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Aerosol indirect effects are one of the leading contributors to cloud radiative properties relevant to climate. Aerosol particles become cloud droplets when the ambient relative humidity (saturation ratio) exceeds a critical value, which depends on the particle size and chemical composition. In the traditional formulation of this problem, only average, uniform saturation ratios are considered. Using experiments and theory, we examine the effects of fluctuations, produced by turbulence. Our measurements, from a multiphase, turbulent cloud chamber, show a clear transition from a regime in which the mean saturation ratio dominates to one in which the fluctuations determine cloud properties. The laboratory measurements demonstrate cloud formation in mean-subsaturated conditions (i.e., relative humidity <100%) in the fluctuation-dominant activation regime. The theoretical framework developed to interpret these measurements predicts a transition from a mean- to a fluctuation-dominated regime, based on the relative values of the mean and standard deviation of the environmental saturation ratio and the critical saturation ratio at which aerosol particles activate or become droplets. The theory is similar to the concept of stochastic condensation and can be used in the context of the atmosphere to explore the conditions under which droplet activation is driven by fluctuations as opposed to mean supersaturation. It provides a basis for future development of cloud droplet activation parameterizations that go beyond the internally homogeneous parcel calculations that have been used in the past., Competing Interests: The authors declare no competing interest.

Diet may be a significant determinant of insect gut microbiome composition. However, the extent to which dietary shifts shape both the composition and relevant functions of insect gut microbiomes, and ultimately impact host energy balance (i.e. metabolic phenotype), is not well understood. We investigated the impacts of diet switching on Diploptera punctata females maintained on a dog food (DF) diet relative to those fed a comparatively sub-optimal cellulose-amended dog food (CADF) diet for 4 weeks. After this period, dietary shift resulted in a significantly higher average mass-specific standard metabolic rate (SMR) in CADF-fed females compared with DF-fed females. We also uncovered significant 13 C-enrichment in DF-fed insect samples relative to CADF-fed insect samples and lowered bacterial essential amino acid (EAA) provisioning in CADF-fed samples. Differences in SMR and EAA provisioning were not accompanied by significant differences in overall microbiome composition between the two groups. However, cellulolytic and nitrogen-fixing bacterial families dominant in wild omnivorous cockroaches and wood-feeding termites were significantly enriched in CADF-fed females than in DF-fed females, at the end of the study. We propose that these changes in microbiome composition after dietary shifts are associated with changes in EAA provisioning and possibly SMR. Further studies are needed to comprehensively understand the relative importance of gut microbial functions among the complexity of factors known to underscore SMR responses in insects under varying dietary conditions., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: Transforaminal endoscopic lumbar approaches involve working in Kambin's triangle. These procedures are performed on awake patients or under general anesthesia with continuous electromyography. Potential morbidity of this approach includes injury to exiting and traversing nerve roots, as substantial dissection or cauterization of overlying tissues is required for visualization., Methods: We developed a novel connection system that accepts input from a bipolar radiofrequency probe to allow direct nerve stimulation in conjunction with electromyography. This study included 30 consecutive patients undergoing transforaminal endoscopic lumbar approaches for discectomies (73.3%), foraminal stenosis (23.3%), or lateral recess stenosis (3.3%). Demographic, operative, and outcomes data were collected., Results: Average age of patients was 61.4 years, and the L4-5 segment was most commonly treated (65.6%). Electrophysiologic mapping of the exiting nerve root was attempted in 28 patients with an average stimulation threshold of 8.6 ± 0.9 mA. Mapping of the traversing nerve root was attempted in 12 patients with an average stimulation threshold of 6.0 ± 0.8 mA. There were no instances of new postoperative sensorimotor deficits or dysesthesia. These findings persisted through mean and median follow-up of 294 days and 165 days, respectively. No patient required subsequent lumbar surgery., Conclusions: Our modified instrumentation and technique allow for accurate identification of the exiting and traversing nerve roots with minimal changes to the workflow of transforaminal endoscopic lumbar approaches. Modification of a bipolar radiofrequency device connection arrangement is simple, inexpensive, and reusable. In this study, no patients developed injury or pain related to nerve root dysfunction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown., Objective: The goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging., Methods: Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV 1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV 1  ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV 1 percent predicted among other confounders., Results: In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George's Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P < .001]), exercise performance (6-min walk distance, -45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV 1 alone, or both Dlco and FEV 1 were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes)., Conclusions: Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD., (Copyright © 2019. Published by Elsevier Inc.)

Soot particles form during combustion of carbonaceous materials and impact climate and air quality. When freshly emitted, they are typically fractal-like aggregates. After atmospheric aging, they can act as cloud condensation nuclei, and water condensation or evaporation restructure them to more compact aggregates, affecting their optical, aerodynamic, and surface properties. Here we survey the morphology of ambient soot particles from various locations and different environmental and aging conditions. We used electron microscopy and show extensive soot compaction after cloud processing. We further performed laboratory experiments to simulate atmospheric cloud processing under controlled conditions. We find that soot particles sampled after evaporating the cloud droplets, are significantly more compact than freshly emitted and interstitial soot, confirming that cloud processing, not just exposure to high humidity, compacts soot. Our findings have implications for how the radiative, surface, and aerodynamic properties, and the fate of soot particles are represented in numerical models.

Low fat-free mass index (FFMI) is an independent risk factor for mortality in chronic obstructive pulmonary disease (COPD) not typically measured during routine care. In the present study, we aimed to derive fat-free mass from the pectoralis muscle area (FFM PMA ) and assess whether low FFMI PMA is associated with all-cause mortality in COPD cases. We used data from two independent COPD cohorts, ECLIPSE and COPDGene.Two equal sized groups of COPD cases (n=759) from the ECLIPSE study were used to derive and validate an equation to calculate the FFM PMA measured using bioelectrical impedance from PMA. We then applied the equation in COPD cases (n=3121) from the COPDGene cohort, and assessed survival. Low FFMI PMA was defined, using the Schols classification (FFMI <16 in men, FFMI <15 in women) and the fifth percentile normative values of FFMI from the UK Biobank.The final regression model included PMA, weight, sex and height, and had an adjusted R 2 of 0.92 with fat-free mass (FFM) as the outcome. In the test group, the correlation between FFM PMA and FFM remained high (Pearson correlation=0.97). In COPDGene, COPD cases with a low FFMI PMA had an increased risk of death (HR 1.6, p<0.001).We demonstrated COPD cases with a low FFMI PMA have an increased risk of death., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Background: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids., Methods: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma., Results: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy., Conclusions: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

Background/aims: Selective dorsal rhizotomy for spastic cerebral palsy is an effective and well-validated surgical approach. Multiple techniques have been described in the past including multiple laminectomies and a single-level laminectomy at the level of the conus. There is considerable technical challenge involved with a single-level laminectomy approach., Methods: We report here a modification of the single-level laminectomy that selectively analyzes each individual nerve root with electromyography to separate dorsal and ventral nerve roots through comparison of stimulus responses., Results: In 18 children with cerebral palsy who underwent this operation there was a mean improvement in the Modified Ashworth Scale of 2.0 with no reported incidence of muscle weakness, sensory loss, or neurogenic bladder., Conclusion: This approach allows for a modification of selective dorsal rhizotomy through a single-level laminectomy and tailors the selection of nerve root sectioning to the individual patient of interest while still maintaining its effectiveness., (© 2016 S. Karger AG, Basel.)

In early 2010, leaders within Kaiser Permanente (KP) Northern California's Patient Care Services division embarked on a journey to embrace and embed core tenets of Caring Science into the practice, environment, and culture of the organization. Caring Science is based on the philosophy of Human Caring, a theory articulated by Jean Watson, PhD, RN, AHN-BC, FAAN, as a foundational covenant to guide nursing as a discipline and a profession. Since 2010, Caring Science has enabled KP Northern California to demonstrate its commitment to being an authentic person- and family-centric organization that promotes and advocates for total health. This commitment empowers KP caregivers to balance the art and science of clinical judgment by considering the needs of the whole person, honoring the unique perception of health and healing that each member or patient holds, and engaging with them to make decisions that nurture their well-being. The intent of this article is two-fold: 1) to provide context and background on how a professional practice framework was used to transform the ethic of caring-healing practice, environment, and culture across multiple hospitals within an integrated delivery system; and 2) to provide evidence on how integration of Caring Science across administrative, operational, and clinical areas appears to contribute to meaningful patient quality and health outcomes., Competing Interests: Statement The author(s) have no conflicts of interest to disclose.

Background: The effect of dexmedetomidine on evoked potentials (EPs) has not been elucidated. We aimed to investigate the effect of dexmedetomidine on somatosensory, motor, and visual EPs., Methods: After IRB approval, 40 adult patients scheduled for elective spine surgery using total IV anesthesia with propofol and remifentanil were randomly assigned to receive either dexmedetomidine (n = 20) or placebo (n = 20) in a double-blind, placebo-controlled trial. After obtaining informed consent, positioning, and baseline EPs recording, patients were randomly assigned to either IV dexmedetomidine 0.6 μg/kg infused over 10 minutes, followed by 0.6 μg/kg/h, or a corresponding volume of IV normal saline (placebo). EP measures at 60 ± 30 minutes after initiation of study drug were defined as T1 and at 150 ± 30 minutes were defined as T2. Changes from baseline to T1 (primary end point) and from baseline to T2 (secondary end point) in EP latencies (milliseconds) and amplitudes (microvolts) were compared between groups. Data presented as mean ± SD (95% confidence interval)., Results: Data from 40 patients (dexmedetomidine: n = 20; age, 54 ± 3 years; 10 males; placebo: n = 20; age, 52 ± 2 years; 5 males) were analyzed. There was no difference between dexmedetomidine versus placebo groups in primary end points: change of somatosensory EPs at T1, latency: 0.01 ± 1.3 (-0.64, 0.65) vs 0.01 ± 1.3 (-0.64, 0.65), P = 0.43 (-1.24, 0.45); amplitude: 0.03 ± 0.14 (-0.06, 0.02) vs -0.01 ± 0.13 (-0.07, 0.05), P = 0.76 (-0.074, 0.1); motor EPs amplitude at T1: 65.1 ± 194.8 (-35, 165; n = 18) vs 109.2 ± 241.4 (-24, 243; n = 16), P = 0.57 (-113.5, 241.57); visual EPs at T1 (right eye), amplitude: 2.3 ± 3.6 (-0.4, 5.1; n = 11) vs 0.3 ± 6.0 (-3.3, 3.9; n = 16), P = 0.38 (-6.7, 2.6); latency N1: 2.3 ± 3.6 (-0.4, 5.1) vs 0.3 ± 6.0 (-3.3, 3.9), P = 0.38 (-6.7, 2.6); latency P1: -1.6 ± 13.4 (-11.9, 8.7) vs -1.4 ± 8.1 (-6.3, 3.5), P = 0.97 (-9.3, 9.7) or secondary end points. There were no differences between right and left visual EPs either at T1 or at T2., Conclusions: In clinically relevant doses, dexmedetomidine as an adjunct to total IV anesthesia does not seem to alter EPs and therefore can be safely used during surgeries requiring monitoring of EPs.

Nurse educators assisted the director of professional nursing practice in a large healthcare system to implement a human caring program across 108 nursing units. These educators used transformational learning principles to reunite bedside nurses with the art of caring. Implementation included core content in a 30-minute training session, large-scale leadership conferences, and consistent educator support. Affective growth occurred for both clinicians and educators. The authors provide practical ideas, content, and tools to teach human caring.

Motor evoked potential (MEP) monitoring has been used increasingly in conjunction with somatosensory evoked potential monitoring to monitor neurological changes during complex spinal operations. No published report has demonstrated the effects of segmental spinal cord transection on MEP monitoring. The authors describe the case of an 11-year-old girl with lumbar myelomeningocele and worsening thoracolumbar scoliosis who underwent a T11-L5 fusion and spinal transection to prevent tethering. Intraoperative MEP and somatosensory evoked potential monitoring were performed, and the spinal cord was transected in 4 quadrants. The MEPs were lost unilaterally as each anterior quadrant was sectioned. This is the first reported case that demonstrates the link between spinal cord transection and MEP signaling characteristics. Furthermore, it demonstrates the relatively minor input of the ipsilateral ventral corticospinal tract in MEP physiology at the thoracolumbar junction. Finally, this study further supports the use of MEPs as a specific intraoperative neuromonitoring tool.

Aim: To determine whether fibrinogen levels predict independently progression of coronary artery calcification (CAC) in adults with type 1 diabetes., Methods: Data from a prospective cohort--the Coronary Artery Calcification in Type 1 Diabetes Study--were evaluated. Fibrinogen levels at baseline were separated into quartiles. CAC was measured twice and averaged at baseline and at follow-up 2.4+/-0.4 years later. CAC progressors were defined as participants whose square-root transformed CAC volume increased by >or=2.5 mm3 or development of clinical coronary artery disease during the follow-up period., Results: Fibrinogen levels were higher in progressors than in non-progressors (276+/-61 mg/dl versus 259+/-61 mg/dl, p=0.0003). CAC progression, adjusted for known cardiovascular risk factors, increased in the highest quartile., Conclusions: Higher fibrinogen levels predict CAC progression in type 1 diabetes subjects, independent of standard cardiovascular risk factors., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Abeta-derived diffusible ligands (ADDLs) are abundant in AD brain, bind to hippocampal neurons and induce deficits in rodent cognition. To further investigate ADDL binding to neurons and identify antibodies that block this association, a panel of anti-Abeta and anti-ADDL antibodies was characterized for their ability to immuno-detect neuronally bound ADDLs and attenuate the binding of ADDLs to neurons. The results showed that anti-Abeta and anti-ADDL antibodies were able to abate ADDLs binding to hippocampal neurons, but to different degrees. Quantitative assessment of binding showed that one antibody, ACU-954 was markedly more effective at blocking ADDL binding than other antibodies assessed. ACU-954 was also found to block ADDL binding to hippocampal slice cultures, attenuate the ADDL-induced loss of dendritic spines and detect "natural ADDLs" in human AD tissue. These results demonstrated that antibodies that bind to and block ADDL binding to neurons can be identified, although their efficacy is conformationally specific since it is not readily apparent or predictable based on the core linear epitope or affinity for monomeric Abeta.

Background: Median nerve short-latency somatosensory evoked potentials (SSEPs) are useful in determining prognosis for awakening after coma following hypoxic ischemic encephalopathy, but reliability of interpretation is unclear., Objective: To measure inter- and intra-observer reliability of determining presence or absence of SSEPs in comatose patients following hypoxic ischemic encephalopathy and to identify factors that enhance reliability., Design: Retrospective review by four readers (experience ranging from 2-27 years) of SSEP recordings in 95 comatose patients. Twenty waveforms were presented twice and five waveforms were presented pre- and post-neuromuscular junction (NMJ) blockade., Setting: Academic teaching hospital and level 1 trauma center., Patients: Inpatients in coma due to hypoxic ischemic encephalopathy., Measurements and Main Results: Kappa values among the four readers, reflecting inter-observer reliability, ranged from 0.39 to 0.79 (mean 0.60, SD 0.16), a level of agreement interpreted as "moderate." Better inter-observer reliability was seen when: cortical amplitudes were ≥ 0.7 μV, baseline noise was smaller, and when experience level between reviewers was most similar. In cases examined both pre- and post-NMJ blockade, average kappa values of inter-observer reliability increased significantly from 0.03 pre-NMJ blockade to 0.41 post-NMJ blockade. Intra-observer reliability was higher than that for inter-observer, with a "substantial" average kappa of 0.84 (range 0.79-0.89, SD .06)., Conclusions: Inter- and intra-observer reliability of SSEP interpretation in comatose patients varies from moderate to substantial, respectively. In order to reliably interpret the presence of small cortical responses, NMJ blockade should be used when baseline noise is excessive.

Objective: Establish the efficacy of preoperative facial nerve mapping and continuous intraoperative EMG monitoring in protecting the facial nerve during resection of cervicofacial lymphatic malformations., Methods: Retrospective study in which patients were clinically followed for at least 6 months postoperatively, and long-term outcome was evaluated. Patient demographics, lesion characteristics (i.e., size, stage, location) were recorded. Operative notes revealed surgical techniques, findings, and complications. Preoperative, short-/long-term postoperative facial nerve function was standardized using the House-Brackmann Classification. Mapping was done prior to incision by percutaneously stimulating the facial nerve and its branches and recording the motor responses. Intraoperative monitoring and mapping were accomplished using a four-channel, free-running EMG. Neurophysiologists continuously monitored EMG responses and blindly analyzed intraoperative findings and final EMG interpretations for abnormalities., Results: Seven patients collectively underwent 8 lymphatic malformation surgeries. Median age was 30 months (2-105 months). Lymphatic malformation diagnosis was recorded in 6/8 surgeries. Facial nerve function was House-Brackmann grade I in 8/8 cases preoperatively. Facial nerve was abnormally elongated in 1/8 cases. EMG monitoring recorded abnormal activity in 4/8 cases--two suggesting facial nerve irritation, and two with possible facial nerve damage. Transient or long-term facial nerve paresis occurred in 1/8 cases (House-Brackmann grade II)., Conclusions: Preoperative facial nerve mapping combined with continuous intraoperative EMG and mapping is a successful method of identifying the facial nerve course and protecting it from injury during resection of cervicofacial lymphatic malformations involving the facial nerve.

The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR. BQCA reduces the concentration of ACh required to activate M(1) up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 microM. Furthermore studies in M(1)(-/-) mice demonstrates that BQCA requires M(1) to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M(1) allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M(1), suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M(1) receptor and represents a promising therapeutic strategy for cognitive disorders.

Objective: Depression is associated with poor glycemic control and complications in people with type 1 diabetes. We assessed the prevalence of depression and antidepressant medication use among adults with and without type 1 diabetes and the association between depression and diabetes complications., Research Design and Methods: In 2006-2008, the Coronary Artery Calcification in Type 1 Diabetes Study applied the Beck Depression Inventory II (BDI-II) to 458 participants with type 1 diabetes (47% male, aged 44 +/- 9 years, type 1 diabetes duration 29 +/- 9 years) and 546 participants without diabetes (nondiabetic group) (51% male, aged 47 +/- 9 years). Use of antidepressant medication was self-reported. Depression was defined as a BDI-II score >14 and/or use of antidepressant medication. Occurrence of diabetes complications (retinopathy, blindness, neuropathy, diabetes-related amputation, and kidney or pancreas transplantation) was self-reported., Results: Mean BDI-II score, adjusted for age and sex, was significantly higher in participants with type 1 diabetes than in nondiabetic participants (least-squares mean +/- SE: 7.4 +/- 0.3 vs. 5.0 +/- 0.3; P < 0.0001). Type 1 diabetic participants reported using more antidepressant medications (20.7 vs. 12.1%, P = 0.0003). More type 1 diabetic than nondiabetic participants were classified as depressed by BDI-II cut score (17.5 vs. 5.7%, P < 0.0001) or by either BDI-II cut score or antidepressant use (32.1 vs. 16.0%, P < 0.0001). Participants reporting diabetes complications (n = 209) had higher mean BDI-II scores than those without complications (10.7 +/- 9.3 vs. 6.4 +/- 6.3, P < 0.0001)., Conclusions: Compared with nondiabetic participants, adults with type 1 diabetes report more symptoms of depression and more antidepressant medication usage. Depression is highly prevalent in type 1 diabetes and requires further study on assessment and treatment.

Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5-29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6-388], P = 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes.

A growing body of evidence suggests that soluble oligomeric forms of the amyloid beta peptide known as amyloid-derived diffusible ligands (ADDLs) are the toxic species responsible for neurodegeneration associated with Alzheimer's disease. Accurate biophysical characterization of ADDL preparations is hampered by the peptide's strong tendency to self-associate and the effect of factors such as ionic strength, temperature, and pH on its behavior. In addition, amyloid peptides are known to interact with common laboratory excipients, specifically detergents, further complicating the results from standard analytical methods such as denaturing polyacrylamide gel electrophoresis. We have studied the solution behavior of various amyloid peptide preparations using analytical ultracentrifugation and size exclusion chromatography coupled with multiangle laser light scattering. Our results indicate that ADDL preparations exist in solution primarily as a binary mixture of a monomeric peptide and high-molecular mass oligomers. We relate our findings to previously described characterizations utilizing atomic force microscopy and electrophoretic methods and demonstrate that low-molecular mass oligomers identified by gel electrophoresis likely represent artifacts induced by the peptide's interaction with detergent, while atomic force microscopy results are likely skewed by differential binding of monomeric and oligomeric peptide species. Finally, we confirm that only the high-molecular mass oligomeric components of an ADDL preparation are capable of binding to subpopulations of primary hippocampal neurons in vitro.

Objective: Coronary calcium measured by electron beam CT is associated with coronary disease and can be used to predict coronary disease events. Studies investigating changes in coronary calcium need to address interscan variability as it relates to the overall coronary calcium score in defining progression or regression of coronary calcium over time. SUBJECTS AND METHODS. Electron beam CT was performed on 1,074 participants. Coronary calcium volume scores were repeated 5 min apart. Interscan variability was examined using Bland-Altman plots and homogeneity tests. Transformations of the Box-Cox family (including power, roots, and logarithm) were applied to calcium volume scores. The transformation that stabilized the variation in calcium volume scores was applied to progression of calcium volume scores in 109 subjects with diabetes., Results: The variability in calcium volume score increased as the level of coronary calcium increased (rho = 0.67, p < 0.001 for the relation between the absolute difference and the mean value of calcium volume scores). This heterogeneity was removed using the square root transformation of the calcium volume score (rho = 0.09, p < 0.15 for the relation between the absolute difference in the square root of the calcium volume score and the mean square root of the calcium volume score). This transformation was applied to calcium volume scores taken a mean of 2.7 years apart in 109 subjects with diabetes. A significant change in calcium volume score was defined as a difference between the square root-transformed to calcium volume scores greater than or equal to 2.5 mm(3) (> 99th percentile of interscan variability). Significant progression was observed in 10% of the subjects. The square root of the calcium volume score corrected for the bias in progression of calcium volume because of the level of coronary calcium., Conclusion: Using the square root of the calcium volume score stabilized interscan variability across the range of coronary calcium. Defining change in coronary calcium as greater than or equal to 2.5 mm(3) of the difference in the square root-transformed calcium volume scores provided an estimate that was unbiased with respect to baseline coronary calcium. This analytic technique may facilitate investigations of the relevance of changes in coronary calcium to clinical outcomes and the use of changes in coronary calcium as a measure of the therapeutic impact on subclinical disease in clinical trials.

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.

Serotonin 5-HT(1A) receptor antagonists potentiate the effects of serotonin reuptake inhibitors on extracellular serotonin levels in a variety of brain regions. These effects are quite variable, however, with reports indicating potentiations of anywhere from 100-1900%. One factor that might impact the magnitude of such potentiations is the timing of administration of the two agents; reports in which the reuptake inhibitor is given prior to the serotonin receptor antagonist consistently report larger potentiations than reports in which the antagonist is given first. To test this relationship directly, microdialysis and electrophysiology studies were performed to assess the magnitude of increase in extracellular serotonin and changes in cellular activity produced by the serotonin reuptake inhibitor fluoxetine and the 5-HT(1A) receptor antagonist WAY-100635 under various dosing regimens. In microdialysis studies, when WAY-100635 (0.5 mg/kg s.c.) was administered 80 min after fluoxetine (10 mg/kg i.p.) the increase in serotonin was more than twice that observed when the compounds were coadministered. In electrophysiology studies in vivo, WAY-100635 reversed the depression of cell firing produced by fluoxetine when administered 30 min after fluoxetine, but when the two compounds were coadministered, a depression in firing rate was observed comparable to that produced by fluoxetine alone. In contrast, slice recording studies showed that WAY-100635 blocked the effects of fluoxetine regardless of the order of administration. These results indicate that fluoxetine and WAY-100635 can interact in a fashion not predicted by the currently accepted model. It is likely that neuronal circuitry outside of the raphe nuclei underlies this relationship., (Copyright 2000 Wiley-Liss, Inc.)

The development of selective serotonin reuptake inhibitors (SSRIs) provided a major advancement in the treatment of depression. However, these drugs suffer from a variety of drawbacks, most notably a delay in the onset of efficacy. One hypothesis suggests that this delay in efficacy is due to a paradoxical decrease in serotonergic (5-HT) neuronal impulse flow and release, following activation of inhibitory presynaptic 5-HT1A autoreceptors, following acute administration of SSRIs. According to the hypothesis, efficacy is seen only when this impulse flow is restored following desensitization of 5-HT1A autoreceptors and coincident increases in postsynaptic 5-HT levels are achieved. Clinical proof of this principal has been suggested in studies that found a significant augmenting effect when the beta-adrenergic/5-HT1A receptor antagonist, pindolol, was coadministered with SSRI treatment. In this article, we review preclinical electrophysiological and microdialysis studies that have examined this desensitization hypothesis. We further discuss clinical studies that utilized pindolol as a test of this hypothesis in depressed patients and examine preclinical studies that challenge the notion that the beneficial effect of pindolol is due to functional antagonism of the 5-HT1A autoreceptors.

Nine neonatal Long-Evans rats had continuous (24 h/day) polysomnography for 2 weeks, from age 14 days through age 27 days. A new finding was that six more or less independent measures of REM sleep occurrence decreased in parallel from age 14 days to age 27 days. The measures included parallel decreases of four measures of 24-h REM duration (tonic REM sleep, phasic REM sleep, mean REM period duration, and number of REM periods) along with parallel increases of two measures of REM delay (REM latency and percent of nonsleep onset REM periods). A parsimonious interpretation of the correlated changes is that a common developmental REM sleep inhibitory process accounts for the six parallel changes over time. This hypothesis can be tested empirically by studying inhibitory processes that operate on the pedunculopontine tegmental/latero-dorsal tegmental nuclei, the generators of REM sleep. The study also noted that compared with (same species) normal adults, endogenous depressives had the same distinctive REM sleep characteristics as neonatal rats. The similarity suggests that an underdeveloped, relatively weak REM sleep inhibitory process may account for the REM sleep peculiarities of endogenous depression. This hypothesis can be tested in adult rats made "depressed" by neonatal treatment with antidepressant drugs. Thus, the ontogeny of REM sleep suggests a developmental process that may be altered in humans predisposed to endogenous depression, and may account for the (life-long) REM sleep abnormalities of the disorder.

Transporters are thought to assist in the termination of synaptic transmission at some synapses by removing neurotransmitter from the synapse. To investigate the role of glutamate transport in shaping the time course of excitatory transmission at the mossy fiber-granule cell synapse, the effects of transport impairment were studied using whole-cell voltage- and current-clamp recordings in slices of rat cerebellum. Impairment of transport by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) produced a prolongation of the decay of the AMPA receptor-mediated current after a repetitive stimulus, as well as prolongation of single stimulus-evoked EPSCs when AMPA receptor desensitization was blocked. PDC also produced a prolongation of both single and repetitive-evoked NMDA receptor-mediated EPSCs. Enzymatic degradation of extracellular glutamate did not reverse the PDC-induced prolongation of AMPA receptor-mediated current after a repetitive stimulus, suggesting that transporter binding sites participate in limiting glutamate spillover. In current-clamp recordings, PDC dramatically increased the total area of the EPSP and the burst duration evoked by single and repetitive stimuli. These data indicate that glutamate transporters play a significant role in sculpting the time course of synaptic transmission at granule cell synapses, most likely by limiting the extent of glutamate spillover. The contribution of transporters is particularly striking during repetitive stimulus trains at physiologically relevant frequencies. Hence, the structural arrangement of the glomerulus may enhance the contribution of transporters to information processing by limiting the extent of glutamate spillover between adjacent synapses.

Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral models and that vary with respect to their primary biological target: 1) the nootropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-activated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the acetylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognition-enhancing drugs produced dose-dependent increases in hippocampal theta rhythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthetized rat. These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.

Previous studies indicate that a variety of pharmacological agents interfere with the prepulse inhibition of the acoustic startle (PPI) response including phencyclidine (PCP), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), amphetamine, and apomorphine. Strain differences have been observed in the ability of apomorphine to disrupt PPI, although the degree to which these strain differences occur after administration of nondopaminergic drugs or the degree to which differences can be observed in other models of dopamine (DA) receptor activation has not been elucidated. The present study tested the effects of apomorphine, amphetamine, 8-OH-DPAT, and PCP on PPI in the Sprague Dawley and Wistar rat strains. Because apomorphine disrupts PPI via activation of DA receptors in the nucleus accumbens, apomorphine-induced hyperlocomotion, also a behavioral model of nucleus accumbens DA receptor activation, was measured in both rat strains. Administration of PCP or 8-OH-DPAT attenuated PPI in both strains, whereas apomorphine and amphetamine only attenuated PPI in Wistar rats. The ability of apomorphine to increase motor activity in the absence of a startle-eliciting stimulus was similar in the two strains, as was apomorphine-induced hyperlocomotion. A time course analysis of the effects of apomorphine on startle response in Sprague Dawley rats found that changes in the magnitude of PPI followed changes in basic startle amplitude. Similarly, no apomorphine-induced attenuation of PPI was observed in Sprague Dawley rats after 6-OHDA-induced DA receptor supersensitivity in the nucleus accumbens. These data suggest a dissociation between the effects of DA receptor agonists in PPI and other behavioral models of DA receptor activation.

It is thought that galanin, a 29 amino acid neuropeptide, is involved in various neuronal functions, including the regulation of food intake and hormone release. Consistent with this idea, galanin receptors have been demonstrated throughout the brain, with high levels being observed in the hypothalamus. However, little is known about the mechanisms by which galanin elicits its actions in the brain. Therefore, we studied the effects of galanin and its analogs on synaptic transmission using an in vitro slice preparation of rat hypothalamus. In arcuate nucleus neurons, application of galanin resulted in an inhibition of evoked glutamatergic EPSCs and a decrease in paired-pulse depression, indicating a presynaptic action. The fragments galanin 1-16 and 1-15 produced a robust depression of synaptic transmission, whereas the fragment 3-29 produced a lesser degree of depression. The chimeric peptides C7, M15, M32, and M40, which have been reported to antagonize some actions of galanin, all produced varying degrees of depression of evoked EPSCs. In a minority of cases, C7, M15, and M40 antagonized the actions of galanin. Analysis of mEPSCs in the presence of TTX and Cd2+, or after application of alpha-latrotoxin, indicated a site of action for galanin downstream of Ca2+ entry. Thus, our data suggest that galanin acts via several subtypes of presynaptic receptors to depress synaptic transmission in the rat arcuate nucleus.

The cellular mechanism underlying the genesis of the long-lasting alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor-mediated excitatory postsynaptic currents (EPSCs) at the mossy fiber (MF)-unipolar brush cell (UBC) synapse in rat vestibular cerebellum was examined with the use of whole cell and excised patch-clamp recording methods in thin cerebellar slices. Activation of MFs evokes an all-or-none biphasic AMPA-receptor-mediated synaptic current with a late component that peaks at 100-800 ms, which has been proposed to originate from an entrapment of glutamate in the MF-UBC synaptic cleft and is generated by the steady-state activation of AMPA receptors. Bath application of cyclothiazide, which blocks desensitization of AMPA receptors, produced a dose-dependent enhancement of the amplitude of the synaptic current (median effective dose 30 microM) and slowing of the rise time of the fast EPSC. N-methyl-D-aspartate-receptor-mediated EPSCs in UBCs were not potentiated in amplitude or time course by cyclothiazide (100 microM). The dose-response relations for the steady-state current evoked by glutamate acting at AMPA receptors in excised outside-out patches from UBC and granule somatic membranes was biphasic, peaking at 50 microM and declining to 50-70% of this value at 1 mM glutamate. When glutamate was slowly washed from patches to simulate the gradual decline of glutamate in the synapse, a late hump in the transmembrane current was observed in patches from both cell types. The delivery of a second MF stimulus at the peak of the slow EPSC evoked a fast EPSC of reduced amplitude followed by an undershoot of the subsequent slow current, consistent with the hypothesis that the peak of the slow EPSC reflects the peak of the biphasic steady-state dose-response curve. Estimates of receptor occupancy and glutamate concentration derived from the ratio of fast EPSC amplitudes, and the amplitude and polarity of the initial steady-state current in paired-pulse experiments, predict a slow decline of glutamate with a time constant of 800 ms, declining to ineffective concentrations at 5.4 s. Manipulation of cleft glutamate concentration by lowered extracellular calcium or delivery of brief stimulus trains abolished the slow EPSC and restored the undershoot to paired stimuli, respectively, in a manner consistent with a prolonged lifetime of glutamate in the cleft. The slow component of the EPSC was prolonged in duration by the glutamate reuptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate, suggesting that glutamate transport contributes to the time course of the synaptic current in UBCs. The data support the notion that the MF-UBC synapse represents an ultrastructural specialization to effectively entrap glutamate for unusually prolonged periods of time following release from MF terminals. The properties of the postsynaptic receptors and constraints on diffusional escape of glutamate imposed by synaptic ultrastructure and glutamate transporters act in concert to sculpt the time course of the resulting slow EPSC. This in turn drives a long-lasting train of action potentials in response to single presynaptic stimuli.

We examined the effects of peptides of the neuropeptide Y (NPY)/pancreatic polypeptide (PP) family on synaptic transmission in the arcuate nucleus in rat hypothalamic slices. Application of NPY produced two effects. In some cells NPY produced an outward current that had the properties of a K+ current. NPY also inhibited the evoked glutamatergic EPSC recorded in these arcuate neurons by a presynaptic mechanism. Although the effects of NPY on the K+ current reversed within a few minutes of washout of the peptide, its effects on the EPSC frequently were longer lasting (>30 min). Similar effects were observed using peptide YY or the NPY analog [Leu31, Pro34]NPY. Although K+ current activation by [Leu31,Pro34]NPY was blocked by the selective Y1 antagonist BIBP 3226, inhibition of the EPSC was blocked only partially. Other NPY-related peptides such as NPY(13-36), PP, and [D-Trp32]NPY also inhibited the EPSC. However, none of these peptides produced activation of the K+ current. Thus, activation of more than one NPY receptor produces synaptic inhibition in the arcuate nucleus. A Y1 receptor activates a K+ current postsynaptically, and several receptor types appear to inhibit the EPSC by a presynaptic mechanism.

Extracellular single-unit recording techniques were used to examine the firing characteristics of neurons in the medial septum/diagnol band of Broca complex (MS/DB) following injections of the 5-HT1A agonist, 8-OH-DPAT, into the median raphe nucleus (MRN) of urethane-anesthetized rats. It had previously been shown that MRN injections of 8-OH-DPAT produce hippocampal theta rhythm. Injections of 8-OH-DPAT into the MRN produced a change in firing characteristics of MS/DB neurons from an irregular discharge to a pattern of rhythmical bursting in synchrony with hippocampal theta rhythm. Cross-correlational and coherence analyses demonstrated that the rhythmical firing pattern of MS/DB neurons strongly correlated with rhythmical fluctuations in the hippocampal EEG during periods of hippocampal theta produced by 8-OH-DPAT injections, but not during baseline conditions (i.e. hippocampal desynchronization). The results suggest that MRN control of the hippocampal EEG is modulated by the MS/DB. Serotonergic projections from the MRN to the MS/DB may normally act to inhibit the rhythmical bursting of MS/DB neurons, thereby producing hippocampal desynchronization. Suppression of MRN 5-HT neurons by MRN injections of 8-OH-DPAT would disinhibit MS/DB neurons, allowing them to burst rhythmically and thereby produce hippocampal theta rhythm.

Recent evidence suggests that the supramammillary nucleus of the posterior hypothalamus serves as an important relay in a brainstem to septum/hippocampus pathway involved in the generation of hippocampal theta rhythm. In order to examine the role of the supramammillary nucleus as a possible relay/mediator of hippocampal theta rhythm, electrolytic lesions and procaine injections were administered to the supramammillary nucleus of freely moving and urethane-anesthetized rats, respectively. In the urethane-anesthetized rat, it was found that procaine injections attenuated both the frequency and amplitude of theta rhythm elicited by stimulation of the pontine reticular formation. These data suggest that the pontine reticular elicitation of hippocampal theta rhythm is mediated through connections with the supramammillary nucleus. However, it was found that lesions of the supramammillary nucleus failed to produce significant changes in the hippocampal electroencephalogram of freely moving animals. Several explanations concerning this apparent discrepancy are discussed. The most compelling is that multiple brainstem to septum/hippocampus pathways may serve to generate or facilitate the generation of theta rhythm in the freely moving animal. The present report demonstrates that the supramammillary nucleus plays a questionable role in the mediation of hippocampal electroencephalogram signals which are thought to be important for mnemonic processes.

The effects of experimental history on responding under a progressive-ratio schedule of reinforcement were examined. Sixteen pigeons were divided into four equal groups. Groups 1 to 3 were trained to peck a key for food under a fixed-ratio, variable-ratio, or differential-reinforcement-of-low-rate schedule of reinforcement. After training, these pigeons were shifted to a progressive-ratio schedule, later were shifted back to their original schedule (with decreased rates of reinforcement), and finally were returned to the progressive-ratio schedule. Pigeons in Group 4 (control) were maintained on the progressive-ratio schedule for the entire experiment. To test for potential "latent history" effects, pigeons responding under the progressive-ratio schedule were injected with d-amphetamine and given behavioral-momentum tests of prefeeding and extinction. Experimental histories affected responding in the immediate transition to the progressive-ratio schedule; response rates of pigeons with variable-ratio and fixed-ratio histories were higher than rates of pigeons with differential-reinforcement-of-low-rate and progressive-ratio-only histories. Pigeons with differential-reinforcement-of-low-rate histories, and to a lesser degree pigeons with variable-ratio and fixed-ratio histories, also had shorter postreinforcement pauses than pigeons with only a progressive-ratio history. No consistent long-term effects of prior contingencies on responding under the progressive-ratio schedule were evident. d-Amphetamine and resistance-to-change tests failed to reveal consistent latent history effects. The data suggest that history effects are sometimes transitory and not susceptible to latent influences.

Adult queens were treated with one of two sources of follicle stimulating gonodotropin (follicle stimulating hormone or pregnant mares' serum gonodotropin) to induce ovarian follicle development and estrus. Treatment involving single injections of follicle stimulating hormone stimulated mature follicle development but resulted in inconsistent display of sexual receptivity and variable ovulation rates. Single or multiple injections of pregnant mares' serum gonadotropin induced follicel growth, but follicle rupture often occurred prior to estrus and the mating stimulus. When compared to results obtained from queens mated while in natural estrus, cats receiving a series of injections of follicle stimulating hormone or pregnant mares' serum gonadotropin demonstrated ovarian hypersensitivity and produced follicular cysts which failed to rupture. The most effective hormone regimen for inducing follicle growth and estrus consisted of 2.0 mg follicle stimulating hormone injected daily intramuscularly until estrus. Queens receiving this treatment were capable of ovulating following mating or human chorionic gonodotropin administration and were capable of conceiving if mated.