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AIMS - To examine the impact of frailty on treatment outcomes for overactive bladder (OAB) in older adults starting pharmacotherapy, onabotulinumtoxinA, and sacral neuromodulation.
METHODS - This is a prospective study of men and women age ≥60 years starting pharmacotherapy, onabotulinumtoxinA, or sacral neuromodulation. Subjects were administered questionnaires at baseline and again at 1- and 3-months. Frailty was assessed at baseline using the timed up and go test (TUGT), whereby a TUGT time of ≥12 seconds was considered to be slow, or frail. Response to treatment was assessed using the overactive bladder symptom score (OABSS) and the OAB-q SF (both Bother and HRQOL subscales). Information on side effects/adverse events was also collected. Mixed effects linear modeling was used to model changes in outcomes over time both within and between groups.
RESULTS - A total of 45 subjects enrolled in the study, 40% (N = 18) of whom had a TUGT ≥12 seconds. Both TUGT groups demonstrated improvement in OAB symptoms over time and there were no statistically significant differences in these responses per group (all P-values >.05). Similar trends were found for both OAB-q SF Bother and OAB-q SF HRQOL questionnaire responses. Side effects and adverse events were not significantly different between groups (all P's >.05).
CONCLUSIONS - Adults ≥60 years of age starting second- and third-line treatments for OAB, regardless of TUGT time, demonstrated improvement in OAB symptoms at 3 months. These findings suggest that frail older adults may receive comparable benefit and similar rates of side effects compared with less frail older individuals.
© 2019 Wiley Periodicals, Inc.
Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.
PURPOSE - Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.
PATIENTS AND METHODS - Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
RESULTS - Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank = .01) and overall survival (log-rank < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CONCLUSION - CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
OBJECTIVE - Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) has reported seizure freedom rates between 36% and 78% with at least 1 year of follow-up. Unfortunately, the lack of robust methods capable of incorporating the inherent variability of patient anatomy, the variability of the ablated volumes, and clinical outcomes have limited three-dimensional quantitative analysis of surgical targeting and its impact on seizure outcomes. We therefore aimed to leverage a novel image-based methodology for normalizing surgical therapies across a large multicenter cohort to quantify the effects of surgical targeting on seizure outcomes in LITT for mTLE.
METHODS - This multicenter, retrospective cohort study included 234 patients from 11 centers who underwent LITT for mTLE. To investigate therapy location, all ablation cavities were manually traced on postoperative magnetic resonance imaging (MRI), which were subsequently nonlinearly normalized to a common atlas space. The association of clinical variables and ablation location to seizure outcome was calculated using multivariate regression and Bayesian models, respectively.
RESULTS - Ablations including more anterior, medial, and inferior temporal lobe structures, which involved greater amygdalar volume, were more likely to be associated with Engel class I outcomes. At both 1 and 2 years after LITT, 58.0% achieved Engel I outcomes. A history of bilateral tonic-clonic seizures decreased chances of Engel I outcome. Radiographic hippocampal sclerosis was not associated with seizure outcome.
SIGNIFICANCE - LITT is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center. Consideration of surgical factors is imperative to the complete assessment of LITT. Based on our model, ablations must prioritize the amygdala and also include the hippocampal head, parahippocampal gyrus, and rhinal cortices to maximize chances of seizure freedom. Extending the ablation posteriorly has diminishing returns. Further work is necessary to refine this analysis and define the minimal zone of ablation necessary for seizure control.
Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.
AIM - To examine the location of midurethral slings (MUS) at the time of excision to determine associations between presenting symptoms and sling location at explant.
METHODS - We performed an IRB approved, retrospective review of MUS explants between January 2011 and March 2016. Symptoms and physical examination findings were compared between women with slings explanted from the mid-urethra (MU) and women with slings explanted from the proximal urethra/bladder neck (PU/BN).
RESULTS - We included 95 consecutive women who underwent MUS explant in the analysis. Presenting symptoms included pain in 69 women (72.6%), urinary urgency in 66 (66.5%), voiding dysfunction in 55 (57.9%), urge urinary incontinence (UUI) in 41 (43.2%), stress urinary incontinence in 34 (35.8%), and recurrent urinary tract infections in 22 (23.2%). At sling explant, 2 (2.1%) slings were found at the distal urethra, 33 (34.7%) at the MU and 60 (63.2%) at the PU/BN. Women with slings explanted from the PU/BN were more likely to present with urgency (78.3% vs 54.5%; P = 0.017) and UUI (53.3% vs 27.3%; P = 0.015) and less likely to present with pain on examination (48.3% vs 75.8%; P = 0.01).
CONCLUSIONS - The majority of MUS requiring explant in this cohort were found at the PU/BN. The most common presenting symptom before MUS explant was pain, followed by urgency and voiding dysfunction. PU/BN location of MUS is likely a factor in the development of urgency and UUI in women who ultimately undergo explant.
© 2019 Wiley Periodicals, Inc.
There is great interest in safe and effective alternative therapies that could benefit patients with inflammatory bowel diseases (IBD). L-arginine (Arg) is a semi-essential amino acid with a variety of physiological effects. In this context, our aim was to investigate the role of dietary Arg in experimental colitis. We used two models of colitis in C57BL/6 mice, the dextran sulfate sodium (DSS) model of injury and repair, and infection. Animals were given diets containing (1) no Arg (Arg), 6.4 g/kg (Arg), or 24.6 g/kg Arg (Arg); or (2) the amino acids downstream of Arg: 28 g/kg L-ornithine (Orn) or 72 g/kg L-proline (Pro). Mice with DSS colitis receiving the Arg diet had increased levels of Arg, Orn, and Pro in the colon and improved body weight loss, colon length shortening, and histological injury compared to Arg and Arg diets. Histology was improved in the Arg vs. Arg group. Orn or Pro diets did not provide protection. Reduction in colitis with Arg diet also occurred in -infected mice. Diversity of the intestinal microbiota was significantly enhanced in mice on the Arg diet compared to the Arg or Arg diets, with increased abundance of Bacteroidetes and decreased Verrucomicrobia. In conclusion, dietary supplementation of Arg is protective in colitis models. This may occur by restoring overall microbial diversity and Bacteroidetes prevalence. Our data provide a rationale for Arg as an adjunctive therapy in IBD.
Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer's disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At the end of the study, brain tissue was collected for analysis of PKC (PKCζ, PKCι, PKCα, PKCγ, PKCɛ), GSK-3β, pGSK-3βser9, pGSK-3βtyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ, and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3βser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and pTau. The current study lends support to the therapeutic potential of metformin for AD.
Vagus nerve stimulation (VNS) was the first neuromodulation device approved for treatment of epilepsy. In more than 20 years of study, VNS has consistently demonstrated efficacy in treating epilepsy. After 2 years, approximately 50% of patients experience at least 50% reduced seizure frequency. Adverse events with VNS treatment are rare and include surgical adverse events (including infection, vocal cord paresis, and so forth) and stimulation side effects (hoarseness, voice change, and cough). Future developments in VNS, including closed-loop and noninvasive stimulation, may reduce side effects or increase efficacy of VNS.
Copyright © 2018 Elsevier Inc. All rights reserved.
BACKGROUND - Microvascular decompression (MVD) is a potentially curative surgery for drug-resistant trigeminal neuralgia (TN). Predictors of pain freedom after MVD are not fully understood.
OBJECTIVE - To describe rates and predictors for pain freedom following MVD.
METHODS - Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, PubMed, Cochrane Library, and Scopus were queried for primary studies examining pain outcomes after MVD for TN published between 1988 and March 2018. Potential biases were assessed for included studies. Pain freedom (ie, Barrow Neurological Institute score of 1) at last follow-up was the primary outcome measure. Variables associated with pain freedom on preliminary analysis underwent formal meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for possible predictors.
RESULTS - Outcome data were analyzed for 3897 patients from 46 studies (7 prospective, 39 retrospective). Overall, 76.0% of patients achieved pain freedom after MVD with a mean follow-up of 1.7 ± 1.3 (standard deviation) yr. Predictors of pain freedom on meta-analysis using random effects models included (1) disease duration ≤5 yr (OR = 2.06, 95% CI = 1.08-3.95); (2) arterial compression over venous or other (OR = 3.35, 95% CI = 1.91-5.88); (3) superior cerebellar artery involvement (OR = 2.02, 95% CI = 1.02-4.03), and (4) type 1 Burchiel classification (OR = 2.49, 95% CI = 1.32-4.67).
CONCLUSION - Approximately three-quarters of patients with drug-resistant TN achieve pain freedom after MVD. Shorter disease duration, arterial compression, and type 1 Burchiel classification may predict more favorable outcome. These results may improve patient selection and provider expectations.
Copyright © 2019 by the Congress of Neurological Surgeons.
Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the "inflamed" immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.