BAC Transgenic Expression of Human TREM2-R47H Remodels Amyloid Plaques but Unable to Reprogram Plaque-associated Microglial Reactivity in 5xFAD Mice.

Background: Genetic study of late-onset Alzheimer's disease (AD) reveals that a rare Arginine-to-Histamine mutation at amino acid residue 47 (R47H) in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) results in increased disease risk. TREM2 plays critical roles in regulating microglial response to amyloid plaques in AD, leading to their clustering and activation surrounding the plaques. We previously showed that increasing human TREM2 gene dosage exerts neuroprotective effects against AD-related deficits in amyloid depositing mouse models of AD. However, the in vivo effects of the R47H mutation on human TREM2-mediated microglial reprogramming and neuroprotection remains poorly understood. Method: Here we created a BAC transgenic mouse model expressing human TREM2 with the R47H mutation in its cognate genomic context (BAC-TREM2-R47H). Importantly, the BAC used in this study was engineered to delete critical exons of other TREM-like genes on the BAC to prevent confounding effects of overexpressing multiple TREM-like genes. We crossed BAC-TREM2- R47H mice with 5xFAD [1], an amyloid depositing mouse model of AD, to evaluate amyloid pathologies and microglial phenotypes, transcriptomics and in situ expression of key TREM2 -dosage dependent genes. We also compared the key findings in 5xFAD/BAC-TREM2-R47H to those observed in 5xFAD/BAC-TREM2 mice. Result: Both BAC-TREM2 and BAC-TREM2-R47H showed proper expression of three splicing isoforms of TREM2 that are normally found in human. In 5xFAD background, elevated TREM2-R47H gene dosages significantly reduced the plaque burden, especially the filamentous type. The results were consistent with enhanced phagocytosis and altered NLRP3 inflammasome activation in BAC- TREM2-R47H microglia in vitro. However, unlike TREM2 overexpression, elevated TREM2- R47H in 5xFAD failed to ameliorate cognitive and transcriptomic deficits. In situ analysis of key TREM2 -dosage dependent genes and microglial morphology uncovered that TREM2-R47H showed a loss-of-function phenotype in reprogramming of plaque-associated microglial reactivity and gene expression in 5xFAD. Conclusion: Our study demonstrated that the AD-risk variant has a previously unknown, mixture of partial and full loss of TREM2 functions in modulating microglial response in AD mouse brains. Together, our new BAC-TREM2-R47H model and prior BAC-TREM2 mice are invaluable resource to facilitate the therapeutic discovery that target human TREM2 and its R47H variant to ameliorate AD and other neurodegenerative disorders.

Mapping brain gene coexpression in daytime transcriptomes unveils diurnal molecular networks and deciphers perturbation gene signatures.

Brain tissue transcriptomes may be organized into gene coexpression networks, but their underlying biological drivers remain incompletely understood. Here, we undertook a large-scale transcriptomic study using 508 wild-type mouse striatal tissue samples dissected exclusively in the afternoons to define 38 highly reproducible gene coexpression modules. We found that 13 and 11 modules are enriched in cell-type and molecular complex markers, respectively. Importantly, 18 modules are highly enriched in daily rhythmically expressed genes that peak or trough with distinct temporal kinetics, revealing the underlying biology of striatal diurnal gene networks. Moreover, the diurnal coexpression networks are a dominant feature of daytime transcriptomes in the mouse cortex. We next employed the striatal coexpression modules to decipher the striatal transcriptomic signatures from Huntington's disease models and heterozygous null mice for 52 genes, uncovering novel functions for Prkcq and Kdm4b in oligodendrocyte differentiation and bipolar disorder-associated Trank1 in regulating anxiety-like behaviors and nocturnal locomotion.

Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice.

In Huntington's disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively.

Dissecting mechanisms of brain aging by studying the intrinsic excitability of neurons.

Several studies using vertebrate and invertebrate animal models have shown aging associated changes in brain function. Importantly, changes in soma size, loss or regression of dendrites and dendritic spines and alterations in the expression of neurotransmitter receptors in specific neurons were described. Despite this understanding, how aging impacts intrinsic properties of individual neurons or circuits that govern a defined behavior is yet to be determined. Here we discuss current understanding of specific electrophysiological changes in individual neurons and circuits during aging.

Severe hypotension after interscalene block for outpatient shoulder surgery: a case report.

The case of a 43 year-old woman who underwent successful right interscalene brachial plexus block for arthroscopic shoulder surgery is presented. During the surgery, she subsequently exhibited signs of neuraxial spread of local anesthetic. Bilateral motor block was noted postoperatively. Spontaneous ventilation was maintained throughout the case, and she was successfully discharged home several hours after the procedure with no residual symptoms.

Survey of the utilization of regional and general anesthesia in a tertiary teaching hospital.

BACKGROUND: Although the subspecialty of regional anesthesiology has become an important focus during residency training, there are many factors that might influence a resident's experience in regional anesthesia (RA). There are few data examining the utilization of regional techniques in an anesthesiology residency program. We undertook a prospective observational study to determine the frequency and reasons for not choosing RA in cases for which it was considered an option. METHODS: All scheduled operative procedures that were amenable to neuraxial or major peripheral regional anesthetic techniques were surveyed. Data recorded included the type of intraoperative anesthetic used, type of anesthesiology faculty performing the regional block (regional anesthesiologist vs general anesthesiologist), and reasons for not choosing RA when a regional anesthetic technique was feasible. RESULTS: Of the 2301 surgical procedures amenable to a regional technique, 839 (36.5%) involved use of regional anesthetic, and 1462 (63.5%) involved only a general anesthetic. Of the subjects receiving RA, 32% were performed by general anesthesiology faculty, and 68% were performed by regional anesthesiology faculty. The most common type of regional anesthetic performed by the general anesthesiology faculty was neuraxial blockade (95.2%) (vs 52.5% by regional anesthesiology faculty). Of the cases not involving RA, the reasons were anesthesiology related (40%), surgeon related (34%), patient related (12%), and medical contraindication related (14%). CONCLUSIONS: Our prospective observational study suggests that anesthesiology-related reasons may be an important factor for not undertaking these techniques. Although we did not specifically examine the effect on resident education, our study does provide some evidence to support program directors and department chiefs to set up their regional rotations with faculty most likely to perform RA.

Efficacy of bicarbonate in decreasing pain on intradermal injection of local anesthetics: a meta-analysis.

OBJECTIVE: Intradermal injection of local anesthetic often results in pain on injection due in part to the acidic pH of commercially prepared solutions, which are optimized to prolong shelf life. Although there are other possible explanations (eg, noxious properties of local anesthetics, pressure effect of infiltration), the etiology is most likely multifactorial. Although addition of bicarbonate to local anesthetics may decrease pain on intradermal injection, the extent of this analgesic effect is uncertain. We performed a meta-analysis of available trials investigating pain during intradermal injection of buffered local anesthetic preparations. METHODS: We searched the National Library of Medicine's PubMed database for all relevant articles published on the topic through November 2006. Inclusion criteria included double-blind, randomized controlled trials and use of a visual analog scale to measure pain on infiltration of local anesthetic buffered with sodium bicarbonate compared with that of unbuffered local anesthetic. Meta-analysis was performed using the Review Manager 4.2.7 (The Cochrane Collaboration, 2004). A random-effects model was used. RESULTS: Our search resulted in 86 abstracts, of which 12 articles met all inclusion criteria. Overall, there were 609 observations for buffered local anesthetic and 615 for unbuffered local anesthetic. Use of buffered local anesthetic resulted in a statistically lower weighted mean difference in visual analog scale of -1.17 (95% confidence interval, -1.68 to -0.67) compared with unbuffered local anesthetic. CONCLUSIONS: Our systematic review suggests that the use of buffered local anesthetics seems to be associated with a statistical decrease in pain of infiltration when compared with unbuffered local anesthetic.

Pain levels within 24 hours after UFE: a comparison of morphine and fentanyl patient-controlled analgesia.

The purpose of this study was to assess the presence and severity of pain levels during 24 h after uterine fibroid embolization (UFE) for symptomatic leiomyomata and compare the effectiveness and adverse effects of morphine patient-controlled analgesia (PCA) versus fentanyl PCA. We carried out a prospective, nonrandomized study of 200 consecutive women who received UFE and morphine or fentanyl PCA after UFE. Pain perception levels were obtained on a 0-10 scale for the 24-h period after UFE. Linear regression methods were used to determine pain trends and differences in pain trends between two groups and the association between pain scores and patient covariates. One hundred eighty-five patients (92.5%) reported greater-than-baseline pain after UFE, and 198 patients (99%) required IV opioid PCA. One hundred thirty-six patients (68.0%) developed nausea during the 24-h period. Seventy-two patients (36%) received morphine PCA and 128 (64%) received fentanyl PCA, without demographic differences. The mean dose of morphine used was 33.8 +/- 26.7 mg, while the mean dose of fentanyl was 698.7 +/- 537.4 lg. Using this regimen, patients who received morphine PCA had significantly lower pain levels than those who received fentanyl PCA (p \ 0.0001). We conclude that patients develop pain requiring IV opioid PCA within 24 h after UFE. Morphine PCA is more effective in reducing post-uterine artery embolization pain than fentanyl PCA. Nausea is a significant adverse effect from opioid PCA.

Unrecognized contralateral intrapleural catheter: bilateral blockade may obscure detection of failed epidural catheterization.

Thoracic epidural analgesia has been widely used to reduce both postoperative and posttraumatic pain. We describe a case of inadvertent right-sided interpleural catheter placement and pneumothorax during attempted epidural catheter placement for left-sided rib fractures that went unrecognized because of bilateral blockade and adequate analgesia.

Correlation of postoperative epidural analgesia on morbidity and mortality after colectomy in Medicare patients.

STUDY OBJECTIVE: To examine, with a large database, the effect of postoperative epidural analgesia (vs systemic analgesia) on mortality after colectomy is unclear. DESIGN: Retrospective cohort (database) design. SETTING: Medicare beneficiaries undergoing elective colectomy. PATIENTS: We examined a cohort of 12817 patients obtained from a 5% nationally random sample of Medicare beneficiaries from 1997 to 2001 who underwent elective partial excision of the large intestine. INTERVENTIONS: Patients were divided into two groups depending on the presence or absence of billing for postoperative epidural analgesia (Current Procedural Terminology code 01996). MEASUREMENTS: The primary outcomes assessed were death at 7 and 30 days after the procedure. The rates of major morbidity were also compared. Multivariate regression analysis incorporating race, gender, age, comorbidities, hospital size, hospital teaching status, and hospital technology status was performed to determine whether the presence of postoperative epidural analgesia had an independent effect on mortality or major morbidity. MAIN RESULTS: Multivariate regression analysis revealed that there was no difference between the groups with regard to overall major morbidity; however, the presence of epidural analgesia was associated with a significantly lower odds of death at 7 days (odds ratio, 0.35; 95% confidence interval, 0.21-0.59; P < 0.0001) and 30 days (odds ratio, 0.54; 95% confidence interval, 0.42-0.70; P < 0.0001) after surgery. CONCLUSIONS: The presence of postoperative epidural analgesia may decrease the odds of death after elective colectomy; however, the mechanism of such a benefit is not clear from our analysis.

Does neuraxial anesthesia reduce intraoperative blood loss? A meta-analysis.

STUDY OBJECTIVE: To perform a meta-analysis of available randomized controlled trials to determine if neuraxial anesthesia would decrease blood loss, compared with general anesthesia. DESIGN: Retrospective analysis. SETTING: University medical center. MEASUREMENTS: The National Library of Medicine's PubMed database was searched from the period of 1966 to December 10, 2003 for all abstracts containing words related to neuraxial anesthesia and general anesthesia. The search was limited to randomized controlled trials and the English language and yielded 667 articles. MAIN RESULTS: A total of 66 articles met inclusion criteria and were used for the analysis. Overall, the use of spinal anesthesia resulted in significantly less estimated blood loss (EBL) (P < 0.0001), compared with epidural anesthesia (EA), which, in turn, resulted in significantly less EBL compared with general anesthesia (GA) or combined GA-EA (P < 0.0001). No significant difference between GA and GA-EA was noted when analysis was limited to studies directly comparing GA-EA and GA. CONCLUSIONS: Use of spinal anesthesia or EA is associated with a significant decrease in EBL when compared with that for GA or combined GA-EA.

Bevel direction and postdural puncture headache: a meta-analysis.

BACKGROUND: The effect of lumbar puncture needle bevel direction on the incidence of postdural puncture headache (PDPH) is somewhat controversial. We performed a meta-analysis of available trials to determine if bevel direction during lumbar puncture would influence the incidence of PDPH. REVIEW SUMMARY: Studies were identified primarily by searching the National Library of Medicine's PubMed database (1966 to November 29, 2004) and abstracts from several national meetings (American Society of Anesthesiology, International Anesthesia Research Society, American Society of Regional Anesthesia, Society of Obstetric Anesthesia and Perinatology) for terms related to needle and bevel direction. Inclusion criteria were assessment of the incidence of PDPH after lumbar puncture with a cutting needle (eg, Quincke, Tuohy), comparison of a "parallel" (bevel oriented in a longitudinal or cephalad to caudad direction) to "perpendicular" (bevel oriented in a transverse direction) orientation during needle insertion, randomized trials, and trials primarily in adult populations. Data on study characteristics and incidence of PDPH were abstracted from qualified studies and subsequently analyzed. The search resulted in 52 abstracts from which the original articles were obtained and data abstracted, with ultimately a total of 5 articles meeting all inclusion criteria. Insertion of a non-pencil-point/cutting needle with the bevel oriented in a parallel/longitudinal fashion resulted in a significantly lower incidence of PDPH compared with that oriented in a perpendicular/transverse fashion (unadjusted rates of 10.9% versus 25.8%; odds ratio = 0.29 [95% CI = 0.17-0.50]). CONCLUSIONS: Our meta-analysis indicates that with use of a cutting needle, insertion in a parallel/longitudinal fashion may significantly reduce the incidence of PDPH, although the reasons for this decrease are unclear.

Efficacy of periprostatic local anesthetic for prostate biopsy analgesia: a meta-analysis.

OBJECTIVES: To perform a meta-analysis of available randomized trials investigating the analgesic efficacy of periprostatic block with local anesthetic. METHODS: The National Library of Medicine's PubMed database was searched for the time period 1966 to August 16, 2005 for all relevant articles. Inclusion criteria included subjects undergoing prostate biopsy, trials that were randomized with one arm of the randomization using local anesthetic for periprostatic block before prostate biopsy, and where the assessment of biopsy pain was measured and available in a form compatible for statistical analysis in our meta-analysis. RESULTS: Our search resulted in 107 abstracts, of which a total of 16 articles met all inclusion criteria. There were 660 subjects who received local anesthetics for a periprostatic block and 616 subjects who did not. The weighted mean difference between the groups indicates that subjects receiving local anesthetic periprostatic block would have a statistically lower pain score compared with those who did not (weighted mean difference in visual analogue pain of -1.66 [95% confidence interval -2.03 to -1.29]). CONCLUSIONS: Our meta-analysis suggests that periprostatic block with local anesthetic for prostate biopsy might result in significantly lower levels of pain during the biopsy procedure. Because periprostatic block with local anesthetic is relatively easy to administer and does not seem to be associated with increased morbidity, clinicians performing prostate biopsies should consider using this technique on a routine basis.

Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.

BACKGROUND & AIMS: Individuals with a strong family history of pancreatic cancer and persons with Peutz-Jeghers syndrome (PJS) have an increased risk for pancreatic cancer. This study screened for early pancreatic neoplasia and compared the pancreatic abnormalities in high-risk individuals and control subjects. METHODS: High-risk individuals with PJS or a strong family history of pancreatic cancer were prospectively evaluated with baseline and 12-month computed tomography (CT) scan and endoscopic ultrasonography (EUS). If EUS was abnormal, EUS-fine-needle aspiration and endoscopic retrograde cholangiopancreatography (ERCP) were performed. Surgery was offered to patients with potentially neoplastic lesions. Radiologic findings and pathologic diagnoses were compared. Patients undergoing EUS and/or ERCP for benign non-pancreatic indications were concurrently enrolled as control subjects. RESULTS: Seventy-eight high-risk patients (72 from familial pancreatic cancer kindreds, 6 PJS) and 149 control patients were studied. To date, 8 patients with pancreatic neoplasia have been confirmed by surgery or fine-needle aspiration (10% yield of screening); 6 patients had 8 benign intraductal papillary mucinous neoplasms (IPMNs), 1 had an IPMN that progressed to invasive ductal adenocarcinoma, and 1 had pancreatic intraepithelial neoplasia. EUS and CT also diagnosed 3 patients with 5 extrapancreatic neoplasms. At EUS and ERCP abnormalities suggestive of chronic pancreatitis were more common in high-risk patients than in control subjects. CONCLUSIONS: Screening EUS and CT diagnosed significant asymptomatic pancreatic and extrapancreatic neoplasms in high-risk individuals. IPMN should be considered a part of the phenotype of familial pancreatic cancer. Abnormalities suggestive of chronic pancreatitis are identified more commonly at EUS and ERCP in high-risk individuals.

Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis.

Although most randomized clinical trials conclude that the addition of continuous peripheral nerve blockade (CPNB) decreases postoperative pain and opioid-related side effects when compared with opioids, studies have included relatively small numbers of patients and the majority failed to show statistical significance during all time periods for reduced pain or side effects. We identified studies primarily by searching Ovid Medline (1966-May 21, 2004) for terms related to postoperative analgesia with CPNB and opioids. Each article from the final search was reviewed and data were extracted from tables, text, or extrapolated from figures as needed. Nineteen articles, enrolling 603 patients, met all inclusion criteria. Inclusion criteria were a clearly defined anesthetic technique (combined general/regional anesthesia, general anesthesia alone, peripheral nerve block), randomized trial, adult patient population (> or =18 yr old), CPNB (or analgesia) used postoperatively (intrapleural catheters were deemed not to be classified as a peripheral nerve catheter), and opioids administered for postoperative analgesia in groups not receiving peripheral nerve block. Perineural analgesia provided better postoperative analgesia compared with opioids (P < 0.001). This effect was seen for all time periods measured for both mean visual analog scale and maximum visual analog scale at 24 h (P < 0.001), 48 h (P < 0.001), and 72 h (mean visual analog scale only) (P < 0.001) postoperatively. Perineural catheters provided superior analgesia to opioids for all catheter locations and time periods (P < 0.05). Nausea/vomiting, sedation, and pruritus all occurred more commonly with opioid analgesia (P < 0.001). A reduction in opioid use was noted with perineural analgesia (P < 0.001). CPNB analgesia, regardless of catheter location, provided superior postoperative analgesia and fewer opioid-related side effects when compared with opioid analgesia.

A comparison of regional versus general anesthesia for ambulatory anesthesia: a meta-analysis of randomized controlled trials.

Both regional anesthesia and general anesthesia have been proposed to provide optimal ambulatory anesthesia. We searched MEDLINE and other databases for randomized controlled trials comparing regional anesthesia and general anesthesia in ambulatory surgery patients for meta-analysis. Only major conduction blocks were considered to be regional anesthesia. Regional anesthesia was further separated into central neuraxial block and peripheral nerve block. Fifteen (1003 patients) and 7 (359 patients) trials for central neuraxial block and peripheral nerve block were included in the meta-analysis. Both central neuraxial block and peripheral nerve block were associated with increased induction time, reduced pain scores, and decreased need for postanesthesia care unit analgesics. However, central neuraxial block was not associated with decreased postanesthesia care unit bypass or time or reduced nausea despite reduced analgesics, and it was associated with a 35-min increase in total ambulatory surgery unit time. In contrast, peripheral nerve block was associated with decreased postanesthesia care unit need and decreased nausea but, again, not with decreased ambulatory surgery unit time. This meta-analysis indicates potential advantages for regional anesthesia, such as decreased postanesthesia care unit use, nausea, and postoperative pain. Although these factors have been proposed to reduce ambulatory surgery unit stay, neither central neuraxial block nor peripheral nerve block were associated with reduced ambulatory surgery unit time. Other factors, such as unsuitable discharge criteria and limitations of meta-analysis, may explain this discrepancy.

Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis.

The authors performed a meta-analysis and found that epidural analgesia overall provided superior postoperative analgesia compared with intravenous patient-controlled analgesia. For all types of surgery and pain assessments, all forms of epidural analgesia (both continuous epidural infusion and patient-controlled epidural analgesia) provided significantly superior postoperative analgesia compared with intravenous patient-controlled analgesia, with the exception of hydrophilic opioid-only epidural regimens. Continuous epidural infusion provided statistically significantly superior analgesia versus patient-controlled epidural analgesia for overall pain, pain at rest, and pain with activity; however, patients receiving continuous epidural infusion had a significantly higher incidence of nausea-vomiting and motor block but lower incidence of pruritus. In summary, almost without exception, epidural analgesia, regardless of analgesic agent, epidural regimen, and type and time of pain assessment, provided superior postoperative analgesia compared to intravenous patient-controlled analgesia.