Intraoperative Use of Albumin in Major Noncardiac Surgery: Incidence, Variability, and Association With Outcomes.

BACKGROUND: The impact of albumin use during major surgery is unknown, and a dearth of evidence governing its use in major noncardiac surgery has long precluded its standardization in clinical guidelines. OBJECTIVE: In this study, we investigate institutional variation in albumin use among medical centers in the United States during major noncardiac surgery and explore the association of intraoperative albumin administration with important postoperative outcomes. METHODS: The study is an observational retrospective cohort analysis performed among 54 U.S. hospitals in the Multicenter Perioperative Outcomes Group and includes adult patients who underwent major noncardiac surgery under general anesthesia between January 2014 and June 2020. The primary endpoint was the incidence of albumin administration. Secondary endpoints are acute kidney injury (AKI), net-positive fluid balance, pulmonary complications, and 30-day mortality. Albumin-exposed and albumin-unexposed cases were compared within a propensity score-matched cohort to evaluate associations of albumin use with outcomes. RESULTS: Among 614,215 major surgeries, predominantly iso-oncotic albumin was administered in 15.3% of cases and featured significant inter-institutional variability in use patterns. Cases receiving intraoperative albumin involved patients of higher American Society of Anesthesiologists physical status and featured larger infused crystalloid volumes, greater blood loss, and vasopressor use. Overall, albumin was most often administered at high-volume surgery centers with academic affiliation, and within a propensity score-matched cohort (n=153,218), the use of albumin was associated with AKI (aOR 1.24, 95% CI 1.20-1.28, P <0.001), severe AKI (aOR 1.45, 95% CI 1.34-1.56, P <0.001), net-positive fluid balance (aOR 1.18, 95% CI 1.16-1.20, P <0.001), pulmonary complications (aOR 1.56, 95% CI 1.30-1.86, P <0.001), and 30-day all-cause mortality (aOR 1.37, 95% CI 1.26-1.49, P <0.001). CONCLUSIONS: Intravenous albumin is commonly administered among noncardiac surgeries with significant inter-institutional variability in use in the United States. Albumin administration was associated with an increased risk of postoperative complications.

Fluids, vasopressors, and acute kidney injury after major abdominal surgery between 2015 and 2019: a multicentre retrospective analysis.

BACKGROUND: Practice patterns related to intraoperative fluid administration and vasopressor use have potentially evolved over recent years. However, the extent of such changes and their association with perioperative outcomes, such as the development of acute kidney injury (AKI), have not been studied. METHODS: We performed a retrospective analysis of major abdominal surgeries in adults across 26 US hospitals between 2015 and 2019. The primary outcome was AKI as defined by the Kidney Disease Improving Global Outcomes definition (KDIGO) using only serum creatinine criteria. Univariable linear predictive additive models were used to describe the dose-dependent risk of AKI given fluid administration or vasopressor use. RESULTS: Over the study period, we observed a decrease in the volume of crystalloid administered, a decrease in the proportion of patients receiving more than 10 ml kg-1 h-1 of crystalloid, an increase in the amount of norepinephrine equivalents administered, and a decreased duration of hypotension. The incidence of AKI increased between 2016 and 2019. An increase of crystalloid administration from 1 to 10 ml kg-1 h-1 was associated with a 58% decreased risk of AKI. CONCLUSIONS: Despite decreased duration of hypotension during the study period, decreased fluid administration and increased vasopressor use were associated with increased incidence of AKI. Crystalloid administration below 10 ml kg-1 h-1 was associated with an increased risk of AKI. Although no causality can be concluded, these data suggest that prevention and treatment of hypotension during abdominal surgery with liberal use of vasopressors at the expense of fluid administration is associated with an increased risk of postoperative AKI.

Postoperative delirium prediction using machine learning models and preoperative electronic health record data.

BACKGROUND: Accurate, pragmatic risk stratification for postoperative delirium (POD) is necessary to target preventative resources toward high-risk patients. Machine learning (ML) offers a novel approach to leveraging electronic health record (EHR) data for POD prediction. We sought to develop and internally validate a ML-derived POD risk prediction model using preoperative risk features, and to compare its performance to models developed with traditional logistic regression. METHODS: This was a retrospective analysis of preoperative EHR data from 24,885 adults undergoing a procedure requiring anesthesia care, recovering in the main post-anesthesia care unit, and staying in the hospital at least overnight between December 2016 and December 2019 at either of two hospitals in a tertiary care health system. One hundred fifteen preoperative risk features including demographics, comorbidities, nursing assessments, surgery type, and other preoperative EHR data were used to predict postoperative delirium (POD), defined as any instance of Nursing Delirium Screening Scale ≥2 or positive Confusion Assessment Method for the Intensive Care Unit within the first 7 postoperative days. Two ML models (Neural Network and XGBoost), two traditional logistic regression models ("clinician-guided" and "ML hybrid"), and a previously described delirium risk stratification tool (AWOL-S) were evaluated using the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, positive likelihood ratio, and positive predictive value. Model calibration was assessed with a calibration curve. Patients with no POD assessments charted or at least 20% of input variables missing were excluded. RESULTS: POD incidence was 5.3%. The AUC-ROC for Neural Net was 0.841 [95% CI 0. 816-0.863] and for XGBoost was 0.851 [95% CI 0.827-0.874], which was significantly better than the clinician-guided (AUC-ROC 0.763 [0.734-0.793], p < 0.001) and ML hybrid (AUC-ROC 0.824 [0.800-0.849], p < 0.001) regression models and AWOL-S (AUC-ROC 0.762 [95% CI 0.713-0.812], p < 0.001). Neural Net, XGBoost, and ML hybrid models demonstrated excellent calibration, while calibration of the clinician-guided and AWOL-S models was moderate; they tended to overestimate delirium risk in those already at highest risk. CONCLUSION: Using pragmatically collected EHR data, two ML models predicted POD in a broad perioperative population with high discrimination. Optimal application of the models would provide automated, real-time delirium risk stratification to improve perioperative management of surgical patients at risk for POD.

Epidemiology of sepsis and septic shock.

PURPOSE OF REVIEW: The epidemiology of sepsis and septic shock has been challenging to study for multiple reasons. These include changing diagnostic definitions, as well a high concentration of sepsis-related studies published from high-income countries (HICs), despite a large global burden. This section attempts to address the incidence of sepsis throughout the years and worldwide. RECENT FINDINGS: The incidence of sepsis and septic shock has continued to increase since the first consensus definitions (Sepsis-1) were established in 1991, and the latest definitions (Sepsis-3) provide a better reflection of mortality risk for a diagnosis of sepsis. Several studies argue that the incidence of sepsis is overreported in HICs, based on billing and coding practices, and may lead to overutilization of resources. However, recent estimates of the true global burden of sepsis, including low-income countries, are likely much higher than reported, with calls for better allocation of resources. SUMMARY: The true epidemiology of sepsis worldwide continues to be a highly debated subject, and more research is needed among low-income countries and high-risk subpopulations.

Improved analgesia and reduced post-operative nausea and vomiting after implementation of an enhanced recovery after surgery (ERAS) pathway for total mastectomy.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways have been shown in multiple surgical disciplines to improve outcomes, including reduced opioid consumption, length of stay, and post-operative nausea and vomiting (PONV). However, very few studies describe the application of ERAS to breast surgery and even fewer describe ERAS for outpatient surgery. We describe the implementation and efficacy of an Enhanced Recovery After Surgery (ERAS) pathway for total skin-sparing mastectomy with immediate reconstruction in an outpatient setting. METHODS: We implemented an evidence-based, multimodal ERAS pathway for all patients undergoing total skin-sparing mastectomy surgery with immediate reconstruction at a single 23-h stay surgery center. Highlights of the ERAS pathway included: preoperative acetaminophen, gabapentin, and scopolamine; regional anesthesia for the breast (Pectoral blocks type 1 and 2 or paravertebral block); and intraoperative dexamethasone and ondansetron. This retrospective study included all American Society of Anesthesiology (ASA) Class 1-3 patients undergoing total skin-sparing mastectomy surgery with immediate reconstruction between July 2013 and April 2016. We compared 96 patients who were in the ERAS pathway (ERAS group) to a retrospective cohort of 276 patients (Pre group). The primary outcome was total perioperative opioid consumption. Secondary outcomes were highest postoperative pain scores, incidence of PONV, and length of stay. RESULTS: Patients in the ERAS group had significantly lower total perioperative opioid consumption compared to the Pre group (mean (SD): 111.4 mg (46.0) vs. 163.8 mg (73.2) oral morphine equivalents, p < 0.001). Patients in the ERAS group also had a lower incidence of PONV (28% vs. 50%, p < 0.001). Patients in the ERAS group reported less pain in the recovery room, with a two-point decrease in highest pain score (median [interquartile range (IQR)]: 4 [2,6] in ERAS group vs. 6 [4,7] in Pre group, p < 0.001). There was no clinically significant difference in length of stay (median [IQR]: 1144 min [992, 1259] in ERAS group vs. 1188 [1058, 1344] in Pre group, p = 0.006). CONCLUSION: Implementation of an ERAS pathway for total skin-sparing mastectomy with reconstruction that incorporates regional anesthesia is feasible in a 23-h-stay hospital. Patients in the ERAS pathway had improved post-operative analgesia and reduced post-operative nausea and vomiting.

Grammar intervention using graduated input type variation (GITV) for pre-primary children: A single-case experimental design study.

PURPOSE: This study examined the early efficacy of a new theory-driven principle of grammar intervention, graduated input type variation (GITV). METHOD: Three Cantonese-speaking children, aged between 4;01 and 5;10, with oral language difficulties participated in this single baseline within-participant single case experimental study. The children received a total of 300 teaching episodes of the target serial verb construction via focused stimulation and recast over 10 30- to 45-minute sessions. The 30 exemplars of the target included low type variation of the verbs in each of the first five sessions, followed by high type variation in the remaining sessions. RESULT: Visual analysis revealed that all children improved their performance in the target construction but not the control vocabulary in the probes, suggesting a treatment effect. Maintenance of treatment effects was also observed in all children. Positive results in across-behaviour generalisation to the untrained construction were observed in all children. Generalisation to other less structured linguistic contexts and to the narrative retell discourse context was minimal and observed in one child only. CONCLUSION: Preliminary evidence suggested early efficacy of GITV as a principle for grammar intervention. Modifications in the research methodology are recommended for future studies involving children with developmental language disorder.

Negativity and Positivity in the ICU: Exploratory Development of Automated Sentiment Capture in the Electronic Health Record.

OBJECTIVES: To develop proof-of-concept algorithms using alternative approaches to capture provider sentiment in ICU notes. DESIGN: Retrospective observational cohort study. SETTING: The Multiparameter Intelligent Monitoring of Intensive Care III (MIMIC-III) and the University of California, San Francisco (UCSF) deidentified notes databases. PATIENTS: Adult (≥18 yr old) patients admitted to the ICU. MEASUREMENTS AND MAIN RESULTS: We developed two sentiment models: 1) a keywords-based approach using a consensus-based clinical sentiment lexicon comprised of 72 positive and 103 negative phrases, including negations and 2) a Decoding-enhanced Bidirectional Encoder Representations from Transformers with disentangled attention-v3-based deep learning model (keywords-independent) trained on clinical sentiment labels. We applied the models to 198,944 notes across 52,997 ICU admissions in the MIMIC-III database. Analyses were replicated on an external sample of patients admitted to a UCSF ICU from 2018 to 2019. We also labeled sentiment in 1,493 note fragments and compared the predictive accuracy of our tools to three popular sentiment classifiers. Clinical sentiment terms were found in 99% of patient visits across 88% of notes. Our two sentiment tools were substantially more predictive (Spearman correlations of 0.62-0.84, p values < 0.00001) of labeled sentiment compared with general language algorithms (0.28-0.46). CONCLUSION: Our exploratory healthcare-specific sentiment models can more accurately detect positivity and negativity in clinical notes compared with general sentiment tools not designed for clinical usage.

A descriptive appraisal of quality of reporting in a cohort of machine learning studies in anesthesiology.

BACKGROUND: The field of machine learning is being employed more and more in medicine. However, studies have shown that the quality of published studies frequently lacks completeness and adherence to published reporting guidelines. This assessment has not been done in the subspecialty of anesthesiology. METHODS: We appraised the quality of reporting of a convenience sample of 67 peer-reviewed publications sourced from the scoping review by Hashimoto et al. Each publication was appraised on the presence of reporting elements (reporting compliance) selected from 4 peer-reviewed guidelines for reporting on machine learning studies. Results are described in several cross sections, including by section of manuscript (e.g. abstract, introduction, etc.), year of publication, impact factor of journal, and impact of publication. RESULTS: On average, reporting compliance was 64% ± 13%. There was marked heterogeneity of reporting based on section of manuscript. There was a mild trend towards increased quality of reporting with increasing impact factor of journal of publication and increasing average number of citations per year since publication, and no trend regarding recency of publication. CONCLUSION: The quality of reporting of machine learning studies in anesthesiology is on par with other fields, but can benefit from improvement, especially in presenting methodology, results, and discussion points, including interpretation of models and pitfalls therein. Clinicians in today's learning health systems will benefit from skills in appraisal of evidence. Several reporting guidelines have been released, and updates to mainstream guidelines are under development, which we hope will usher in improvement in reporting quality.

Four-dimensional breast imaging, part I: introduction of a technology-driven, evidence-based approach to breast augmentation planning.

Although there are many three-dimensional imaging systems currently available on the market, all of them require a high degree of interaction on the part of the user, making them clinically impractical. Moreover, though claims have been made regarding the validity of these systems for imaging the breast form, there have been no previous reports validating any commercially-available implant simulation models in the plastic surgery literature. In this article, the authors describe the development and evaluate the efficacy of a novel four-dimensional (automated three-dimensional) breast imaging system, validating it as an evidence-based simulation tool for patient consultation, surgical planning, and outcomes analysis in cosmetic breast augmentation. This report, based on a series of longitudinal correlation studies with several patient cohorts, found a highly statistically significant degree of correlation and reliability between the automated measurements obtained with the four-dimensional system and manual measurements.

Four-dimensional breast imaging, part II: clinical implementation and validation of a computer imaging system for breast augmentation planning.

BACKGROUND: No publications exist describing the impact of three-dimensional imaging on the consultation process for breast augmentation, nor have existing software products claiming simulation features been validated. OBJECTIVES: The authors describe the application of four-dimensional technology during patient consultation to assist in planning implant size and type. METHODS: Forty-six primary breast augmentation patients underwent preoperative consultation with 4D simulation software; 35 out of 46 also received follow-up imaging. At six months postoperatively, simulated measurements were compared to actual measurements and questionnaires were mailed to patients asking them to assess the imaging experience. A follow-up phone survey 18 months postoperatively examined the persistence of patient attitudes about implant size and imaging. Practice productivity was evaluated by comparing specific parameters (such as scheduling rates) between three separate time periods for the same clinic. RESULTS: Across all parameters, breast augmentation simulations correlated highly with positive surgical outcomes (R-value = 0.68). The majority (95%) of patients believed the simulations were accurate; 89% also expressed that it enhanced trust in the surgeon and 74% reporting that it helped in choosing an implant size. Despite 48% also indicating that they would select a larger implant if they were to undergo surgery again, no patients have undergone reoperations of any kind. Compared to historical controls, scheduling rates in the practice increased from 40% to 77% after addition of simulation software. CONCLUSIONS: 4D breast imaging appears to be an accurate system for analysis, planning, simulation, and patient education for women considering primary breast augmentation, and application of this technology during the consultation process was correlated with a high degree of patient satisfaction and practice productivity.

Carcinoid Crisis-Induced Acute Systolic Heart Failure.

Carcinoid crisis is a life-threatening manifestation of carcinoid syndrome characterized by profound autonomic instability in the setting of catecholamine release from stress, tumor manipulation, or anesthesia. Here, we present an unusual case of carcinoid crisis leading to acute systolic heart failure requiring mechanical circulatory support. (Level of Difficulty: Intermediate.).

Acute Respiratory Distress Syndrome in a Preterm Pregnant Patient With Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Data suggest that pregnant women are not at elevated risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or developing severe disease compared with nonpregnant patients. However, management of pregnant patients who are critically ill with coronavirus disease 2019 (COVID-19) infection is complicated by physiologic changes and other pregnancy considerations and requires balancing maternal and fetal well-being. CASE: We report the case of a patient at 28 weeks of gestation with acute respiratory distress syndrome (ARDS) from COVID-19 infection, whose deteriorating respiratory condition prompted delivery. Our patient's oxygenation and respiratory mechanics improved within hours of delivery, though she required prolonged mechanical ventilation until postpartum day 10. Neonatal swabs for SARS-CoV-2 and COVID-19 immunoglobulin (Ig) G and IgM were negative. CONCLUSION: We describe our multidisciplinary management of a preterm pregnant patient with ARDS from COVID-19 infection and her neonate.

"Doctor, Make My Decisions": Decision Control Preferences, Advance Care Planning, and Satisfaction With Communication Among Diverse Older Adults.

CONTEXT: Culturally diverse older adults may prefer varying control over medical decisions. Decision control preferences (DCPs) may profoundly affect advance care planning (ACP) and communication. OBJECTIVES: To determine the DCPs of diverse, older adults and whether DCPs are associated with participant characteristics, ACP, and communication satisfaction. METHODS: A total of 146 participants were recruited from clinics and senior centers in San Francisco. We assessed DCPs using the control preferences scale: doctor makes all decisions (low), shares with doctor (medium), makes own decisions (high). We assessed associations between DCPs and demographics; prior advance directives; ability to make in-the-moment goals of care decisions; self-efficacy, readiness, and prior asked questions; and satisfaction with patient-doctor communication (on a five-point Likert scale), using Chi-square and Kruskal-Wallis analysis of variance. RESULTS: Mean age was 71 ± 10 years, 53% were non-white, 47% completed an advance directive, and 70% made goals of care decisions. Of the sample, 18% had low DCPs, 33% medium, and 49% high. Older age was the only characteristic associated with DCPs (low: 75 ± 11 years, medium: 69 ± 10 years, high: 70 ± 9 years, P = 0.003). DCPs were not associated with ACP, in-the-moment decisions, or communication satisfaction. Readiness was the only question-asking behavior associated (low: 3.8 ± 1.2, medium: 4.1 ± 1.2, high: 4.3 ± 1.2, P = 0.05). CONCLUSION: Nearly one-fifth of diverse, older adults want doctors to make their medical decisions. Older age and lower readiness to ask questions were the only demographic variables significantly associated with low DCPs. Yet, older adults with low DCPs still engaged in ACP, asked questions, and reported communication satisfaction. Clinicians can encourage ACP and questions for all patients, but should assess DCPs to provide the desired amount of decision support.

SAPCD2 Controls Spindle Orientation and Asymmetric Divisions by Negatively Regulating the Gαi-LGN-NuMA Ternary Complex.

Control of cell-division orientation is integral to epithelial morphogenesis and asymmetric cell division. Proper spatiotemporal localization of the evolutionarily conserved Gαi-LGN-NuMA protein complex is critical for mitotic spindle orientation, but how this is achieved remains unclear. Here we identify Suppressor APC domain containing 2 (SAPCD2) as a previously unreported LGN-interacting protein. We show that SAPCD2 is essential to instruct planar mitotic spindle orientation in both epithelial cell cultures and mouse retinal progenitor cells in vivo. Loss of SAPCD2 randomizes spindle orientation, which in turn disrupts cyst morphogenesis in three-dimensional cultures, and triples the number of terminal asymmetric cell divisions in the developing retina. Mechanistically, we show that SAPCD2 negatively regulates the localization of LGN at the cell cortex, likely by competing with NuMA for its binding. These results uncover SAPCD2 as a key regulator of the ternary complex controlling spindle orientation during morphogenesis and asymmetric cell divisions.

P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer's disease: preliminary observations.

P-glycoprotein (P-gp), part of the blood-brain barrier, limits drug access to the brain and is the target for therapies designed to improve drug penetration. P-gp also extrudes brain amyloid-beta (Aß). Accumulation of Aß is a hallmark of Alzheimer's disease (AD). Aß accumulates in normal aging and in AD primarily due to decreased Aß clearance. This is a preliminary report on the relative protein and messenger RNA expression of P-gp in human brains, ages 20-100 years, including AD subjects. In these preliminary studies, cortical endothelial P-gp expression decreased in AD compared with controls (p < 0.001). Trends in P-gp expression in human aging are similar to aging rats. Microvessel P-gp messenger RNA remained unchanged with aging and AD. Aß plaques were found in 42.8% of normal subjects (54.5% of those older than 50 years). A qualitative analysis showed that P-gp expression is lower than the group mean in subjects older than 75 years but increased if younger. Decreased P-gp expression may be related to Aß plaques in aging and AD. Downregulating P-gp to allow pharmaceuticals into the central nervous system may increase Aß accumulation.

KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression.

The small GTPase Rap1 regulates inside-out integrin activation and thereby influences cell adhesion, migration, and polarity. Several Rap1 effectors have been described to mediate the cellular effects of Rap1 in a context-dependent manner. Radil is emerging as an important Rap effector implicated in cell spreading and migration, but the molecular mechanisms underlying its functions are unclear. We report here that the kinesin KIF14 associates with the PDZ domain of Radil and negatively regulates Rap1-mediated inside-out integrin activation by tethering Radil on microtubules. The depletion of KIF14 led to increased cell spreading, altered focal adhesion dynamics, and inhibition of cell migration and invasion. We also show that Radil is important for breast cancer cell proliferation and for metastasis in mice. Our findings provide evidence that the concurrent up-regulation of Rap1 activity and increased KIF14 levels in several cancers is needed to reach optimal levels of Rap1-Radil signaling, integrin activation, and cell-matrix adhesiveness required for tumor progression.

Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months.

BACKGROUND: Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aß) accumulation in the aging rat brain. METHODS: Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aß40 and Aß42 concentrations in the cortex and hippocampus were measured by ELISA. RESULTS: There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p < 0.01); 3-30 months (p < 0.001). CSF production rate increased from 3-12 months (p < 0.01) and decreased from 12-30 months (p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day-1) to 12 months (11.30 day-1) and then a decrease to 20 months (10.23 day-1) and 30 months (6.62 day-1). Aß40 and Aß42 concentrations in brain increased from 3-30 months (p < 0.001). Both Aß42 and Aß40 concentrations approached a steady state level by 30 months. CONCLUSIONS: In young rats there is no correlation between CSF turnover and Aß brain concentrations. After 12 months, CSF turnover decreases as brain Aß continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.

Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent.

BACKGROUND: Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is an accumulation of amyloid-beta peptides (Aß) in both the AD brain and the normal aging brain. Clearance of Aß from the brain occurs via active transport at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). With increasing age, the expression of the Aß efflux transporters is decreased and the Aß influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aß transporters at the choroid plexus (CP) epithelium as a function of aging was the subject of this study. METHODS: This project investigated the changes in expression of the Aß transporters, the low density lipoprotein receptor-related protein-1 (LRP-1), P-glycoprotein (P-gp), LRP-2 (megalin) and the receptor for advanced glycation end-products (RAGE) at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC) to measure transporter protein in isolated rat CP. RESULTS: There was an increase in the transcription of the Aß efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aß42 concentration in the CP, as measured by quantitative IHC, was associated with these Aß transporter alterations. CONCLUSIONS: Age-dependent alterations in the CP Aß transporters are associated with a decrease in Aß42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aß clearance in aging.

C. elegans ZAG-1, a Zn-finger-homeodomain protein, regulates axonal development and neuronal differentiation.

Neurons acquire distinct cell identities and implement differential gene programs to generate their appropriate neuronal attributes. On the basis of position, axonal structure and synaptic connectivity, the 302 neurons of the nematode Ceanorhabditis elegans are divided into 118 classes. The development and differentiation of many neurons require the gene zag-1, which encodes a deltaEF1/ZFH-1 Zn-finger-homeodomain protein. zag-1 mutations cause misexpression of neuron-specific genes, block formation of stereotypic axon branches, perturb neuronal migrations, and induce various axon-guidance, fasciculation and branching errors. A zag-1-GFP translational reporter is expressed transiently in most or all neurons during embryogenesis and in select neurons during the first larval stage. Analysis of the zag-1 promoter reveals that zag-1 is expressed in neurons and specific muscles, and that ZAG-1 directly represses its own expression. zag-1 activity also downregulates expression of genes involved in either the synthesis or reuptake of serotonin, dopamine and GABA. We propose that ZAG-1 acts as a transcriptional repressor to regulate multiple, discrete, neuron-specific aspects of terminal differentiation, including cell migration, axonal development and gene expression.