-treat group. The average 20-minute PWG of participants was 17.2±33.6 g at baseline and significantly dropped to 5.3±16.2 g at visit 3 with device application. A total of 87.2% of participants exhibited a reduction ratio of PWG by 50% or more, surpassing the clinical trial success benchmark of 76%. The mean compliance was recorded as 76.6%±26.6%, the average visual analogue scale score for patient satisfaction was 6.4±2.6, and the sensation of a foreign body, measured on a 5-point Likert scale, was 3.1±1.2 after 1 week of device use. No serious adverse events were reported; there was 1 instance of microscopic hematuria and 2 cases of pyuria, all of which recovered. CONCLUSION: The investigated device demonstrated significant clinical effectiveness and safety for patients with stress urinary incontinence. It was easy to use, showing favorable patient compliance. We propose that these disposable intravaginal pessaries could potentially be an alternative treatment for patients with stress urinary incontinence who are seeking nonsurgical options or are unable to undergo surgery. Trial Registration: The study was registered as a clinical trial (KCT0008369).

Evaluation of Sensitive Urine DNA-Based PENK Methylation Test for Detecting Bladder Cancer in Patients with Hematuria.

Hematuria is a prevalent symptom associated with bladder cancer (BC). However, the invasiveness and cost of cystoscopy, the current gold standard for BC diagnosis in patients with hematuria, necessitate the development of a sensitive and accurate noninvasive test. This study introduces and validates a highly sensitive urine-based DNA methylation test. The test improves sensitivity in detecting PENK methylation in urine DNA using linear target enrichment followed by quantitative methylation-specific PCR. In a case-control study comprising 175 patients with BC and 143 patients without BC with hematuria, the test's optimal cutoff value was determined by distinguishing between two groups, achieved an overall sensitivity of 86.9% and a specificity of 91.6%, with an area under the curve of 0.892. A prospective validation clinical study involving 366 patients with hematuria scheduled for cystoscopy assessed the test's performance. The test demonstrated an overall sensitivity of 84.2% in detecting 38 cases of BC, a specificity of 95.7%, and an area under the curve of 0.900. Notably, the sensitivity for detecting Ta high grade and higher stages of BC reached 92.3%. The test's negative predictive value was 98.2%, and the positive predictive value was 68.7%. These findings highlight the potential of the PENK methylation in urine DNA using linear target enrichment followed by quantitative methylation-specific PCR test in urine as a promising molecular diagnostic tool for detecting primary BC in patients with hematuria, which may reduce the need for cystoscopy.

Transcriptomic Profiling Analysis of Castration-Resistant Prostate Cancer Cell Lines Treated with Chronic Intermittent Hypoxia.

Castration-resistant prostate cancer (CRPC) is still a major concern in men's health, with 375,000 cancer deaths annually. Hypoxia, which is a marked characteristic of advanced solid tumors, has been suggested to induce prostate cancer towards CRPC, metastasis and treatment resistance. To evaluate the effect of hypoxia on prostate cancer, two and five cycles of hypoxia and reoxygenation were administered using 22Rv1 cell lines and denominated as 22Rv1-CI and 22Rv1-PCI, respectively. Cancer cell migration was promoted in 22Rv1-CI compared to controls, and the expression of COL13A1 was significantly up-regulated in 22Rv1-CI according to differentially expressed gene analysis of RNA sequencing among groups. Cancer cell migration was impeded in a wound healing assay after transfecting si-COL13A1. Moreover, the expression of COL13A1 was also higher in the cell line originating from bone metastatic prostate cancer compared to other cell lines. Using the open database GEO, we also confirmed that the expression of COL13A1 was higher in bone metastatic prostate cancer tissue than in localized prostate cancer tissue in patients. Therefore, COL13A1 may be closely related to the bony metastasis of prostate cancer, and our findings may provide valuable information on the pathophysiology of the metastatic niche induced by hypoxia in patients with CRPC.

Conditioned Medium of Human Pluripotent Stem Cell-Derived Neural Precursor Cells Exerts Neurorestorative Effects against Ischemic Stroke Model.

Previous studies have shown that early therapeutic events of neural precursor cells (NPCs) transplantation to animals with acute ischemic stroke readily protected neuronal cell damage and improved behavioral recovery through paracrine mechanisms. In this study, we tested the hypothesis that administration of conditioned medium from NPCs (NPC-CMs) could recapitulate the beneficial effects of cell transplantation. Rats with permanent middle cerebral artery occlusion (pMCAO) were randomly assigned to one of the following groups: PBS control, Vehicle (medium) controls, single (NPC-CM(S)) or multiple injections of NPC-CM(NPC-CM(M)) groups. A single intravenous injection of NPC-CM exhibited strong neuroregenerative potential to induce behavioral recovery, and multiple injections enhanced this activity further by suppressing inflammatory damage and inducing endogenous neurogenesis leading to histopathological and functional recovery. Proteome analysis of NPC-CM identified a number of proteins that are known to be associated with nervous system development, neurogenesis, and angiogenesis. In addition, transcriptome analysis revealed the importance of the inflammatory response during stroke recovery and some of the key hub genes in the interaction network were validated. Thus, our findings demonstrated that NPC-CM promoted functional recovery and reduced cerebral infarct and inflammation with enhanced endogenous neurogenesis, and the results highlighted the potency of NPC-CM in stroke therapy.

Combination therapy with tamsulosin and traditional herbal medicine for lower urinary tract symptoms due to benign prostatic hyperplasia: A double-blinded, randomized, pilot clinical trial.

OBJECTIVES: To evaluate the efficacy and safety of tamsulosin and Hachimijiogan or Ryutanshakanto in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. METHODS: A prospective, randomized, double-blind method was used to determine the efficacy and safety of the combination or placebo at baseline and 4, 8, and 12 weeks of study. The International Prostate Symptom Score, quality of life index, complete voiding diary, and National Institutes of Health-Chronic Prostatitis Symptom Index were studied. Uroflowmetery and postvoid residual urine volume were measured and compared. Laboratory tests including prostate-specific antigen were performed. RESULTS: In all groups, International Prostate Symptom Score and quality of life showed improvement, but no significant differences were shown among the groups. Prostate volume increased after treatment, and uroflowmetric parameters showed improvements after treatment without significance among the three groups. The total score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant improvement in all groups, without significant differences among the groups. Only the pain sub-score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant decrease in the tamsulosin with Ryutanshakanto group compared to the control group. A total of 11 adverse reactions occurred, but they were mild and not related to the study drugs. CONCLUSION: Ryutanshakanto can provide pain relief in patients with chronic prostatitis and chronic pelvic pain syndrome. If more research is conducted, Hachimijiogan and Ryutanshakanto may be applied as add-on treatments in patients with storage symptoms with alpha-blocker monotherapy.

Is PSA density of the peripheral zone as a useful predictor for prostate cancer in patients with gray zone PSA levels?

BACKGROUND: Serum prostate-specific antigen (PSA) is widely used in screening tests for prostate cancer. As the low specificity of PSA results in unnecessary and invasive prostate biopsies, we evaluated the clinical significance of various PSAs and PSA density (PSAD) related to peripheral zones in patients with gray zone PSA level (4-10 ng/mL). METHODS: A total of 1300 patients underwent transrectal ultrasonography-guided prostate biopsy from 2014 to 2019. Among them, 545 patients in the gray zone were divided into the prostate cancer diagnosis group and the non-prostate cancer diagnosis group, and PSA, relative extra transitional zone PSA (RETzPSA), estimated post holmium laser enucleation of the prostate PSA (EPHPSA), PSAD, peripheral zone PSA density (PZPSAD) and extra-transitional zone density (ETzD) were compared and analyzed using receiver-operating characteristics (ROC) analysis after 1:1 matching using propensity score. RESULTS: Area under the ROC curve values of PSA, EPHPSA, RETzPSA, PSA density, ETzD, and PZPSAD were 0.553 (95% CI: 0.495-0.610), 0.611 (95% CI: 0.554-0.666), 0.673 (95% CI: 0.617-0.725), 0.745 (95% CI: 0.693-0.793), 0.731 (95% CI: 0.677-0.780) and 0.677 (95% CI: 0.611-0.719), respectively. PSAD had 67.11% sensitivity, 71.71% specificity, and 70.34% positive predictive rate at 0.18 ng/mL/cc. ETzD had 69.08% sensitivity, 64.47% specificity, and 66.04% positive predictive rate at 0.04 ng/mL/cc. When the cut-off value of PSAD was increased to 0.18 ng/mL/cc, the best results were obtained with an odds ratio of 5.171 (95% CI: 3.171-8.432), followed by ETzD with 4.054 (95% CI: 2.513-6.540). CONCLUSIONS: These results suggested that volume-adjusted parameters (ETzD and PSAD) might be more sensitive and accurate than various PSA in gray zone patients who required prostate biopsy to reduce unnecessary biopsy.

Transobturator four-arms mesh in the surgical management of cystocele: a long-term follow-up.

We studied the long-term efficacy and safety of cystocele operation by polypropylene mesh. A total of 198 women with stage ≥2 cystocele who had anterior vaginal wall repair with transobturator four-arm polypropylene mesh during 2003 to 2015 were evaluated. Outcomes including clinical characteristics and complications were reviewed by extracting patient data from electronic medical records. In addition, telephone interviews were conducted using a validated questionnaire along with physical examination. The follow-up period was 9.3±0.3 years. The cystocele stage in patients was significantly decreased post-operation compared to that preoperation. The anatomical cure rate for cystocele was 93.4%, and that for stress urinary incontinence was 95%. Comparing the three questionnaires indicated overall average score was improved significantly, except for Female Sexual Function Index Assessment. Early complications were either resolved spontaneously or controlled medically in four cases of hematoma or abscess, three cases of vaginal infection and urinary tract infection, and four cases of difficult micturition. In late complications, four cases of pain were managed, five cases of recurrence were observed and two cases of mesh exposure were treated with ointment and local excision. Transobturator four-arms mesh is an effective and safe method for cystocele repair with low rate of recurrence and complications. We suggest that the use of transobturator four-arm mesh is a still good choice for the old patients with cystocele who are not suitable for general anesthesia and reside in areas where laparoscopy and robots are not available.

Expression of bladder α1-adrenoceptor subtype after relief of partial bladder outlet obstruction in a rat model.

Purpose: Many patients with benign prostatic hyperplasia require treatment for persistent storage symptoms, even when the obstruction is successfully relieved by surgery. Previous studies identified a characteristic increase in α1D-adrenoceptor levels in the bladder in a bladder outlet obstruction (BOO) model. Here, we investigated the expression of α1-adrenoceptor subtypes in the bladder after relief of partial BOO (pBOO) in a rat model. Materials and Methods: A total of 60 female Sprague-Dawley rats were randomly divided into three groups (sham-operated, pBOO, and pBOO relief groups), and the expression of α1-adrenoceptor subtypes in the urothelium and detrusor muscle tissues was examined by western blot. Results: The expression of the α1D-adrenoceptor was significantly higher in the urothelium and detrusor muscle tissue of the pBOO and pBOO relief groups than in the corresponding tissue of the sham-operated group. Additionally, the α1A-adrenoceptor was predominant in the sham-operated group but significantly decreased in the urothelium in the pBOO group. No significant differences were found in α1A-adrenoceptor levels in detrusor muscle or whole bladder. Conclusions: Our results showed that α1D-adrenoceptor levels were consistently increased with pBOO, even after relief, suggesting that the α1D-adrenoceptor might be a cause of persistent storage symptoms after relief of pBOO.

Combination of Human Mesenchymal Stem Cells and Repetitive Transcranial Magnetic Stimulation Enhances Neurological Recovery of 6-Hydroxydopamine Model of Parkinsonian's Disease.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been in use for the treatment of various neurological diseases, including depression, anxiety, stroke and Parkinson's disease (PD), while its underlying mechanism is stills unclear. This study was undertaken to evaluate the potential synergism of rTMS treatment to the beneficial effect of human mesenchymal stem cells (hMSCs) administration for PD and to clarify the mechanism of action of this therapeutic approach. METHODS: The neuroprotective effect in nigral dopamine neurons, neurotrophic/growth factors and anti-/pro-inflammatory cytokine regulation, and functional recovery were assessed in the rat 6-hydroxydopamine (6-OHDA) model of PD upon administration of hMSCs and rTMS. RESULTS: Transplanted hMSCs were identified in the substantia nigra, and striatum. Enhancement of the survival of SN dopamine neurons and the expression of the tyrosine hydroxylase protein were observed in the hMSCs + rTMS compared to that of controls. Combination therapy significantly elevated the expression of several key neurotrophic factors, of which the highest expression was recorded in the rTMS + hMSC group. In addition, the combination therapy significantly upregulated IL-10 expression while decreased IFN-γ and TNF-α production in a synergistic manner. The treadmill locomotion test (TLT) revealed that motor function was improved in the rTMS + hMSC treatment with synergy. CONCLUSION: Our findings demonstrate that rTMS treatment and hMSC transplantation could synergistically create a favorable microenvironment for cell survival within the PD rat brain, through alteration of soluble factors such as neurotrophic/growth factors and anti-/pro-inflammatory cytokines related to neuronal protection or repair, with preservation of DA neurons and improvement of motor functions.

Reversion of in vivo fibrogenesis by novel chromone scaffolds.

BACKGROUND: Myofibroblasts are known to play a key role in the development of idiopathic pulmonary fibrosis (IPF). Two drugs, pirfenidone and nintedanib, are the only approved therapeutic options for IPF, but their applications are limited due to their side effects. Thus, curative IPF drugs represent a huge unmet medical need. METHODS: A mouse hepatic stellate cell (HSC) line was established that could robustly differentiate into myofibroblasts upon treatment with TGF-ß. Eupatilin was assessed in diseased human lung fibroblasts from IPF patients (DHLFs) as well as in human lung epithelial cells (HLECs). The drug's performance was extensively tested in a bleomycin-induced lung fibrosis model (BLM). Global gene expression studies and proteome analysis were performed. FINDINGS: Eupatilin attenuated disease severity of BLM in both preventative and therapeutic studies. The drug inhibited the in vitro transdifferantiation of DHLFs to myofibroblasts upon stimulation with TGF-ß. No such induction of the in vitro transdifferantiation was observed in TGF-ß treated HLECs. Specific carbons of eupatilin were essential for its anti-fibrotic activity. Eupatilin was capable of dismantling latent TGF-ß complex, specifically by eliminating expression of the latent TGF-ß binding protein 1 (LTBP1), in ECM upon actin depolymerization. Unlike eupatilin, pirfenidone was unable to block fibrosis of DHLFs or HSCs stimulated with TGF-ß. Eupatilin attenuated phosphorylation of Smad3 by TGF-ß. Eupatilin induced myofibroblasts to dedifferentiate into intermediate HCS-like cells. INTERPRETATION: Eupatilin may act directly on pathogenic myofibroblasts, disarming them, whereas the anti-fibrotic effect of pirfenidone may be indirect. Eupatilin could increase the efficacy of IPF treatment to curative levels.

Pancreatic-cancer-cell-derived trefoil factor 2 impairs maturation and migration of human monocyte-derived dendritic cells in vitro.

Pancreatic cancer is a challenging disease with a high mortality rate. While the importance of crosstalk between cancer and immune cells has been well documented, the understanding of this complex molecular network is incomplete. Thus, identification of the secreted proteins contributing to the immunosuppressive microenvironment in pancreatic cancer is crucial for effective diagnosis and/or therapy. We utilized a public microarray dataset (GSE16515) from the Gene Expression Omnibus database to identify genes for secreted proteins in pancreatic cancer. RT-PCR and ELISA of the pancreatic cancer cell lines validated the cellular origin of the selected genes. For functional assay of the selected proteins, we utilized human-monocyte-derived dendritic cells (DCs). From the list of the secreted proteins, trefoil factor 2 (TFF2) was further examined as a potential chemokine/cytokine. While TFF2 did not significantly affect the phenotypic maturation and the allostimulatory capacity of DCs, TFF2 preferentially attracted immature (but not mature) DCs and inhibited their endocytic activity. Our data suggest that TFF2 from pancreatic cancer cells may attract immature DCs and affect the initial stage of DC maturation, thereby contributing to the induction of immune tolerance against pancreatic cancer.

Host susceptibility to MERS-CoV infection, a retrospective cohort study of the 2015 Korean MERS outbreak.

To evaluate host susceptibility factors to Middle East respiratory syndrome coronavirus (MERS-CoV) infection, we conducted a retrospective cohort study from the single largest exposure event of the 2015 Korean MERS outbreak. A total of 175 patients were closely exposed to a super-spreader, 26 of which were infected (14.9%). In a multivariate analysis, history of autologous stem cell transplantation (HR, 31.151; 95% CI, 5.447-178.145; P < 0.001) and tachypnea at ED (HR, 4.392; 95% CI, 1.402-13.761; P = 0.011) were significantly associated with MERS-CoV infection.

Effect of an epinephrine mixture for interscalene block on hemodynamic changes after the beach chair position under general anesthesia: a retrospective study.

BACKGROUND: The beach chair position (BCP) can cause significant hypotension. Epinephrine is used to prolong the duration of local anesthetics; it is also absorbed into blood and can exert systemic effects. This study determined the effects of epinephrine mixed with ropivacaine for an interscalene block (ISB) on hemodynamic changes related to BCP. METHODS: Patient data collected from March 2013 to August 2014 were used retrospectively. We divided the patients into three groups: 1) ISB only, 2) I+G (general anesthesia after ISB without epinephrine), and 3) I+E+G (general anesthesia after ISB with epinephrine). Mean blood pressure (MBP) and heart rate (HR) were measured for 30 minutes at 5-minute intervals. RESULTS: The study analyzed data from 431 patients. MBP tended to decrease gradually in the groups I+G and I+E+G. There were significant differences in MBP between the groups I+G and I, and between the groups I+G and I+E+G. Group I+E+G showed a significant increase in HR compared with the other two groups. CONCLUSIONS: ISB with an epinephrine mixture did not prevent hypotension caused by the BCP after general anesthesia. HR increased only in response to the epinephrine mixture. A well-planned prospective study is required to compare hemodynamic changes in that context.

Serologic Evaluation of MERS Screening Strategy for Healthcare Personnel During a Hospital-Associated Outbreak.

To evaluate the appropriateness of the screening strategy for healthcare personnel (HCP) during a hospital-associated Middle East Respiratory Syndrome (MERS) outbreak, we performed a serologic investigation in 189 rRT-PCR-negative HCP exposed and assigned to MERS patients. Although 20%-25% of HCP experienced MERS-like symptoms, none of them showed seroconversion by plaque reduction neutralization test (PRNT). Infect Control Hosp Epidemiol 2017;38:234-238.

Extracellular Vesicles in Neurodegenerative Diseases: A Double-Edged Sword.

Extracellular vesicles (EVs), a heterogenous group of membrane-bound particles, are virtually secreted by all cells and play important roles in cell-cell communication. Loaded with proteins, mRNAs, non-coding RNAs and membrane lipids from their donor cells, these vesicles participate in normal physiological and pathogenic processes. In addition, these sub-cellular vesicles are implicated in the progression of neurodegenerative disorders. Accumulating evidence suggests that intercellular communication via EVs is responsible for the propagation of key pathogenic proteins involved in the pathogenesis of amyotrophic lateral sclerosis, Parkinson's diseases, Alzheimer's diseases and other neurodegenerative disorders. For therapeutic perspective, EVs present advantage over other synthetic drug delivery systems or cell therapy; ability to cross biological barriers including blood brain barrier (BBB), ability to modulate inflammation and immune responses, stability and longer biodistribution with lack of tumorigenicity. In this review, we summarized the current state of EV research in central nervous system in terms of their values in diagnosis, disease pathology and therapeutic applications.

Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke.

Transplantation of mesenchymal stem cells (MSCs) was reported to improve functional outcomes in a rat model of ischemic stroke, and subsequent studies suggest that MSC-derived microvesicles (MVs) can replace the beneficial effects of MSCs. Here, we evaluated three different MSC-derived MVs, including MVs from untreated MSCs (MSC-MVs), MVs from MSCs treated with normal rat brain extract (NBE-MSC-MVs), and MVs from MSCs treated with stroke-injured rat brain extract (SBE-MSC-MVs), and tested their effects on ischemic brain injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. NBE-MSC-MVs and SBE-MSC-MVs had significantly greater efficacy than MSC-MVs for ameliorating ischemic brain injury with improved functional recovery. We found similar profiles of key signalling proteins in NBE-MSC-MVs and SBE-MSC-MVs, which account for their similar therapeutic efficacies. Immunohistochemical analyses suggest that brain-extract-treated MSC-MVs reduce inflammation, enhance angiogenesis, and increase endogenous neurogenesis in the rat brain. We performed mass spectrometry proteomic analyses and found that the total proteomes of brain-extract-treated MSC-MVs are highly enriched for known vesicular proteins. Notably, MSC-MV proteins upregulated by brain extracts tend to be modular for tissue repair pathways. We suggest that MSC-MV proteins stimulated by the brain microenvironment are paracrine effectors that enhance MSC therapy for stroke injury.

Clinical Features and Risk Factors for Development of Breakthrough Gram-Negative Bacteremia during Carbapenem Therapy.

With the increasing use of carbapenems, carbapenem-resistant Gram-negative bacteria have become a major concern in health care-associated infections. The present study was performed to evaluate the clinical and microbiological features of breakthrough Gram-negative bacteremia (GNB) during carbapenem therapy and to assess risk factors for development of breakthrough GNB. A case-control study was performed at a tertiary hospital from 2005 to 2014. Case patients were defined as individuals whose blood cultures grew Gram-negative bacteria while the patients were receiving carbapenems for at least 48 h before breakthrough GNB. Age-, sex-, and date-matched controls were selected from patients who received carbapenem for at least 48 h and did not develop breakthrough GNB during carbapenem treatment. A total of 101 cases of breakthrough GNB were identified and compared to 100 controls. The causative microorganisms for breakthrough GNB were Stenotrophomonas maltophilia (n = 33), Acinetobacter baumannii (n = 32), Pseudomonas aeruginosa (n = 21), and others (n = 15). Approximately 90% of S. maltophilia isolates were susceptible to levofloxacin and trimethoprim-sulfamethoxazole. The most common infection types were primary bacteremia (38.6%) and respiratory infections (35.6%). More than half of the patients died within a week after bacteremia, and the 30-day mortality rate was 70.3%. In a multivariate analysis, a longer hospital stay, hematologic malignancy, persistent neutropenia, immunosuppressant use, and previous colonization by causative microorganisms were significantly associated with breakthrough GNB. Our data suggest that S. maltophilia, A. baumannii, and P. aeruginosa are the major pathogens of breakthrough GNB during carbapenem therapy, in association with a longer hospital stay, hematologic malignancy, persistent neutropenia, immunosuppressant use, and previous colonization.