Neuromodulation of Brain State and Behavior.

Neural activity and behavior are both notoriously variable, with responses differing widely between repeated presentation of identical stimuli or trials. Recent results in humans and animals reveal that these variations are not random in their nature, but may in fact be due in large part to rapid shifts in neural, cognitive, and behavioral states. Here we review recent advances in the understanding of rapid variations in the waking state, how variations are generated, and how they modulate neural and behavioral responses in both mice and humans. We propose that the brain has an identifiable set of states through which it wanders continuously in a nonrandom fashion, owing to the activity of both ascending modulatory and fast-acting corticocortical and subcortical-cortical neural pathways. These state variations provide the backdrop upon which the brain operates, and understanding them is critical to making progress in revealing the neural mechanisms underlying cognition and behavior.

Patterns of metformin use and glycated haemoglobin trends among patients with newly diagnosed type 2 diabetes in Alberta, Canada.

AIM: Canadian guidelines recommend metformin as first-line therapy for incident uncomplicated type 2 diabetes and the vast majority of patients are treated accordingly. However, only 54% 65% remain on treatment after 1 year, with the highest discontinuation rates within the first 3 months. The purpose of this study was: (a) to identify individual and clinical factors associated with metformin discontinuation among patients with newly diagnosed uncomplicated type 2 diabetes in Alberta, Canada, and (b) describe glycated haemoglobin (HbA1c) trajectories in the first 12 months after initiation of pharmacotherapy, stratified by metformin usage pattern. MATERIALS AND METHODS: We conducted a retrospective cohort study using linked administrative datasets from 2012 to 2017 to define a cohort of individuals with uncomplicated incident type 2 diabetes. Using logistic regression, we determined individual and clinical characteristics associated with metformin discontinuation. We categorized individuals based on patterns of metformin use and then used mean HbA1c measurements over a 12-month follow-up period to determine glycaemic trajectories for each pattern. RESULTS: Characteristics associated with metformin discontinuation were younger age, lower baseline HbA1c and having fewer comorbidities. Sex, income and location (urban/rural) were not significantly associated with metformin discontinuation. Individuals who continued metformin with higher adherence and individuals who discontinued metformin entirely had lowest HbA1c values at 12 months from treatment initiation. Those who changed therapy or had additional therapies added had higher HbA1c values at 12 months. CONCLUSION: Identifying characteristics associated with discontinuation of metformin and individuals' medication usage patterns provide an opportunity for targeted interventions to support patients' glycaemic management.

Leveraging the biotechnological promise of the hagfish variable lymphocyte receptors: tools for aquatic microbial diseases.

The jawless vertebrates (agnathans/cyclostomes) are ancestral animals comprising lampreys and hagfishes as the only extant representatives. They possess an alternative adaptive immune system (AIS) that uses leucine-rich repeats (LRR)-based variable lymphocyte receptors (VLRs) instead of the immunoglobulin (Ig)-based antigen receptors of jawed vertebrates (gnathostomes). The different VLR types are expressed on agnathan lymphocytes and functionally resemble gnathostome antigen receptors. In particular, VLRB is functionally similar to the B cell receptor and is expressed and secreted by B-like lymphocytes as VLRB antibodies that bind antigens with high affinity and specificity. The potential repertoire scale of VLR-based antigen receptors is believed to be at least comparable to that of Ig-based systems. VLR proteins inherently possess characteristics that render them excellent candidates for biotechnological development, including tractability to recombinant approaches. In recent years, scientists have explored the biotechnological development and utility of VLRB proteins as alternatives to conventional mammalian antibodies. The VLRB antibody platform represents a non-traditional approach to generating a highly diverse repertoire of unique antibodies. In this review, we first describe some aspects of the biology of the AIS of the jawless vertebrates, which recognizes antigens by means of unique receptors. We then summarize reports on the development of VLRB-based antibodies and their applications, particularly those from the inshore hagfish (Eptatretus burgeri) and their potential uses to address microbial diseases in aquaculture. Hagfish VLRB antibodies (we call Ccombodies) are being developed and improved, while obstacles to the advancement of the VLRB platform are being addressed to utilize VLRBs effectively as tools in immunology. VLRB antibodies for novel antigen targets are expected to emerge to provide new opportunities to tackle various scientific questions. We anticipate a greater interest in the agnathan AIS in general and particularly in the hagfish AIS for greater elucidation of the evolution of adaptive immunity and its applications to address microbial pathogens in farmed aquatic animals and beyond.

Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: A randomized cross-over clinical study.

AIM: To evaluate the albuminuria-lowering effect of dapagliflozin, exenatide, and the combination of dapagliflozin and exenatide in patients with type 2 diabetes and microalbuminuria or macroalbuminuria. METHODS: Participants with type 2 diabetes, an estimated glomerular filtration rate (eGFR) of more than 30 ml/min/1.73m2 and an urinary albumin: creatinine ratio (UACR) of more than 3.5 mg/mmol and 100 mg/mmol or less completed three 6-week treatment periods, during which dapagliflozin 10 mg/d, exenatide 2 mg/wk and both drugs combined were given in random order. The primary outcome was the percentage change in UACR. Secondary outcomes included blood pressure, HbA1c, body weight, extracellular volume, fractional lithium excretion and renal haemodynamic variables as determined by magnetic resonance imaging. RESULTS: We enrolled 20 patients, who completed 53 treatment periods in total. Mean percentage change in UACR from baseline was -21.9% (95% CI: -34.8% to -6.4%) during dapagliflozin versus -7.7% (95% CI: -23.5% to 11.2%) during exenatide and -26.0% (95% CI: -38.4% to -11.0%) during dapagliflozin-exenatide treatment. No correlation was observed in albuminuria responses between the different treatments. Numerically greater reductions in systolic blood pressure, body weight and eGFR were observed during dapagliflozin-exenatide treatment compared with dapagliflozin or exenatide alone. Renal blood flow and effective renal plasma flow (ERPF) did not significantly change with either treatment regimen. However, all but four and two patients in the dapagliflozin and dapagliflozin-exenatide groups, respectively, showed reductions in ERPF. The filtration fraction did not change during treatment with dapagliflozin or exenatide, and decreased during dapagliflozin-exenatide treatment (-1.6% [95% CI: -3.2% to -0.01%]; P = .048). CONCLUSIONS: In participants with type 2 diabetes and albuminuria, treatment with dapagliflozin, exenatide and dapagliflozin-exenatide reduced albuminuria, with a numerically larger reduction in the combined dapagliflozin-exenatide treatment group.

Bilateral treatment of the masseter with botulinum toxin: Consequences for mastication, muscle force and the mandibular condyle.

BACKGROUND: Clinical use of botulinum neurotoxins (BoNTs) in masticatory muscles is usually bilateral, but most studies on the functional consequences of BoNT treatment have used unilaterally treated animals. OBJECTIVES: To test the hypothesis that bilateral BoNT treatment of the rabbit masseter hampers mastication and to assess its effects on bone density of the mandibular condyles. METHODS: Ten 5-month-old female rabbits received injections of BoNT into both masseter muscles and nine sham animals received saline. Body weight, incisor bite force during masseter tetany, and surface and fine-wire electromyography (EMG) of the masseter and medial pterygoid muscles were assessed at regular intervals. Half the sample was terminated after 4 weeks and the remainder after 12 weeks. Muscles were weighed and mandibular condyles were scanned with microCT to analyse bone density. RESULTS: BoNT rabbits lost weight and required a soft-food diet. Incisor occlusal force plummeted after BoNT injection and remained lower than the shams. The duration of masticatory cycles was increased in the BoNT rabbits for 5 weeks, with most of the increase due to the adductor burst. Masseteric EMG amplitude began to improve at Week 5, but remained low on the working side throughout the experiment. At the 12-week endpoint, masseter muscles were smaller in the BoNT rabbits. Medial pterygoid muscles did not compensate. Condylar bone density was reduced. CONCLUSION: Bilateral treatment of the rabbit masseter by BoNT severely affected chewing performance. Even after a 3-month recovery period, deficits remained in bite force, muscle size and condylar bone density.

Activation of Phase Change Contrast Agents Using Ionizing Radiation.

The feasibility of activating phase change contrast agents (PCCA) made from Definity (Lantheus Medical Imaging) using X-rays was investigated. A 10 mL of Definity PCCA (0.1 mL PCCA/mL) were injected into gelatin phantoms and irradiated using doses of 0, 30, 50, and 100 Gy. Size distribution and PCCA activation were measured after irradiation. Definity PCCAs were activated at a threshold of 50 Gy. Changes were visible with microscopy, visual inspection of T-flasks, and ultrasound imaging of gelatin phantoms. Moreover, increasing the radiation dose above 50 Gy appeared to further activate PCCA. These results indicate Definity PCCAs may be useful for ultrasound-based radiation dosimetry.

Protocols for inducing homeostatic plasticity reflected in the corticospinal excitability in healthy human participants: A systematic review and meta-analysis.

Homeostatic plasticity complements synaptic plasticity by stabilising neural activity within a physiological range. In humans, homeostatic plasticity is investigated using two blocks of non-invasive brain stimulation (NIBS) with an interval without stimulation between blocks. The aim of this systematic review and meta-analysis was to investigate the effect of homeostatic plasticity induction protocols on motor evoked potentials (MEP) in healthy participants. Four databases were searched (Medline, Scopus, Embase and Cochrane library). Studies describing the application of two blocks of NIBS of the primary motor cortex with an interval of no stimulation between blocks reporting changes in corticospinal excitability by MEP amplitude were included. Thirty-seven reports with 55 experiments (700 participants) were included. Study quality was considered poor overall, with heterogeneity in study size, sample and designs. Two blocks of excitatory stimulation at the primary motor cortex produced a homeostatic response (decreased MEP) between 0 and 30 min post-protocols, when compared with a single stimulation block. Two blocks of inhibitory stimulation at the primary motor cortex using interval duration of 10 min or less produced a homeostatic response (increased MEP) between 0 and 30 min post-protocols, when compared with a single stimulation block. There were no differences in MEPs when compared with baseline MEPs. In conclusion, homeostatic plasticity induction using two blocks of NIBS with an interval of 10 min or less without stimulation between blocks produces a homeostatic response up to 30 min post-protocol. Improvements in participant selection, sample sizes and protocols of NIBS techniques are needed.

First-line pharmacotherapy for incident type 2 diabetes: Prescription patterns, adherence and associated costs.

AIMS: To use real-world prescription data from Alberta, Canada to: (a) describe the prescribing patterns for initial pharmacotherapy for those with newly diagnosed uncomplicated type 2 diabetes; (b) describe medication-taking behaviours (adherence and persistence) in the first year after initiating pharmacotherapy; and (c) explore healthcare system costs associated with prescribing patterns. METHODS: We employed a retrospective cohort design using linked administrative datasets from 2012 to 2017 to define a cohort of those with uncomplicated incident diabetes. We summarized the initial prescription patterns, adherence and costs (healthcare and pharmaceutical) over the first year after initiation of pharmacotherapy. Using multivariable regression, we determined the association of these outcomes with various sociodemographic characteristics. RESULTS: The majority of individuals for whom metformin was indicated as first-line therapy received a prescription for metformin monotherapy (89%). Older individuals, those with higher baseline A1C and those with no comorbidities, were most likely to be started on non-metformin agents. Adherence with the initially prescribed regimen was suboptimal overall, with nearly half (48%) being non-adherent over the first year. One-third of those who started metformin discontinued it in the first 3 months. Those started on non-metformin agents had roughly twice the healthcare costs, and five to seven times higher medication costs, compared to those started on metformin, in the first year after starting therapy. CONCLUSIONS: With the addition of new classes of medications, healthcare providers who look after those with type 2 diabetes have more pharmaceutical options than ever. Most individuals continue to be prescribed metformin monotherapy. However, adherence is suboptimal, and drops off considerably within the first 3 months.

Assessment of distal ureteral and ureterovesical junction visualization on contrast-enhanced voiding urosonography.

BACKGROUND: Contrast-enhanced voiding urosonography (CEVUS) uses intravesically administered microbubble contrast to detect vesicoureteral reflux (VUR) and urethral anomalies with ultrasound. Multiple studies have suggested CEVUS can replace voiding cystourethrogram (VCUG) as a radiation-free alternative. Analysis of the ureterovesical junction and ureters on VCUG documenting the ureterovesical junction position, ureteral duplication, periureteral diverticula and ureteroceles is important as anatomical variations may affect management and surgical approach. OBJECTIVE: Our purpose was to assess distal ureteral and ureterovesical junction region visualization in children with VUR detected on CEVUS. MATERIALS AND METHODS: CEVUS studies performed between June 2018 and March 2019 with reported VUR were retrospectively reviewed by two pediatric radiologists to confirm VUR and to qualitatively assess the ureterovesical junction region for each renal moiety using a 3-point scale for clear, limited or absent visualization of the distal ureter, ureterovesical junction, ureteral duplication, periureteral diverticula and ureteroceles. RESULTS: Thirty-four studies with VUR on CEVUS were identified. Sixty-seven renal moieties were evaluated including a solitary kidney in one child. VUR was detected in 52 moieties by reader 1 and in 53 by reader 2. A single moiety with discrepancy between readers regarding VUR was excluded from statistical analysis. No diverticula were detected by either reader and one ureterocele was detected by both readers. Visualization of the ureterovesical junction was described as clear in 5/52, limited in 14/52 and absent in 33/52 refluxing renal moieties by reader 1 and as clear in 12/52, limited in 20/52 and absent in 20/52 by reader 2. The ureterovesical junction was clearly visualized in 5/52 (9.6%) by reader 1 and 12/52 (23.1%) by reader 2. The Kappa value of -0.29 (confidence interval [CI] -0.25, 0.21) reveals a lack of agreement between the readers for clear versus limited or absent ureterovesical junction visualization. Distal ureteral visualization was described as clear in 14/52, limited in 16/52 and absent in 22/52 refluxing renal moieties by reader 1 and as clear in 27/52, limited in 7/52 and absent in 18/52 by reader 2. The distal ureter was clearly visualized in 14/52 (26.9%) by reader 1 and 27/52 (51.9%) by reader 2. The Kappa of 0.43 (CI 0.22, 0.64) reveals moderate agreement between the readers for clear versus limited or absent distal ureteral visualization. Duplication of the renal collecting system was identified in 13/52 refluxing kidneys by reader 1 and 11/52 refluxing kidneys by reader 2. Visualization of ureteral duplication was described as clear in 9, limited in 4 and absent in 39 of 52 refluxing renal moieties by reader 1 and as clear in 9, limited in 2 and absent in 41 by reader 2. Ureteral duplication was clearly visualized in 9/52 (17.3%) by reader 1 and 9/52 (17.3%) by reader 2. Kappa of 0.87 (CI 0.68, 1) reveals high agreement between the readers for clear versus limited or absent identification of ureteral duplication. CONCLUSION: The distal ureter and ureterovesical junction region frequently are not clearly visualized in refluxing renal moieties on CEVUS. Awareness of this limitation is important as there may be implications when evaluating patients for surgical management of VUR.

Voluntary Wheel Running Partially Compensates for the Effects of Global Estrogen Receptor-α Knockout on Cortical Bone in Young Male Mice.

Estrogen receptor-α knockout (ERKO) in female, but not male, mice results in an impaired osteogenic response to exercise, but the mechanisms behind this ability in males are unknown. We explored the main and interactive effects of ERKO and exercise on cortical geometry, trabecular microarchitecture, biomechanical strength, and sclerostin expression in male mice. At 12 weeks of age, male C57BL/6J ERKO and WT animals were randomized into two groups: exercise treatment (EX) and sedentary (SED) controls, until 22 weeks of age. Cortical geometry and trabecular microarchitecture were measured via µCT; biomechanical strength was assessed via three-point bending; sclerostin expression was measured via immunohistochemistry. Two-way ANOVA was used to assess sclerostin expression and trabecular microarchitecture; two-way ANCOVA with body weight was used to assess cortical geometry and biomechanical strength. ERKO positively impacted trabecular microarchitecture, and exercise had little effect on these outcomes. ERKO significantly impaired cortical geometry, but exercise was able to partially reverse these negative alterations. EX increased cortical thickness regardless of genotype. There were no effects of genotype or exercise on sclerostin expression. In conclusion, male ERKO mice retain the ability to build bone in response to exercise, but altering sclerostin expression is not one of the mechanisms involved.

Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1 mouse model of amyotrophic lateral sclerosis.

KEY POINTS: Although in vitro recordings using neonatal preparations from mouse models of amyotrophic lateral sclerosis (ALS) suggest increased motoneurone excitability, in vivo recordings in adult ALS mouse models have been conflicting. In adult G93A SOD1 models, spinal motoneurones have previously been shown to have deficits in repetitive firing, in contrast to the G127X SOD1 mouse model. Our in vivo intracellular recordings in barbiturate-anaesthetized adult male G93A SOD1 mice reveal that the incidence of failure to fire with current injection was equally low in control and ALS mice (∼2%). We show that failure to fire repetitively can be a consequence of experimental protocol and should not be used alone to classify otherwise normal motoneurones as hypo-excitable. Motoneurones in the G93A SOD1 mice showed an increased response to inputs, with lower rheobase, higher input-output gains and increased activation of persistent inward currents. ABSTRACT: In vitro studies from transgenic amyotrophic lateral sclerosis models have suggested an increased excitability of spinal motoneurones. However, in vivo intracellular recordings from adult amyotrophic lateral sclerosis mice models have produced conflicting findings. Previous investigations using barbiturate anaesthetized G93A SOD1 mice have suggested that some motoneurones are hypo-excitable, defined by deficits in repetitive firing. Our own previous recordings in G127X SOD1 mice using different anaesthesia, however, showed no repetitive firing deficits and increased persistent inward currents at symptom onset. These discrepancies may be a result of differences between models, symptomatic stage, anaesthesia or technical differences. To investigate this, we repeated our original experiments, but in adult male G93A SOD1 mice, at both presymptomatic and symptomatic stages, under barbiturate anaesthesia. In vivo intracellular recordings from antidromically identified spinal motoneurones revealed that the incidence of failure to fire with current injection was equally low in control and G93A SOD1 mice (∼2%). Motoneurones in G93A SOD1 mice fired significantly more spontaneous action potentials. Rheobase was significantly lower and the input resistance and input-output gain were significantly higher in both presymptomatic and symptomatic G93A SOD1 mice. This was despite a significant increase in the duration of the post-spike after-hyperpolarization in both presymptomatic and symptomatic G93A SOD1 mice. Finally, evidence of increased activation of persistent inward currents was seen in both presymptomatic and symptomatic G93A SOD1 mice. Our results do not confirm previous reports of hypo-excitability of spinal motoneurones in the G93A SOD1 mouse and demonstrate that the motoneurones show an increased response to inputs.

Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice.

Aromatase catalyzes conversion of testosterone to estradiol and is expressed in a variety of tissues, including the brain. Suppression of aromatase adversely affects metabolism and physical activity behavior, but mechanisms remain uncertain. The hypothesis tested herein was that whole body aromatase deletion would cause gene expression changes in the nucleus accumbens (NAc), a brain regulating motivated behaviors such as physical activity, which is suppressed with loss of estradiol. Metabolic and behavioral assessments were performed in male and female wild-type (WT) and aromatase knockout (ArKO) mice. NAc-specific differentially expressed genes (DEGs) were identified with RNAseq, and associations between the measured phenotypic traits were determined. Female ArKO mice had greater percent body fat, reduced spontaneous physical activity (SPA), consumed less energy, and had lower relative resting energy expenditure (REE) than WT females. Such differences were not observed in ArKO males. However, in both sexes, a top DEG was Pts, a gene encoding an enzyme necessary for catecholamine (e.g., dopamine) biosynthesis. In comparing male and female WT mice, top DEGs were related to sexual development/fertility, immune regulation, obesity, dopamine signaling, and circadian regulation. SPA correlated strongly with Per3, a gene regulating circadian function, thermoregulation, and metabolism (r = -0.64, P = .002), which also correlated with adiposity (r = 0.54, P = .01). In conclusion, aromatase ablation leads to gene expression changes in NAc, which may in turn result in reduced SPA and related metabolic abnormalities. These findings may have significance to post-menopausal women and those treated with an aromatase inhibitor.

Feasibility of removable balloon implant for simultaneous magnetic nanoparticle heating and HDR brachytherapy of brain tumor resection cavities.

AIM: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant. METHODS: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (>0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz. RESULTS: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies. CONCLUSIONS: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme.

Invert sugar induces glucose intolerance but does not cause injury to the pancreas nor permanent DNA damage in rats.

The high consumption of sugars is linked to the intermediate hyperglycemia and impaired glucose tolerance associated with obesity, inducing the prediabetes. However, the consequences of excessive invert sugar intake on glucose metabolism and genomic stability were poorly studied. The aim of this study was to evaluate the effects of invert sugar overload (32%) in rats, analyzing changes in obesity, glucose tolerance, pancreatic/hepatic histology and primary and permanent DNA damage. After 17 weeks, the rats became obese and had an excessive abdominal fat, as well as presented impaired glucose tolerance, caused by higher sugar caloric intake. Primary DNA damage, evaluated by the comet assay, was increased in the blood, however not in the pancreas. No protein carbonylation was seen in serum. Moreover, no increase in permanent DNA damage was seen in the bone marrow, evaluated using the micronucleus test. Some rats presented liver steatosis and that the pancreatic islets were enlarged, but not significantly. In this study, invert sugar altered the glucose metabolism and induced primary DNA damage in blood, but did not cause significant damage to the pancreas or liver, and neither changes in the levels of oxidative stress or permanent DNA damage.

Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver.

The role of estrogen receptor-α (ERα) signaling in immunometabolic function is established in females. However, its necessity in males, while appreciated, requires further study. Accordingly, we first determined whether lower metabolic function in male mice compared with females is related to reduced ERα expression. ERα protein expression in metabolically active tissues was lower in males than in females, and this lower expression was associated with worse glucose tolerance. Second, we determined whether ERα is required for optimal immunometabolic function in male mice consuming a chow diet. Despite lower expression of ERα in males, its genetic ablation (KO) caused an insulin-resistant phenotype characterized by enhanced adiposity, glucose intolerance, hepatic steatosis, and metaflammation in adipose tissue and liver. Last, we determined whether ERα is essential for exercise-induced metabolic adaptations. Twelve-week-old wild-type (WT) and ERα KO mice either remained sedentary (SED) or were given access to running wheels (WR) for 10 wk while fed an obesogenic diet. Body weight and fat mass were lower in WR mice regardless of genotype. Daily exercise obliterated immune cell infiltration and inflammatory gene transcripts in adipose tissue in both genotypes. In the liver, however, wheel running suppressed hepatic steatosis and inflammatory gene transcripts in WT but not in KO mice. In conclusion, the present findings indicate that ERα is required for optimal immunometabolic function in male mice despite their reduced ERα protein expression in metabolically active tissues. Furthermore, for the first time, we show that ERα signaling appears to be obligatory for exercise-induced prevention of hepatic steatosis.

Robot-Assisted Laparoscopic Reoperative Repair for Failed Pyeloplasty in Children: An Updated Series.

PURPOSE: Reoperative pyeloplasty is commonly used in children with recurrent obstruction after pyeloplasty. We previously reported on reoperative robot-assisted laparoscopic repair for failed pyeloplasty in 16 children and concluded that short-term and intermediate outcomes were comparable to open reoperative repair. In this updated series we describe longer term outcomes from an extended study. MATERIALS AND METHODS: We retrospectively reviewed outcomes of consecutive children with prior failed primary pyeloplasty who underwent robot-assisted laparoscopic reoperative repair at a single institution from January 2008 to June 2018. RESULTS: Overall, 36 children 0.6 to 15.2 years old (median 3.7) underwent robot-assisted laparoscopic reoperative repair (pyeloplasty in 31, ureterocalicostomy in 5) at a median of 24.3 months (range 3.9 to 136.7) after primary repair. Median reoperative time was 285.0 minutes (range 207 to 556) and median length of stay was 1 day (1 to 8). Crossing vessels were present in 8 of 30 children (26.7%) with prior open repair and in 0 of 6 with prior minimally invasive repair. Clavien-Dindo grade 1 to 2 perioperative complications occurred in 4 children (11.1%) and grade 3 to 5 complications in 2 (5.6%). Median followup was 35.3 months (range 1.4 to 108.3), with 18 children (50.0%) being followed for more than 3 years. Postoperative ultrasound in 34 children revealed improvement in 31 (91.2%), stability in 2 (5.9%) and worsening hydronephrosis in 1 (2.9%). All 11 children undergoing preoperative and postoperative diuretic renography demonstrated stable or improved differential renal function. All children were symptom-free at last followup. CONCLUSIONS: To our knowledge, this is the largest series of robot-assisted laparoscopic reoperative repair for failed pyeloplasty in children. Our results indicate the feasibility, efficacy, safety and durability of this procedure.

Corticomotor excitability reduction induced by experimental pain remains unaffected by performing a working memory task as compared to staying at rest.

Experimental pain inhibits primary motor cortex (M1) excitability. Attenuating pain-related inhibition of M1 excitability may be useful during rehabilitation in individuals with pain. One strategy to attenuate M1 excitability is to influence prefrontal and premotor cortex activity. Working memory tasks, e.g. the two-back task (TBT), engage prefrontal and premotor cortices and may influence M1 excitability. We hypothesized that performing the TBT during pain would influence pain-related changes in M1 excitability. Participants (n = 28) received rigorous training in the TBT before baseline testing. Experimental pain was induced by injecting hypertonic saline into the first dorsal interosseous (FDI) muscle. Participants rated pain intensity on a 0-10 numerical rating scale (NRS) every second min until pain-resolved (PR) during the performance of the TBT (n = 14) or during REST (n = 14). In the TBT, letters were presented pseudo-randomly, and accuracy and reaction time to identified letters corresponding to letters shown two times back were recorded. M1 excitability was assessed using transcranial magnetic stimulation. Motor-evoked potentials (MEPs) were recorded at baseline, and at PR, PR + 10, PR + 20, and PR + 30 min. Four minutes after hypertonic saline injection, the pain NRS scores were higher in the TBT group than the REST group (p = 0.009). No time × group interaction was found for MEPs (p = 0.73), but a main effect of time (p < 0.0005) revealed a reduction of MEPs at PR up until PR + 30 (p < 0.008). The TBT accuracy improved at PR + 30 in both groups (p = 0.019). In conclusion, the pain-induced reduction in corticomotor excitability was unaffected by performing a working memory task, despite greater pain in the TBT group.

Predicting opioid use disorder in patients with chronic pain who present to the emergency department.

BACKGROUND: Emergency department (ED) patients with chronic pain challenge providers to make quick and accurate assessments without an in-depth pain management consultation. Emergency physicians need reliable means to determine which patients may receive opioid therapy without exacerbating opioid use disorder (OUD). METHODS: Eighty-nine ED patients with a chief complaint of chronic pain were enrolled. Researchers administered questionnaires and reviewed medical and state prescription monitoring database information. Participants were classified as either OUD or non-OUD. Statistical analysis included a bivariate analysis comparing differences between groups and multivariate logistic regression evaluating ORs. RESULTS: The 45 participants categorised as OUD had a higher proportion of documented or reported psychiatric diagnoses (p=0.049), preference of opioid treatment (p=0.005), current oxycodone prescription (p=0.043), borrowed pain medicine (p=0.004) and non-authorised dose increase (p<0.001). The state prescription monitoring database revealed the OUD group to have an increased number of opioid prescriptions (p=0.005) and pills (p=0.010). Participants who borrowed pain medicine and engaged in non-authorised dose increase were 5.2 (p=0.025, 95% CI 1.24 to 21.9) and 6.1 times (p=0.001, 95% CI 1.55 to 24.1) more likely to have OUD, respectively. LIMITATIONS: Major limitations of our study include a small sample size, self-reported measures and convenience sample which may introduce selection bias. CONCLUSION: Patients with chronic pain with OUD have distinguishable characteristics. Emergency physicians should consider such evidence-based variables prior to opioid therapy to ameliorate the opioid crisis and limit implicit bias.

Breast Cancer Brain Metastasis Response to Radiation After Microbubble Oxygen Delivery in a Murine Model.

OBJECTIVES: Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying microbubbles (MBs) would enhance the response of breast cancer metastases to radiation. METHODS: Nude mice (n = 15) received stereotactic injections of brain-seeking MDA-MB-231 breast cancer cells into the right hemisphere. Animals were randomly assigned into 1 of 5 treatment groups: no intervention, 10 Gy radiation using a small-animal radiation research platform, nitrogen-carrying MBs combined with US-mediated MB rupture immediately before 10 Gy radiation, oxygen-carrying MBs immediately before 10 Gy radiation, and oxygen-carrying MBs with US-mediated MB rupture immediately before 10 Gy radiation. Tumor progression was monitored with 3-dimensional US, and overall survival was noted. RESULTS: All groups except those treated with oxygen-carrying MB rupture and radiation had continued rapid tumor growth after treatment. Tumors treated with radiation alone showed a mean increase in volume ± SD of 337% ± 214% during the week after treatment. Tumors treated with oxygen-carrying MBs and radiation without MB rupture showed an increase in volume of 383% ± 226%. Tumors treated with radiation immediately after rupture of oxygen-carrying MBs showed an increase in volume of only 41% ± 1% (P = 0.045), and this group also showed a 1 week increase in survival time. CONCLUSIONS: Adding US-ruptured oxygen-carrying MBs to radiation therapy appears to delay tumor progression and improve survival in a murine model of metastatic breast cancer.

Quercetin Potentiates Docosahexaenoic Acid to Suppress Lipopolysaccharide-induced Oxidative/Inflammatory Responses, Alter Lipid Peroxidation Products, and Enhance the Adaptive Stress Pathways in BV-2 Microglial Cells.

High levels of docosahexaenoic acid (DHA) in the phospholipids of mammalian brain have generated increasing interest in the search for its role in regulating brain functions. Recent studies have provided evidence for enhanced protective effects when DHA is administered in combination with phytochemicals, such as quercetin. DHA and quercetin can individually suppress lipopolysaccharide (LPS)⁻induced oxidative/inflammatory responses and enhance the antioxidative stress pathway involving nuclear factor erythroid-2 related factor 2 (Nrf2). However, studies with BV-2 microglial cells indicated rather high concentrations of DHA (IC50 in the range of 60⁻80 µM) were needed to produce protective effects. To determine whether quercetin combined with DHA can lower the levels of DHA needed to produce protective effects in these cells is the goal for this study. Results showed that low concentrations of quercetin (2.5 µM), in combination with DHA (10 µM), could more effectively enhance the expression of Nrf2 and heme oxygenase 1 (HO-1), and suppress LPS⁻induced nitric oxide, tumor necrosis factor-α, phospho-cytosolic phospholipase A2, reactive oxygen species, and 4-hydroxynonenal, as compared to the same levels of DHA or quercetin alone. These results provide evidence for the beneficial effects of quercetin in combination with DHA, and further suggest their potential as nutraceuticals for improving health.