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Schizophrenia is associated with robust white matter (WM) abnormalities but influences of potentially confounding variables and relationships with cognitive performance and symptom severity remain to be fully determined. This study was designed to evaluate WM abnormalities based on diffusion tensor imaging (DTI) in individuals with schizophrenia, and their relationships with cognitive performance and symptom severity. Data from individuals with schizophrenia (SZ; n=138, mean age±SD=39.02±11.82; 105 males) and healthy controls (HC; n=143, mean age±SD=37.07±10.84; 102 males) were collected as part of the Function Biomedical Informatics Research Network Phase 3 study. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were compared between individuals with schizophrenia and healthy controls, and their relationships with neurocognitive performance and symptomatology assessed. Individuals with SZ had significantly lower FA in forceps minor and the left inferior fronto-occipital fasciculus compared to HC. FA in several tracts were associated with speed of processing and attention/vigilance and the severity of the negative symptom alogia. This study suggests that regional WM abnormalities are fundamentally involved in the pathophysiology of schizophrenia and may contribute to cognitive performance deficits and symptom expression observed in schizophrenia., Competing Interests: Declaration of competing interest Dr. Nakahara is supported by Astellas, Inc. Dr. Potkin has financial interests in Bristol-Myers Squibb, Eisai, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Lundbeck, Merck, Novartis, Organon, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, Novartis, Lundbeck, Merck, Sunovion and has received grant funding from Amgen, Baxter, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Merck, Otsuka, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, NIAAA, NIBIB,NIH/NCRR, University of Southern California, UCSF, UCSD, Baylor College of Medicine. Dr. Preda consulted for Boehringer Ingelheim. Dr. Bustillo consulted with Novartis and Otsuka Pharmaceuticals. Dr. Mathalon is a consultant for Bristol-Myers Squibb. The remaining authors declare no potential conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

This study examined associations between resting-state amplitude of low frequency fluctuations (ALFF) and negative symptoms represented by total scores, second-order dimension (motivation and pleasure, expressivity), and first-order domain (anhedonia, avolition, asociality, alogia, blunted affect) factor scores in schizophrenia (n = 57). Total negative symptom scores showed positive associations with ALFF in temporal and frontal brain regions. Negative symptom domain scores showed predominantly stronger associations with regional ALFF compared to total scores, suggesting domain scores may better map to neural signatures than total scores. Improving our understanding of the neuropathology underlying negative symptoms may aid in addressing this unmet therapeutic need in schizophrenia., Competing Interests: Declaration of Competing Interest Dr. Daniel H. Mathalon consulted for Neurocrine Biosciences, Gilgamesh Pharmaceuticals, and Recognify Life Sciences, and served on a data safety monitoring/advisory board for Neurocrine Biosciences. The other authors have no conflict of interest to report., (Copyright © 2023. Published by Elsevier B.V.)

The rewetting of degraded peatlands has been adopted as a method to address climate change. Concerns have been raised about the effects of peat inundation and drying cycles, in more extreme climate events, on the potential release of nitrogen (N) species, in particular ammonium (NH 4 -N), once rewetted, as well as the physico-chemical and biological properties of the peat. This study used intact peat cores to measure the impact of two different cycles of peat inundation and drying (1 month and 2 month) over a total study duration of 56 weeks on the (1) NH 4 -N, nitrate-N (NO 3 -N) and dissolved reactive phosphorus (DRP) in the soil pore water; (2) microbial community structure; (3) physico-chemical properties of the peat; and (4) the structure of the peat, and therefore its ability to mitigate flood risks and storm surges. The study found that rewetted cores released NO 3 -N in the pore water up to a concentration of 6.25 mg L -1 , but had no appreciable impact on NH 4 -N, which remained below 1.7 mg L -1 over the study duration. DRP moved quickly though the upper layers of the cores, but physico-chemical analysis suggested it was adsorbed to more iron-rich soil, which was present at depths below 0.4 m in the cores. Time intervals between inundation produced no significant difference on the forms of inorganic N released, nor did it compact the soil or change the microbial community structure. The depth of the water table, however, had a significant impact on inorganic N release, particularly NO 3 -N, which indicates that this N species, and not NH 4 -N, may be problematic in rewetted peatlands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The HeartWare left ventricular assist device has been in use for over 12 years. We sought to determine how outcomes at our centre have improved over time., Methods: Review of electronic hospital records at the Freeman Hospital, Newcastle upon Tyne, United Kingdom., Results: A total of 255 first time adult implants were divided into 2 eras: Era 1: 2009-2015 (N = 154) and Era 2: 2016-2020 (N = 101). We prospectively aimed to avoid higher risk Intermacs Classifications in Era 2, which resulted in significant changes in Intermacs class to lower risk in Era 2 (P < 0.001). There was a significant improvement in survival in Era 2, with 1 year survival increasing from 70 to 80% (P < 0.05). This was particularly associated with lower 30 day mortality in Era 2 (1.7 ± 2.3 vs 15.5 ± 7%, P < 0.005). This was associated with better right ventricular function in Era 2, and there was a trend to more temporary right ventricular assist devices used in Era 2 (28 ± 13 vs 12 ± 14%, P = 0.06). Deaths from intracranial haemorrhage, sepsis and right heart failure were unchanged between eras, though there was a trend towards less deaths in Era 2 from combined thromboses deaths (stroke and device thrombosis; 3.3 ± 5.4 vs 11.1 ± 7.4%, P = 0.07)., Conclusions: Better patient selection in association with more use of temporary right ventricular assist support has resulted in a significant improvement in survival. Intracranial haemorrhage, sepsis and right heart failure remain significant problems., Competing Interests: Declaration of Competing Interest GMG and SS are consultants to Medtronic., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Mild traumatic brain injury (mTBI; concussion) is a common and costly public health concern that exhibits diverse patterns of recovery, making ascertainment of prognosis difficult. Interpersonal factors are critical determinants of health and linked to both adjustment to injury and illness and may critically impact mTBI outcomes. However, their potential role remains largely unexplored at present., Objectives: To provide a framework for incorporating interpersonal factors into the study and treatment of mTBI., Methods: We provide a narrative summary of the existing literature on adjustment to mTBI and present an overview of interpersonal biopsychosocial frameworks for adjustment to injury and illness., Results: We discuss ways of applying interpersonal framework models to the study of mTBI. In addition, we identified several factors or themes shared across frameworks that mTBI researchers and clinicians can integrate into their work. Finally, we discuss gaps in the literature and suggest directions for future research., Conclusions: Adding an interpersonal framework to established biopsychosocial models in mTBI would allow for novel opportunities for prediction of symptom course and for the development of novel interventions., (Copyright © 2020 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess whether subjective breast density categorization remains the most useful way to categorize mammographic breast density and whether variations exist across geographic regions with differing national legislation., Methods: Breast radiologists from two countries (UK, USA) were voluntarily recruited to review sets of anonymized mammographic images (n = 180) and additional repeated images (n = 70), totaling 250 images, to subjectively rate breast density according to the Breast Imaging Reporting and Data system (BI-RADS) categorization. Images were reviewed using standardized viewing conditions and Ziltron software. Inter-rater reliability was analyzed using the Kappa test., Results: The US radiologists (n = 25) judged fewer images as being "mostly fatty" than UK radiologists (n = 24), leading a greater number of images classified in the higher BI-RADS categories, particularly in BI-RADS 3. Overall agreement for all data sets was k = 0.654 indicating substantial agreement between the two cohorts. When the data were split into BI-RADS categories, the level of agreement varied from fair to substantial., Conclusion: Variations in how radiologists from the USA and UK classify breast density was established, especially when the data were divided into breast density categories. This variation supports the need for a reliable breast density assessment method to enhance the individualized supplemental screening pathways for dense breasts. The use of two-scale categorization method demonstrated improved agreement., Advances in Knowledge: Larger sample of radiologists from different breast density jurisdictions confirms international subjective variability in density categorization and improved agreement with the two-scale (low, high) categorization. With this variability, a standardized and automated breast density assessment shows to be timely., (Copyright © 2019. Published by Elsevier Inc.)

Recent identification of a cancer stem cell (CSC) phenotype in solid tumors has greatly enhanced the understanding of the mechanisms responsible for cancer cell metastasis. In keeping with Pagets 'seed and soil' theory, CSCs display dependence upon stromal derived factors found within the niche in which they reside. Inflammatory mediators act as a 'fertilizer' within this niche when interacting with CSCs at the tumor-stromal interface and can potentiate the metastatic ability of CSCs. Interestingly, the same components of the pro-inflammatory milieu experienced by cancer patients perioperatively are known to promote the metastagenic potential of CSCs. On the basis of this observation we discuss how surgery-induced inflammation potentiates colon CSC involvement in the metastatic process. We hypothesize that the high rates of recurrence and metastasis associated with tumor resection are potentiated by the effects of surgery-induced inflammation on CSCs. Finally we discuss potential therapeutic strategies for use in the perioperative window to protect cancer patients from the oncological effects of the pro-inflammatory milieu., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To examine the day-to-day reproducibility of the QT-variability index (QTVI) and the QT-apex variability index (QTaVI) in individuals with spinal cord injury (SCI)., Methods: Ten individuals with SCI participated in the current study (C2-T10; AIS A-D; 8.6 ± 7.8 years post-injury). On two occasions, with a 10-day interval, a 10-minute resting electrocardiogram was obtained from each participant. The QTVI and QTaVI were analyzed from 256 electrocardiographic beats from all participants, and a separate analysis was performed on those with injuries above the 4th thoracic level. An intraclass correlation coefficient (ICC) test was performed to measure day-to-day reproducibility of these measures and a Bland-Altman test was performed on all participants in order to examine the skewness of the measures., Results: The reproducibility values were found to be high for both the QTVI (all participants: R=0.892; above T4: R=0.893) and the QTaVI (all participants: R=0.908; above T4: R=0.915). In addition, the reproducibility of QTVI and QTaVI did not appear to be skewed as indicated by Bland-Altman plots., Conclusion: Both the QTVI and the QTaVI may be used as reproducible means of assessing cardiac autonomic function in individuals with SCI. Further, a reduction in cardiac sympathetic regulation after high thoracic and cervical level SCI does not appear to influence the day-to-day reproducibility of these measures., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Evidence in the literature shows that increasing the source to image-receptor distance (SID) can optimize specific radiographic projections; yet, despite this evidence base, the technique is not commonly practiced within all radiology departments. The present work aimed to bridge the gap between evidence and practice by interviewing allied health professionals to investigate the feasibility of implementing the technique in clinical practice. Opinions were sought from multiple sources to triangulate the data including radiographers, medical physicists, professional body council members, and university lecturers. Data were collected via telephone and departmental surveys, self-administered questionnaires, focus groups, and individual interviews. Analysis via keywords and themes was undertaken. Tradition, the capacity to change practice, and radiographic equipment were perceived as the main obstacles against clinical implementation. Seventy-five percent of radiographers working with modern equipment did not perceive any disadvantage to the radiographer in extending the SID by 30-50 cm compared with 59% of radiographers working with older equipment. However, when radiographer perceptions of implementing the technique were analysed, 100% of radiographers responded positively to increased SID implementation, especially "if given more information." The key to effective clinical implementation is to adopt a multidisciplinary approach and to actively disseminate information among hospital management and radiographers. There are no insurmountable issues preventing the implementation of the increased SID technique in clinical practice, and encouraging radiographers to explore optimization strategies has the potential to advance evidence-based practice within the profession., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate the prognostic value and test characteristics of coronary artery calcium (CAC) score for the identification of obstructive coronary artery disease (CAD) in comparison with coronary computed tomography angiography (CCTA) among symptomatic patients., Methods: Retrospective cohort study at two large hospitals, including all symptomatic patients without prior CAD who underwent both CCTA and CAC. Accuracy of CAC for the identification of ≥ 50% and ≥ 70% stenosis by CCTA was evaluated. Prognostic value of CAC and CCTA were compared for prediction of major adverse cardiovascular events (MACE, defined as non-fatal myocardial infarction, cardiovascular death, late coronary revascularization (>90 days), and unstable angina requiring hospitalization)., Results: Among 1145 included patients, the mean age was 55 ± 12 years and median follow up 2.4 (IQR: 1.5-3.5) years. Overall, 406 (35%) CCTA were normal, 454 (40%) had <50% stenosis, and 285 (25%) had ≥ 50% stenosis. The prevalence of ≥ 70% stenosis was 16%. Among 483 (42%) patients with CAC zero, 395 (82%) had normal CCTA, 81 (17%) <50% stenosis, and 7 (1.5%) ≥ 50% stenosis. 2 (0.4%) patients had ≥ 70% stenosis. For diagnosis of ≥ 50% stenosis, CAC had a sensitivity of 98% and specificity of 55%. The negative predictive value (NPV) for CAC was 99% for ≥ 50% stenosis and 99.6% for ≥ 70% stenosis by CCTA. There were no adverse events among the 7 patients with zero calcium and ≥ 50% CAD. For prediction of MACE, the c-statistic for clinical risk factors of 0.62 increased to 0.73 (p < 0.001) with CAC versus 0.77 (p = 0.02) with CCTA., Conclusion: Among symptomatic patients with CAC zero, a 1-2% prevalence of potentially obstructive CAD occurs, although this finding was not associated with future coronary revascularization or adverse prognosis within 2 years., (Published by Elsevier Ireland Ltd.)

Objective: We evaluated family history as a predictor of incident and progressive coronary artery calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA)., Background: MESA is a multi-center prospective study of 6814 asymptomatic individuals. The relationship between family history of coronary heart disease (CHD) and CAC incidence or progression has not been described previously., Methods: A total of 5099 participants had detailed information about family history of CHD (late versus premature and parental versus sibling history). The mean time between CAC scans was 3.1 ± 1.3 years. The association of late versus premature family history was assessed against CAC change using multivariate regression model adjusted for demographics and cardiac risk factors., Results: A family history of premature CHD was associated with an odds ratio (OR) of 1.55 (p < 0.01) for incident development of CAC after adjusting for risk factors and demographics. A premature family history was associated with 14.4 units (p < 0.01) greater volume scores compared to those with no family history in similarly adjusted models by median regression analysis. A combined parental and sibling family history was associated with the greatest incidence and progression in demographic-adjusted models. Caucasians demonstrated the most consistent predictive relationship between family history of premature CHD and incidence (p < 0.01) and progression (p < 0.05) of CAC, though no significant interaction with ethnicity was noted., Conclusions: Family history of premature CHD is associated with enhanced development and progression of subclinical disease, independent of other risk factors, in a multiethnic, population-based study., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

This investigation proposes that an increased source to the image-receptor distance (SID) technique can be used to optimize occipital frontal and lateral cranial radiographs acquired with direct digital radiography. Although cranial radiography is not performed on a routine basis, it should nonetheless be optimized to keep the dose to the patient as low as reasonably achievable, particularly because it can form part of the facial bone and sinus series. Dose measurements were acquired at various SIDs, and image quality was assessed using visual grading analysis. Statistically significant reductions in the effective dose between 19.2% and 23.9% were obtained when the SID was increased from the standard 100 to 150 cm (P ≤ .05), and visual grading analysis scores indicate that image quality remained diagnostically acceptable for both projections. This investigation concludes that increasing the SID effectively optimizes occipital frontal and lateral skull radiographs. Radiology departments must be advised of the benefits of this technique with the goal of introducing an updated reference SID of 150 cm into clinical practice., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Selecting the correct tibial nail length is essential for satisfactory outcomes. Nails that are inserted and are found to be of inappropriate length should be removed. Accurate preoperative nail estimation has the potential to reduce intra-operative errors, operative time and radiation exposure., Methods: We compared the most commonly used radiological, anthropometric and intra-operative techniques to determine ideal nail lengths for 16 paired cadaveric tibiae. Five different anthropometric measurements were taken from each intact cadaver including: knee joint line to ankle joint line distance (JJD), medial knee joint line to medial malleolus distance (MMD), tibial tuberosity to medial malleolus distance (TMD), olecranon to 5th metacarpal head distance (OMD) and body height (BHR). Each tibia also underwent antero-posterior (AP) and lateral scanograms. Computerised tomography was used to determine the ideal nail length for each tibia. Each anthropometric and radiological measurement was recorded by two orthopaedic surgeons independently. An expert tibial nail was then inserted after nail length estimation was performed using a guidewire technique and an intra-operative radiographic ruler., Results: The AP scanogram was found to be 100% accurate in selecting ideal nail length. The lateral scanogram was also found to be reasonably accurate but in 19% (3/16) of cases it led to a nail being too long. The intra-operative radiographic ruler was found to give a good indication of the ideal nail size, as did the guidewire technique, with only 6% (1/16) of cases producing an incorrect nail size. In general, the anatomical measurements gave a poor indication of ideal nail size compared with the other techniques. The following accuracies were noted: JJD 56%, MMD 50%, TMD 38%, BHR 13% and OMD 56%., Conclusions: We found that radiological methods such as using an AP radiograph with known magnification and intra-operative radiographic ruler were able to predict nail length very accurately and we suggest that these measurements should be performed routinely. The guidewire technique was also effective but we recommend that it not be used in isolation as errors can occur. We found that anatomical measurements are not accurate for predicting tibial nail length., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Traditionally, surgical education has been confined to operating and lecture theaters. Access to the World Wide Web and services, such as YouTube and iTunes has expanded enormously. Each week throughout Ireland, nonconsultant hospital doctors work hard to create presentations for surgical teaching. Once presented, these valuable presentations are often never used again., Aims: We aimed to compile surgical presentations online and establish a new online surgical education tool. We also sought to measure the effect of this educational tool on surgical presentation quality., Methods: Surgical presentations from Cork University Hospital and Beaumont Hospital presented between January 2010 and April 2011 were uploaded to http://www.pilgrimshospital.com/presentations. A YouTube channel and iTunes application were created. Web site hits were monitored. Quality of presentations was assessed by 4 independent senior surgical judges using a validated PowerPoint assessment form. Judges were randomly given 6 presentations; 3 presentations were pre-web site setup and 3 were post-web site setup. Once uploading commenced, presenters were informed., Results: A total of 89 presentations have been uploaded to date. This includes 55 cases, 17 journal club, and 17 short bullet presentations. This has been associated with 46,037 web site page views. Establishment of the web site was associated with a significant improvement in the quality of presentations. Mean scores for pre- and post-web site group were 6.2 vs 7.7 out of 9 respectively, p = 0.037., Conclusions: This novel educational tool provides a unique method to enable surgical education become more accessible to trainees, while also improving the overall quality of surgical teaching PowerPoint presentations., (Copyright © 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. This study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD., Design: Population-based, cross-sectional epidemiologic study., Participants: Nine hundred twenty-seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis., Methods: Diabetic retinopathy was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision-threatening DR (VTDR) was defined as severe nonproliferative DR, proliferative DR, or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score of 400 or more; low ankle-brachial index (ABI), defined as ABI of less than 0.9; high ABI, defined as ABI of 1.4 or more; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as more than 25% stenosis or presence of carotid plaque., Main Outcome Measures: Associations between DR and subclinical CVD measures., Results: The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively, and VTDR was associated with a high CAC score (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.15-4.73), low ABI (OR, 2.54; 95% CI, 1.08-5.99), and high ABI (OR, 12.6; 95% CI, 1.14-140.6) after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, antihypertensive, and cholesterol-lowering medications. Diabetic retinopathy was not significantly associated with measures of carotid artery disease., Conclusions: In persons with diabetes without a history of clinical CVD, the presence of advanced-stage DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score., Methods: In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT., Results: The prevalence of TAC was 28% (n=1846) and the mean maximum (+SD) CIMT was 0.87+/-0.19mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, p<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups., Conclusions: Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.

Objective: The vestibular system is a major pathway to nausea and vomiting, and the vestibuloocular reflex (VOR) is a central component; its function can be studied using the vestibular autorotation test (VAT). We hypothesize that women with hyperemesis gravidarum (HG) may have VOR abnormalities., Study Design: Women with HG were compared with women without HG using the VAT. Horizontal and vertical VOR gains and phases were evaluated at 3 frequency ranges: low (2.0 to 3.5 Hz), medium (greater than 3.5 to 5.0 Hz), and high (greater than 5.0 to 6.0 Hz) during pregnancy and postpartum., Results: Twenty women with HG and 48 unaffected women were evaluated in early pregnancy. Women with HG had higher horizontal gains at all 3 frequency ranges. Horizontal phase differences were also observed at medium frequencies. No VAT differences were noted postpartum., Conclusion: Women experiencing HG had a higher mean VOR horizontal gain and lower horizontal phase when compared with unaffected women.

The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.

Background: The goal of this study was to compare the extent of cognitive deficits between adolescents and adults early in the course of schizophrenia., Methods: A comprehensive neuropsychological battery was performed on 49 adolescents with childhood- or adolescent-onset schizophrenia, 139 adults with adult-onset schizophrenia, 32 healthy adolescent volunteers, and 240 healthy adult volunteers. Both patient groups were assessed early in the course of their illness and were matched to their respective control groups on age and parental education., Results: The adolescent patients performed significantly worse than the adult patients on tasks of working memory, language, and motor function. The healthy adolescents also performed significantly worse than the healthy adults in working memory and language tasks but were significantly better than the adults in motor function. When accounting for developmental differences in the control group, only motor performance was worse in the adolescent patients compared with the adult patients., Conclusions: These findings, when coupled with published retrospective studies reporting greater cognitive deficits in earlier onset schizophrenia, implicate a cessation in development in specific cognitive domains following the onset of schizophrenia in adolescent patients.

Progression of coronary artery disease was initially evaluated using quantitative coronary angiography with ensuing evidence indicating a strong relationship to adverse cardiovascular outcomes. Since then, several other atherosclerosis imaging techniques have emerged as new tools in cardiovascular medicine to evaluate the effectiveness of preventive therapies through serial monitoring of changes in atherosclerosis burden. Conducting large randomized trials to test new approaches for the medical management of atherosclerosis, with the goal of showing a reduction in event rates, may often be impractical in an era of cost containment and reduced societal resources. Recent evidence has unfolded that investigates alternative ways of assessing therapeutic results such as the attainment of surrogate goals with substantial outcome relevance. Atherosclerosis imaging modalities such as coronary computed tomography, carotid ultrasound, cardiovascular magnetic resonance imaging, and intravascular ultrasound each possess specific imaging abilities and inter-test characteristics that enable their serial use as intermediate endpoints in clinical trials and, increasingly, in individual patient management. The current review focuses on the application of these modalities as emerging tools in cardiovascular prevention.

Total integrated muscle sympathetic nerve activity (MSNA) is composed of bursts that vary in both frequency and amplitude. Various quantifiable indices are currently used to characterize MSNA and its reflex-mediated responses. However, a comprehensive and systematic analysis on the test-retest repeatability of these measures has not been conducted. Therefore, the purpose of this study was to compare the consistency of supine and passive head-up tilt-mediated sympathetic nerve activity using different descriptors of MSNA and a statistical paradigm that included Model II ordinary least products (OLP) regression, Bland-Altman method of differences, and analysis of variance. MSNA (microneurography), stroke volume (SV, Doppler), and arterial blood pressure (ABP, Finapres) were measured during repeated supine and 60 degrees head-up tilt (HUT) conditions separated by a minimum of 3 weeks. MSNA was quantified using; burst frequency (and incidence), burst amplitudes (and total integrated activity) normalized to the largest absolute amplitude within each posture, and calculated percent changes (from supine) in absolute burst amplitude and total integrated activity. Most indices of MSNA showed excellent test-retest repeatability during both postures with neither fixed nor proportional bias. However, MSNA expressed as burst incidence demonstrated both fixed and proportional bias in the supine position, but not during HUT. In addition, HUT-induced percent changes in absolute burst amplitude and total activity displayed a fixed bias with greater increases during the second test (P<0.05). The hemodynamic variables associated with the reflex responses were quite similar between tests (i.e., no bias). It was concluded that, with the exception of burst incidence, the majority of MSNA indices provided reliable markers of sympathetic activity on repeated tests. However, care must be taken when using percent changes in MSNA that incorporate absolute amplitudes.

Using a proprietary technology known as the X-ACT system--Active-metering, Cyclone-separator Technology, a novel multi-dose inhaler (Airmax) was developed to provide accurate and consistent dosing and a high-fine particle fraction ofthe drug. Formoterol, present as a blend with lactose monohydrate was delivered from Airmax to obtain a nominal formoterol dose of 6 or 12 microg. The devices were tested using a five-stage liquid impinger and a unit dose sampling apparatus, operated under conditions specified in European Pharmacopoeia (2000). Fine-particle dose (FPD) was defined as the dose of the aerosolized drug particles with an aerodynamic diameter < 5 microm and fine particle fraction (FPF) was the ratio of FPD to the total recovered dose. Dose per actuation was found to be 97.0+/-11.5% label claim (LC) or 5.8+/-0.7 microg (n = 140), and 100+/-9.4% LC or 12+/-1.1 microg (n=440), for the 6 and 12 microg strengths, respectively. The mass median aerodynamic diameter was 2.4+/-0.1 microm (n = 14), the geometric standard deviation 2.1+/-0.1 (n = 14), and FPF 44.4+/-24% (n= 14) for both strengths. Thus, the combination of active metering and cyclone separator produces highly consistent doses of formoterol that have a large respirable fraction.

A novel multi-dose inhaler has been developed to closely approach the characteristics of an "ideal" inhaler. The new device, Airmax, uses proprietary technologies known as the X-ACT system to provide accurate and consistent dosing and excellent lung deposition--even at low inspiratory flow rates--combined with ease of use by the patient. Dose delivery was close to label claim, with relative standard deviation of typically around 5% for through-life emitted mass and around 10% for dose per actuation. At a flow rate (60-70 l/min), which corresponds to 4 kPa pressure drop across the device, the mean fine particle (<5 microm) dose (FPD) from 100, 200 and 400 microg strength budesonide Airmax was around 46, 98 and 244 microg, respectively. The mean FPD from 100 microg strength salbutamol Airmax was approximately 50 microg at the same flow rate. At 30 l/min, the delivered dose from Airmax is over 85% label claim with fine particle fraction of over 35%. Performance was unaffected by shaking or orientation, provided the device was not used completely upside down, and priming was not required. There was no change in dose content uniformity and aerodynamic particle-size distribution after the devices have been stored unwrapped at 30 degrees C/60% RH up to 24 months. Airmax is robust, portable and intuitive to use.

Background: Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function., Methods: Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow., Results: Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol., Conclusions: The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.

Background: Previous research suggests that schizophrenia may result from disruptions in a cortico-cerebellar-thalamic-cortical circuit (CCTCC) producing a mental incoordination or "cognitive dysmetria." To further evaluate the cerebellar contribution to this disrupted circuitry, medication-free patients with schizophrenia completed classical eyeblink conditioning, a cerebellar-mediated learning task., Methods: For classical eyeblink conditioning, 70 trials with a tone conditioned stimulus (CS) and air puff unconditioned stimulus (US) were presented to 15 patients with schizophrenia and 15 healthy control subjects. Acquisition rate for the conditioned response (CR) and response timing were compared between the two groups., Results: Patients with schizophrenia displayed facilitated conditioning compared to control subjects based on a greater number of CRs during the session and a faster acquisition of the learned response., Conclusions: Facilitated conditioning suggests that an enhanced excitability in the cerebellum occurs as part of a disrupted CCTCC in schizophrenia. The enhanced cerebellar-mediated associative learning may be maladaptive in the context of normal cerebro-cerebellar interactions, leading to the characteristic motor and mental incoordination of the disorder. Classical eyeblink conditioning may provide a useful model system for studying cerebellar involvement in the pathogenesis and treatment of schizophrenia.

Background: Previous structural studies of the frontal lobe in schizophrenia have had somewhat inconsistent results, but most of them have measured the frontal lobe as a single brain structure. To investigate more specific abnormalities in frontal subregions, we measured gray matter volume and cortical surface size in 10 subregions in drug-naive patients during the early stages of the illness., Methods: Magnetic resonance imaging was used to measure frontal subregions in 34 healthy male volunteers, and 26 male, drug-naive schizophrenia patients at early stages of the illness. Frontal subregions were manually traced using our locally developed parcellation method., Results: Patients with schizophrenia had a significant deficit in cortical surface size in the right straight gyrus and left orbitofrontal cortex. No differences were found in gray matter volumes., Conclusions: Frontal structural abnormalities found in drug-naive schizophrenic patients appear to be subtle and circumscribed to ventral portions. Anomalies in the cortical surface size suggest neurodevelopmental abnormalities might occur during the early stages of the gyrogenesis. Further investigations are needed to explore the implications of paralimbic ventral frontal regions (i.e., straight gyrus and orbitofrontal cortex) in the pathophysiology of schizophrenia.

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical-thalamic-cerebellar-cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Thalamocortical axons (TCAs), which originate in dorsal thalamus, project ventrally in diencephalon and then dorsolaterally in ventral telencephalon to their target, the neocortex. To elucidate potentially key decision points in TCA pathfinding and hence the possible localization of guidance cues, we used DiI-tracing to describe the initial trajectory of TCAs in mice. DiI-labeled TCAs extend ventrally on the lateral surface of ventral thalamus. Rather than continuing this trajectory onto the lateral surface of the hypothalamus, TCAs make a sharp lateral turn into ventral telencephalon. This behavior suggests that the hypothalamus is repulsive and the ventral telencephalon attractive for TCAs. In support of this hypothesis, we find that axon outgrowth from explants of dorsal thalamus is biased away from hypothalamus and toward ventral telencephalon when cocultured at a distance in collagen gels. The in vivo DiI analysis also reveals a broad cluster of retrogradely labeled neurons in the medial part of ventral telencephalon positioned within or adjacent to the thalamocortical pathway prior to or at the time TCAs are extending through it. The axons of these neurons extend into or through dorsal thalamus and appear to be coincident with the oppositely extending TCAs. These findings suggest that multiple cues guide TCAs along their pathway from dorsal thalamus to neocortex: TCAs may fasciculate on the axons of ventral telencephalic neurons as they extend through ventral thalamus and the medial part of ventral telencephalon, and chemorepellent and chemoattractant activities expressed by hypothalamus and ventral telencephalon, respectively, may cooperate to promote the turning of TCAs away from hypothalamus and into ventral telencephalon., (Copyright 1999 Academic Press.)

The purpose of the present study was to investigate putative neural substrates of long-term (delayed) memory in schizophrenia and young healthy controls. Ten "low" and 10 "high" memory patients were selected from a large sample of DSM-III-R diagnosed schizophrenia spectrum patients, based on composite verbal and nonverbal delayed recall memory scores. Ten "low" and 9 "high" memory individuals were also selected from a larger sample of young healthy controls. Magnetic resonance imaging scans were acquired on a 1.5-T GE Signa scanner using a SPGR sequence (repetition time = 24 msec, echo time = 5 msec). Hippocampal volumes were computed from manual tracings (intraclass correlation = .96), and temporal lobe and whole brain tissue volumes were obtained using a semiautomated technique. In both the patient sample and controls, there was no significant relationship between delayed memory ability and hippocampal, temporal lobe, or whole brain volume. The integration of results from this study, and from studies on normal aging and Alzheimer's disease, supports a model suggesting that hippocampal size may be an indicator of long-term memory ability, but only when hippocampal measures reflect aging and degenerative hippocampal atrophy. If the hippocampal measures reflect individual differences in hippocampal size prior to the onset of hippocampal atrophy, then hippocampal size does not appear to predict long-term memory ability.

Molecular gradients have been postulated to control the topographic mapping of retinal axons in their central targets. Based initially on their expression patterns, and more recently on functional studies, members of the EphA subfamily of receptor tyrosine kinases and their ephrin-A ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum. The report that a receptor of the EphB subfamily, EphB2/Cek5/Nuk/Sek3, is expressed in a high ventral to low dorsal gradient in the developing chick retina and is present on ganglion cell axons suggests that it may be involved in the mapping of retinal axons along the corresponding dorsal-ventral axis of the tectum. To address this issue, we have determined the expression and distribution of ephrin-B1/LERK-2/Cek5-L and ephrin-B2/LERK-5/Htk-L/ELF-2, ligands for EphB2, in the developing chick retinotectal system using riboprobes, immunocytochemistry, and receptor affinity probes. Both ephrin-B1 and ephrin-B2 transcripts are expressed in a high dorsal to low ventral gradient in the developing retina, complementary to the distribution of EphB2. Ephrin-B1 and ephrin-B2 proteins are predominantly found in the developing plexiform layers, suggesting a role in the development of intraretinal connections. Neither protein is detected on ganglion cell axons. In tectum, ephrin-B1 transcripts are expressed in a high dorsal to low ventral gradient in the neuroepithelium and the protein is present along the processes of radial glia and is concentrated at their endfeet in the stratum opticum, at the time retinal axons are growing through it. This distribution of ephrin-B1 suggests that it influences retinal axon mapping along the dorsal-ventral tectal axis and may also be involved in intratectal development. In contrast, ephrin-B2 transcripts and protein are localized to the deeper retinorecipient laminae in the tectum at the time retinal axons begin to arborize in them, suggesting that this ligand may influence the laminar patterning of retinal axon terminations., (Copyright 1997 Academic Press.)

Background: There have been reports that patients with schizophrenia have decreased metabolic activity in prefrontal cortex. However, findings have been confounded by medication effects, chronic illness, and difficulties of measurement. We aimed to address these problems by examination of cerebral blood flow with positron emission tomography (PET)., Methods: We studied 17 neuroleptic-naïve patients at the early stages of illness by means of image analysis and statistical methods that can detect abnormalities at the gyral level., Findings: An initial omnibus test with a randomisation analysis indicated that patients differed from normal controls at the 0.06 level. In the follow-up analysis, three separate prefrontal regions had decreased perfusion (lateral, orbital, medial), as well as regions in inferior temporal and parietal cortex that are known to be anatomically connected. Regions with increased perfusion were also identified (eg, thalamus, cerebellum, retrosplenial cingulate), which suggests an imbalance in distributed cortical and subcortical circuits., Interpretation: These distributed dysfunctional circuits may form the neural basis of schizophrenia through cognitive impairment of the brain, which prevents it from processing input efficiently and producing output effectively, thereby leading to symptoms such as hallucinations, delusions, and loss of volition.

Recent studies demonstrated associations between occlusive vascular disease and hyperhomocysteinemia of both genetic and nutritional origin. In the present study we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to B vitamins and prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely associated with intakes of folate and vitamin B-6, but not vitamin B-12. Prevalence of high homocysteine (>14 micromol/l) was 29.3% in this cohort, and inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Prevalence of stenosis > or = 25% was 43% in men and 34% in women with an odds ratio of 2.0 for individuals in the highest homocysteine quartile (> or = 14.4 micromol/l) compared with those in the lowest quartile (< or = 9.1 micromol/l), after adjustment for sex, age, high density lipoprotein cholesterol, systolic blood pressure and cigarette smoking (Ptrend < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and folate intake were inversely associated with extracranial carotid stenosis after adjustment for age, sex and other risk factors.

Regional cerebral blood flow (rCBF) was measured using positron emission tomography with oxygen- 15 labeled water as 10 normal subjects listened to three types of auditory stimuli (environmental sounds, meaningless speech, and words) presented binaurally or dichotically. Binaurally presented environmental sounds and words caused similar bilateral rCBF increases in left and right superior temporal gyri. Dichotically presented stimuli (subjects attended to left or right ears) caused asymmetric activation in the temporal lobes, resulting from increased rCBF in temporal lobe regions contralateral to the attended ear and decreased rCBF in the opposite hemisphere. The results indicate that auditorily presented language and non-language stimuli activate similar temporal regions, that dichotic stimulation dramatically changes rCBF in temporal lobes, and that the change is due both to attentional mechanisms and to hemispheric specialization.

Cardiovascular and all-cause mortality are higher in black than white Americans, but racial differences in clinical and subclinical cardiovascular disease (CVD) have not been examined in older adults. Clinical and subclinical CVD and its risk factors were compared in 4926 white and 244 black men and women aged 65 years and older. Black participants had lower socioeconomic status and generally higher prevalences of CVD and its risk factors, except for adverse lipid profiles. Common carotid wall thickness was greater in black than white women, and ankle-arm blood pressure ratios were lower in black women and men (p < 0.01). After adjustment for CVD risk factors, common carotid walls were significantly thicker and ankle-arm ratios were lower in blacks than whites of both sexes, while internal carotid walls were significantly thinner in black women. Racial differences in clinical and subclinical CVD in older adults are similar to those reported in younger populations and do not appear to be explained by CVD risk factors.

The syndrome of schizophrenia presents with a complex array of symptoms that are difficult to explain at the neural level. Data collected using magnetic resonance (MR) and positron emission tomography (PET) suggest that this complex array could occur as a consequence of misconnections and mismatches in midline circuitry that is reticular-thalamic-cingulate-cortical. MR studies have shown a variety of abnormalities, including callosal agenesis, cavum septi pellucidi, decreased thalamic size, decreased frontal size, and changes in signal intensity in white matter tracts between the thalamus and the frontal cortex. PET studies using a dichotic listening paradigm suggest that patients suffering from schizophrenia have brain blood flow abnormalities consistent with a difficulty in focusing or shifting attention, which may reflect the functional substrate of the anatomic abnormalities.

The topographically ordered retinocollicular projection in rats emerges from an initially diffuse projection present in neonates through the elimination of aberrantly positioned axons and arbors. We explore developmental plasticity in this process by making partial retinal lesions at birth and determining the topographic mapping of the remaining retina at later ages when the map normally has a mature, retinotopic order. In normal mature rats, DiI focally injected into the retina labels axons that form a dense focus of overlapping arbors at the topographically correct location in the superior colliculus (SC). Similar injections in rats with partial retinal lesions label axons that form two discrete foci of arborizations; one at the topographically appropriate region of the SC and another in the region of the SC deprived of its normal retinal input by the retinal lesion. A focal injection of DiI into the "deprived" SC region retrogradely labels ganglion cells widely scattered in the retina. Therefore, a partial retinal lesion in developing rats does not lead to an orderly expansion of the remaining retinal projection to cover the entire SC, as it does in amphibians and fish following optic nerve regeneration. Rather, in rats, the remaining partial retina forms two distinct, contiguous projections to the SC: a retinotopically ordered one that retains normal topographic relationships and an aberrant, diffusely ordered one to the SC region topographically matched with the lesioned part of the retina. This abnormal persistence of topographically aberrant axons and arbors indicates that competitive interactions between retinal axons drive the remodeling of the initially diffuse retino-collicular projection into a topographically ordered one.

In adult rats, layer 5 cortical neurons send axons through the corpus callosum to contralateral cortex or through the internal capsule to subcortical targets, but individual neurons reportedly do not have both connections. Here we confirm this adult separation and address whether it develops by extension of axon collaterals to both sets of targets with later elimination of one or the other (a phenomenon common in developing cortex) or by initially selective axon outgrowth. Retrograde tracers Fast Blue and Diamidino Yellow were injected in the subcortical path at the pyramidal decussation and in the contralateral cortex, respectively, of adult and newborn rats. In 16 adults, no cortical neurons were double-labeled, indicating that none project to both sites. In 17 neonates, hundreds of thousands of layer 5 neurons were single-labeled in each brain, but only one was double-labeled. In cases in which the injections to one of the two targets was delayed, again, no double-labeled cells were found. These results indicate that the connectional distinction found in adults is not achieved by the elimination of long transient callosal or subcortical collaterals. To determine if shorter transient collaterals are extended by callosal neurons into the internal capsule, i.e., the subcortical pathway, we injected DiI into one cortical hemisphere of aldehyde-fixed Embryonic Day (E)19 and E21 brains. Two types of axons are seen in the white matter of the cortex opposite the injection: those which turn and extend through the callosum and those which branch, sending collaterals to both ipsilateral and contralateral cortex. Rarely were collaterals seen to extend into or toward the internal capsule. [3H]Thymidine birthdating studies show that layer 5 callosal and subcortically projecting neurons are generated at the same stage of corticogenesis. Thus, from early stages of axon extension, callosal and subcortically projecting cells are distinct classes of neurons and, responding differentially to cues present in cortex, initiate growth toward class-specific and nonoverlapping sets of targets. We conclude that the distinction between the two projection classes in inherent to them and is likely to be determined at an early stage of cortical development, prior to neuronal migration from the neuroepithelium.

The Cardiovascular Health Study (CHS) is a longitudinal population-based study of coronary heart disease and stroke in men and women 65 years and older. The initial CHS cohort consisted of 5201 men and women recruited from a random sample of the Health Care Financing Administration (HCFA) Medicare eligibility lists in four communities in the United States. Extensive historical, physical, and laboratory evaluations were performed at the baseline examination in 1989 to 1990 to identify risk factors and subclinical disease. Periodic contacts are carried out to ascertain and verify incident cardiac and stroke events and their sequelae. Since only a short time has passed since entry of all the patients into the study, data are not available on time trends in the mortality rate of stroke, but we expect to contribute in this area in the years ahead. This article then is a description of the CHS, of methods of assessing stroke in the CHS cohort, and of prevalence of stroke and transient ischemic attacks at the initial examination.

We studied the relationship between extracranial carotid atherosclerosis as measured by high-resolution carotid sonography and serum total cholesterol and high-density-lipoprotein cholesterol (HDL-C) levels which were determined at the time of carotid sonography and 8 years previously in 1189 members of the Framingham cohort, aged 66 to 93 years. Among participants, no carotid disease was found in 30%; 1 to 49% stenosis, in 62%; 50 to 74% stenosis, in 5%; 75 to 99% stenosis, in 2%; and 100% stenosis, in 1%. Total cholesterol measured 8 years prior to the carotid examination showed a strong positive association with the occurrence of stenosis in both men and women. There was no association between concurrently measured cholesterol levels and stenosis for either men or women. For women there was a strong association between both the 8-year HDL-C level and the concurrently measured HDL-C level and the degree of carotid stenosis. For men, neither concurrent nor 8-year HDL-C measurements were significantly related to carotid stenosis. These results suggest that there is a time lag between the observation of an elevated cholesterol level and its expression as an increased degree of carotid atherosclerosis.

We have studied in rats the topographic targeting of retinocollicular axons anterogradely labeled by focal retinal injections of the axon tracer DiI. We find that developing retinal axons widely mistarget along both the medial-lateral and the rostral-caudal axes of the superior colliculus (SC). In neonatal rats, labeled axons originating from injection sites in the temporal periphery covering less than 1% of the retina grow over most of the contralateral SC, suggesting that the growth cones of many axons initially fail to recognize their appropriate target region at the rostral SC border. Some of these axons correct their targeting errors and are retained; most do not and are eliminated. In neonates, peripheral nasal axons transiently develop branches throughout the SC. Branches formed by nasal axons are later restricted to a discrete terminal zone at the topographically appropriate, caudal SC border. At the neonatal stage, injections in temporal or nasal retina do result in a zone of increased labeling in the topographically correct region of the SC, but this zone is considerably larger than that labeled by a similar injection at a later stage. Thus, although the early projection is very diffuse, there is some bias for the correct region of the SC. Our findings indicate that in rats, developing retinal axons show only a limited specificity in their topographic targeting and branching. We conclude that mechanisms in addition to directed axon growth are required to establish the order characteristic of mature mammalian retinal projections.

Late failure of synthetic vascular grafts to small-diameter arteries (less than or equal to 4 mm) is commonly due to anastomotic hyperplasia. Theoretic analysis suggests that conformational changes at the anastomosis lead to high localized arterial wall stress caused by increases in radius of curvature of the artery (law of Laplace: tension = pressure X radius). Nine 3 kg rabbits had a plastic insert implanted into the infrarenal aorta. The insert was designed to recreate the conformational changes caused by the anastomosis of a synthetic graft to a small-diameter artery, without significantly altering blood flow. The increase in arterial wall tension created by the insert was calculated to be 80% to 100% over baseline values. Aortography, real-time ultrasound, and computed tomography (CT) scanning were done to confirm the absence of luminal thrombus formation or migration of the insert. Ultrasound and CT scans also confirmed the desired conformational changes in the aorta at the site of the insert. Aortas, with the inserts in place, were removed from 3 days to 6 months after implantation. Implantation times of 1 to 6 months resulted in a hyperplastic subintimal lesion characterized by fibrous tissue deposition, spindle cells (which may have been fibroblasts), and/or smooth muscle cells covered by endothelium. In contrast, two rabbits that had the insert placed and then removed at 1 minute and were allowed to survive for 37 and 72 days, respectively, demonstrated complete healing of the aorta without anastomotic hyperplasia. The arterial wall conformational changes induced in this experiment led to the formation of a lesion consistent with anastomotic hyperplasia. An increase in wall tension may have been the stimulus for this response. Prevention of anastomotic hyperplasia may require a means of uniting a graft to an artery without increasing wall tension.

The ability of high-resolution ultrasound, angiography, and pathologic examination of endarterectomy specimens to identify and quantitate atherosclerosis was compared in a five-center study. The carotid bifurcation in 900 patients was evaluated by angiography and ultrasound. In 216 cases, high-quality endarterectomy specimens were available for comparison with the preoperative images. All comparisons were made in a blinded fashion. Results indicate that ultrasound is able to differentiate angiographically normal from abnormal arteries with a sensitivity of 88% (1077 of 1233 arteries) and accuracy of 79% (1251 of 1578 arteries). Angiographic stenoses equal to or greater than 50% diameter were accurately identified by ultrasound imaging in 72% (1133 of 1578 arteries) of cases, and this was improved by the addition of other functional data (i.e., Doppler spectral analysis and oculoplethysmography). There was only modest correlation of absolute measurements of lesion width, minimal lumen, and standard lumen by the two imaging techniques (r = 0.28 to 0.55). Ultrasound measurements of lesion width were on the average 2 mm greater than those of angiography. The lumen averaged 1.5 mm larger when measured by ultrasound techniques. In the subset in which data were available from endarterectomy specimens, ultrasound showed the best correlation with lesion width (mean difference -1.1 mm) and angiography correlated best with minimal lumen (mean difference -0.1 mm). Neither examination consistently identified ulcerated plaques. Although ultrasound imaging alone has limited usefulness in quantitating luminal stenosis, this can be improved by the use of Doppler spectral analysis and oculoplethysmography. Ultrasound is superior to angiography for quantifying atherosclerotic plaque (lesion width) and will be an important tool for further study of atherosclerotic lesions.