bluuebunny/crossref_metadata_2025 huggingface dataset:
The 9000-year histo of vegetation development and disturbance patterns of a swamp-forest in Dalama, northern Sweden
Authors: Segerstrom Ulf , Hörnberg Greger , Bradshaw Richard
Published: November 2007

Analysis of pollen and charcoal in peat cores together with age-structure data of a swamp- forest site in the western part of central Sweden show the regional vegetation succession and the disturbance patterns over the last 9000 years. Five major vegetation sequences are identified: 1) Betula- Pinus period (c. 7000 to c. 6000 cal. BC); 2) wetland development (c. 6000 cal. BC to c. cal. AD 300); 3) Picea swamp-forest establishment ( c. cal. AD 300-1000); 4) human exploitation (c. cal. AD 1000-1900); and 5) cessation of human impact ( c. cal. AD 1900- present). Between c. 7000 cal. BC and c. cal. AD 1000, 17 fires were recorded in the peat. During the last 900 years, the area has been under the influence of human impact, mainly by animal grazing and trampling, together with deliberate flooding. These activities have affected the structure and dynamic of the swamp-forest by suppressing the regeneration of Picea and thereby creating an open Picea stand. During the last hundred years, a gradual cessation of human activities has led to increased Picea establishment and a denser swamp-forest. Despite these prolonged anthropogenic disturbances, the swamp-forest has qualities that make it unique in the Swedish forest landscape: 1) it has been forested for about 1700 years, during the last c. 900 years of which fire has been of little or no importance; 2) there are no visual signs of logging; and 3) dynamic processes, with trees continuously establishing, ageing and reaching senescence, have produced a forest with a high abundance of dead wood. The results show that the vegetation has been highly dynamic in response to both anthropogenic and 'natural' disturbance, and to the immigration of Picea. The present high biodiversity, and subsequent conservation interest does not result from long-term stability or absence of fire and other disturbance agencies. Conservation policies should therefore, in addition to species preservation, work to create a mosaic-like landscape where many different forest types are represented, containing structures, substrates and processes that are important for many different species. This provides the species the freedom of movement necessary for survival within the forest landscape in a longer perspective.
Topographic control of equilibrium-line altitude depression on reconstructed 'Little Ice Age' glaciers, Grovabreen, western Norway
Authors: Aa Asbjørn Rune
Published: November 2007

'Little Ice Age' marginal moraines in the Grovabreen area, inner Sunnfjord, are mapped and described. The modem and 'Little Ice Age' (mid-eighteenth century) equilibrium-line altitude (ELA) of the plateau glacier Grovabreen is calculated by the use of an accumulation-area ratio (AAR) of 0.6, giving a 'Little Ice Age' ELA depression of 125 m. AAR-ELA depression of the 'Little Ice Age' glaciers is also calculated for northern and southern outlet glaciers. Different estimates are considered to be the result of topographic differences. Other methods, such as the mean elevation of glaciers (MEG) and the toe-to-headwall altitude ratio (THAR), gave ELA depressions of 260 m and 315 m, respectively. These differences, due to topographic conditions, indicate that only glaciers with a uniform slope should be used to calculate the regional ELA of former glaciers.
The Neolithic transition and Palaeoecology in the Balkans: a comment on Willis and Bennett
Authors: Magri Donatella
Published: November 2007

In examining the Neolithic transition in the Balkans, Willis and Bennett ( 1994) suggest that the spread of agriculture and the timing of forest clearance were not coincident and that the impact of agriculture upon the landscape did not follow a time-transgressive spread. On the basis of a close correlation between the timing of deforestation and pre sent-day mean annual precipitation values in the Balkans, I suggest that the reduction of woodland is clearly time-transgressive along a humidity gradient and that climatic conditions were a major factor in determining the history ot vegetation in the Balkans from the mid-Holocene.
Accumulation rates of carbon in mires in Finland and implications for climate change
Authors: Tolonen Kimmo , Turunen Jukka
Published: November 2007

Stratigraphical analyses based on 1028 dated Holocene peat cores were used to estimate the rate of carbon accumulation in Finnish peatlands. Results were compared with data from other Boreal areas. The basal age of peat columns was found to be the best predictor of carbon accumulation and a significant correlation between depth and age of peat was evident. When normalized for the mean depth of peatlands in Finland ( c. 1.5 m), the average long-term carbon accumulation was 26.1 g C m-2 yr-1. In individual cores the values ranged from 2.8 to 88.6 g (average 22.5 ± 11.6 g) being much higher in bogs than in fens and almost double in southern mires as compared with those in the northern Boreal zone. The modelled rate of actual carbon accumulation is about 2/3 of that above. Boreal mires are actual sinks of carbon for thousands of years ahead in the present climate. The predicted greenhouse warming may shift the present Sphagnum mires northward and the net effect may be to restrain the radiative forcing. Poorly known 3D mass accumulation in mires and unpredictable functioning of northern mire ecosystems to climatic changes (for example via increased mire fires) complicate this interpretation.
Longest instrumental regional and all-India summer monsoon rainfall series using optimum observations: reconstruction and update
Authors: Sontakke N.A. , Singh Nityanand
Published: November 2007

Long period June-to-September total rainfall series are vital for the study of summer monsoon/climatic variability over the Indian region. Owing to high spatial variability in rainfall, the representa tiveness of the summer monsoon rainfall series for the entire country is limited. In order to develop an effective system for monsoon rainfall studies, the country has been divided into six zones, named as North West India (NWI), North Central India (NCI), North East India (NEI), West Peninsular India (WPI), East Peninsular India (EPI) and South Peninsular India (SPI). Fluctuation, empirical orthogonal function (EOF) and cluster analyses of the summer monsoon rainfall of the period AD 1871-1984 of 306 raingauges are carried out for this classifi cation. Updating the different zonal rainfall series on a real-time basis from all the gauges is a difficult task. In the present study, an objective technique is applied to select a subset of gauges whose mean showed the highest correlation with the all-gauges mean series; a total of 116 raingauge stations (19 for NWI, 27 for NCI, 15 for NEI, 18 for WPI, 14 for EPI and 23 for SPI) maintained by the India Meteorological Department (IMD) have been identified for updating the different zonal series. The different zonal series are extended as far as possible backward (prior to AD 1871) by applying an objective technique to the available gauges. The NEI and the EPI series are extended back to 1848, the NWI to 1844, the NCI to 1842, the WPI to 1817 and the SPI to 1813. Though of limited practical value, the all-India series is widely used in studies of long-range monsoon forecasting, teleconnections and large-scale climate dynamics. The all-India monsoon rainfall series from AD 1871 onwards is therefore calculated from the area-weighted mean of the six zones. The series is also extended back to AD 1813 by applying the objective technique on the available gauges. The different recon structed series for the longest instrumental period are reported.
Late-Holocene light-ring chronologies from subfossil black spruce stems in mires of subarctic Québec
Authors: Lavoie Claude , Payette Serge
Published: November 2007

Subfossil black spruce ( Picea mariana [Mill.] B.S.P.) stems from permafrost mires in a 250-km2 area at the arctic tree-line, near the eastern coast of Hudson Bay, were sampled for the construction of a long 'light-ring' chronology spanning the late Holocene. Thirty-three out of the 143 sampled spruce logs were 14C- dated yielding dates between 4580 and 1540 BP (3550-3010 cal. BC - cal. AD 377-649). Light rings (rings with thin-walled latewood cells or showing reduced latewood cell development) were numerous in all the studied stem discs and a set of 47 logs was successfully cross-dated. The cross-dated trees were used to build seven 'floating' light-ring chronologies located between c. 1200 cal. BC and cal. AD 500 (i.e., c. 1200 to 1000 cal. BC, 900 to 800 cal. BC, 700 to 400 cal. BC, 700 to 500 cal. BC, 100 cal. BC to cal. AD 300, cal. AD 50 to 450 and cal. AD 400 to 500). The large number of light rings in mire spruces appears to be associated with particular growth conditions in mires. A comparison of the frequency of light rings in extant spruce growing in mires and in dry-mesic sites showed that light rings were more common in peatland trees during this century. A delayed growing season caused by late peat thaw may possibly explain the difference between the two groups of sampled trees.
Archaeological and environmental evidence for Roman impact on vegetation near Carlisle, Cumbria: a comment on McCarthy
Authors: Dumayne-Peaty Lisa , Barber Keith
Published: November 2007

McCarthy (1995) is critical of our approach in reconstructing Roman impact from mainly palynological evidence. Here we address McCarthy's concerns and comment upon his observations, suggesting that there is a wider lesson to be learnt from this northern English example and that greater collaboration between archaeologists and palaeoenviron mentalists is still needed to resolve the dichotomy between offsite palyno logical and onsite archaeological studies.
A lacustrine pollen record from near altitudinal forest limit, Upper Kolyma Region, northeastern Siberia
Authors: Anderson Patricia M. , Lozhkin Anatoly V. , Belaya Berta V. , Glushkova Olga Yu. , Brubaker Linda B.
Published: November 2007

A sediment core that spans the last c. 15 000 yr BP was raised from Elgennya Lake (62°05'N 149°00'E, 1040 m) which is located near the altitudinal forest limit in the western Annachag Mountains of the Upper Kolyma region, northeastern Siberia. Palynological data indicate the presence of a relatively unpro ductive herb-Salix tundra during full-glacial times. Although Betula shrubs first appeared in this upland valley at c. 12 100 yr BP, they probably were few in number. More significant changes in the vegetation date to c. 10 100 yr BP when Alnus shrubs, and perhaps a few Larix trees, colonized the Elgennya catchment. A Larix dahurica forest established in the valley by c. 9400 yr BP. By c. 8600 yr BP, Pinus pumila grew within the forest understorey and formed a shrub tundra beyond altitudinal tree-line. Arrival times for Betula, Alnus, Larix and Pinus differ by 400 (for both Betula and Pinus), 2500 and 2200 radiocarbon years, respectively, when compared to mid-elevation sites located in the eastern Annachag Mountains. Evidence for tree-line fluctuations, originally inferred from these eastern sites, is absent in the Elgennya record. Palaeoclimatic interpretations of the pollen data from the Upper Kolyma region suggest that both summer temperature and late fall/early winter snowfall play key roles in determining the observed palaeovegetational patterns. This relationship contrasts with the Alaskan pollen records which primarily seem to reflect changes in summer conditions.
Correspondence analysis in medical research
Authors: Greenacre Michael
Published: November 2007

Various applications of correspondence analysis to biomedical data are presented. The basic concepts of profile, mass and chi-squared distance are introduced in an initial simple example using data on the relationship between headache types and age. The main result of the correspondence analysis is a geometric map of this relationship showing how the relative frequencies of headache types change with age. A second example maps the association between personality types and various medical diagnostic groups, while a third example deals with categorical rating scales such as an efficacy scale for a medication or a scale of pain. A final example illustrates the more complex situation when several categorical variables are involved using test data on a collection of bacterial isolates, with the object of comparing bacterial types and understanding the inter-relationships of the different tests.
Review papers : Design and analysis of reliability studies
Authors: Dunn Graham
Published: November 2007

This review covers the design and analysis of essentially two types of reliability study: method comparison studies and generalizability (including inter-rater reliability) experiments. Likelihood-based methods of inference (confirmatory factor analysis and REML estimation of variance components, for example) are advocated, partly because of their ease of use but, primarily as a stimulus to the use of more ambitious designs for the investigation of the quality of measurements. The more sophisticated approaches are not intended to replace the simpler traditional methods, however, but are expected to be used to supplement them.
Controversies in meta-analysis: the case of the trials of serum cholesterol reduction
Authors: Thompson SG
Published: November 2007

There has recently been disagreement in the literature on the results and interpretation of meta-analyses of the trials of serum cholesterol reduction, both in terms of the quantification of the effect on ischaemic heart disease and as regards the evidence of any adverse effect on other causes of death. This paper describes statistical aspects of a recent meta-analysis of these trials, and draws some more general conclusions about the methods used in meta-analysis. Tests of an overall null hypothesis are shown to have a basis clearly distinct from the more extensive assumptions needed to provide an overall estimate of effect. The fixed effect approach to estimation relies on the implausible assumption of homogeneity of treatment effects across the trials, and is therefore likely to yield confidence intervals which are too narrow and conclusions which are too dogmatic. However the conventional random effects method relies on its own set of unrealistic assumptions, and cannot be regarded as a robust solution to the problem of statistical heterogeneity. The random effects method is more usefully regarded as a type of sensitivity analysis in which the weights allocated to each study in estimating the overall effect are modified. However, rather than using a statistical model for the 'unexplained' heterogeneity, greater insight and scientific understanding of the results of a set of trials may be obtained by a careful exploration of potential sources of heterogeneity. In the context of the cholesterol trials, the heterogeneity according to the extent and duration of cholesterol reduction are of prime concern and are investigated using logistic regression. It is concluded that the long-term benefits of serum cholesterol reduction on the risk of heart disease have been seriously underestimated in some previous meta-analyses, while the evidence for adverse effects on other causes of death have been misleadingly exaggerated.
Analysis of DNA sequences
Authors: Weir BS
Published: November 2007

Recent developments in the statistical analysis of DNA sequences are reviewed. The pace with which sequence data are being generated and analysed has increased with the growth of the human genome project. Two areas of activity are emphasized: attention to error rates in recorded sequences, and heterogeneity in structure of sequences. There is now empirical evidence suggesting error rates in the range 0.1% ∼ 1%, and such rates will affect evolutionary studies since these are about the rates at which DNA sequences from different individuals are expected to differ. Heterogeneity for such quantities as base composition, or lengths between successive subsequences of specified types, may be sufficient to account for observed long-range correlations between bases. The need for statistical models and analyses of DNA sequence data will continue, and will offer interesting challenges.
Design and analysis of cancer screening trials
Authors: Etzioni Ruth D , Connor Robert J , Prorok Philip C , Self Steven G
Published: November 2007

This article reviews approaches to the design and analysis of cancer screening trials. After summarizing some basic screening concepts and potential pitfalls, we introduce several possible screening trial designs with examples from the literature. We review in detail methods for analyzing screening trial data, including testing for a significant difference in disease-specific mortality between the control and intervention groups, estimating the mortality differential if one exists, and evaluating the programme lead time, the screen sensitivity and the role of stage shifting. We consider Overall mortality analyses, which are based on the experience of the trial population, and Limited mortality analyses, which are based on the experience of comparable groups of cases in the control and intervention groups. We discuss methods for selecting candidate comparable case groups and confirming that they are in fact comparable. We conclude by showing how the principles discussed have been used in the planning and design of a current screening trial for multiple cancers.
Box-Jenkins modelling in medical research
Authors: Helfenstein Ulrich
Published: November 2007

Notifications of diseases, entries in a hospital, injuries due to accidents, etc., are frequently collected in fixed equally spaced intervals. Such observations are likely to be dependent. In environmental medicine, where series such as daily concentrations of pollutants are collected and analysed, it is evident that dependence of consecutive measurements may be important. A high concentration of a pollutant today has a certain 'inertia', i.e. a tendency to be high tomorrow as well. Dependence of consecutive obser vations may be equally important when data such as blood glucose are recorded within a single patient. ARIMA models (autoregressive integrated moving average models, Box-Jenkins models), which allow the stochastic dependence of consecutive data to be modelled, have become well established in such fields as economics. This article reviews basic concepts of Box-Jenkins modelling. The methods are illustrated by applications. In particular, the following topics are presented: the ARIMA model, transfer function models (assessment of relations between time series) and intervention analysis (assessment of changes of time series).
Structural time series models in medicine
Authors: Harvey Andrew , Koopman Siem Jan
Published: November 2007

Structural time series models are formulated in terms of components, such as trends, seasonals and cycles, which have a direct interpretation. This article describes such models and gives examples of how they can be applied in medicine. Univariate models are considered first, and then extended to include explanatory variables and interventions. Multivariate models are then shown to provide a framework for modelling longitudinal data and for carrying out intervention analysis with control groups. The final sections deal with data irregularities and non-Gaussian observations.
Mixture models in haematology: a series of case studies
Authors: McLaren Christine E
Published: November 2007

Two specific applications of finite mixture distributions in haematology include (1) the analysis of the distribution of red blood cell volumes to characterize and quantify alterations in erythrocyte subpopula tions in anaemia and (2) the analysis of the distribution of transferrin saturation to estimate subpopul ation parameters based on individual genotype for haemochromatosis. For these applications, we describe the comprehensive approach that was taken to distribution modeling. The choice of distri butions and the number of mixture components to be fit were based upon theoretical and physiological considerations and a variety of additional statistical problems were considered. These included fitting mixtures of doubly-truncated data and evaluating model fit in the presence of extremely large sample sizes. As a result of the comprehensive approach taken to statistical problem solving in haematology, methods developed for analysis of red blood cell volume distributions have now been adopted by the International Council for Standardization in Haematology. Additionally, analysis of population trans ferrin saturation distributions from the white population of the USA has led to an independent estimate of the prevalence of homozygotes for haemochromatosis, confirming that the gene for haemochromatosis is common.
Variance estimation for complex surveys using replication techniques
Authors: Rust KF , Rao Jnk
Published: November 2007

The analysis of survey data requires the application of special methods to deal appropriately with the effects of the sample design on the properties of estimators and test statistics. The class of replication techniques represents one approach to handling this problem. This paper discusses the use of these techniques for estimating sampling variances, and the use of such variance estimates in drawing inferences from survey data. The techniques of the jackknife, balanced repeated replication (balanced half-samples), and the bootstrap are described, and the properties of these methods are summarized. Several examples from the literature of the use of replication in analysing large complex surveys are outlined.
System Design Optimization for Product Manufacturing
Authors: Yoshimura Masataka
Published: November 2007

The current ultra-competitive manufacturing arena demands that a multitude of factors be considered during product design and manufacturing, in addition to core concerns such as product performances, product qualities, and manufacturing costs. Safety aspects, environmental impact, recycling issues, and the satisfaction of product consumers and users must all be addressed for a product design to be successful. Optimum system technologies that can concurrently consider a broad range of factors pertaining to product manufacturing, and streamline decision-making for product design and manufacturing are required. This article describes a total system design optimization method that assists decision-making across the entire spectrum of product manufacturing processes, from the conceptual design stage to final product realization. System design optimizations for advanced product manufacturing are discussed, starting from historical changes in manufacturing methodology paradigms and product manufacturing criteria, and the roles of concurrent engineering and collaboration concepts are then clarified as technological concepts that form the basis for innovative product manufacturing from the standpoint of system optimization. Next, aspects of people's involvement in product manufacturing are classified and technologies that support product manufacturing are summarized from the standpoint of providing sophisticated decision-making assistance to design and manufacturing personnel. Finally, based on the foregoing discussions, new methods for optimal decision-making technologies are proposed, with the aim of facilitating effective decision-making during the task of designing sophisticated products for manufacture.
Autopsy Findings in Clinically Normal Thyroids
Authors: Scopa Chrisoula D. , Petrohilos John , Spiliotis John , Melachrinou Maria
Published: November 2007

Thyroid glands obtained from 120 consecutive autopsies performed on patients who died from different causes, other than thyroid diseases, were systematically examined by light microscopy. There were 84 males and 36 females; their ages ranged from 1 day to 100 years. Histopathological findings were noted mainly in patients older than 48 years of age. In all cases thyroid lesions were incidental findings and included nodular goiter (26%), thyroiditis (9%), follicular adenomas (7%), papillary microcarci nomas (6%), follicular carcinoma (0.8%), and hemangioma (0.8%). A number of other morphologic changes of importance to surgical pathologists were also evaluated such as the presence of solid cell nests, intrathyroidal ectopic tissues, fibrosis, fat cell infiltration, and vascular changes. Int J Surg Pathol 1 (I): 25-32, 1993
p53 in Low-grade Gliomas
Authors: Ng Ho-Keung , Phil M. , Lo Kwok-Wai , Huang Dolly P. , Poon Wai-Sang
Published: November 2007

Although the p53 tumor suppressor gene is well known to be involved in the pathogen esis of malignant astrocytomas, its significance in the development of low-grade glio mas, including the nonastrocytic tumors, remains underexplored. In an attempt to further understanding the molecular genetics of glial tumorigenesis, 37 low-grade gliomas of different histologic subtypes were screened for p53 mutations with the polymerase chain reaction, single-strand conformation polymorphism analysis and direct DNA sequencing. Forty-eight tumors, including the previously mentioned 37 cases, were examined immunohistochemically with paraffin-embedded tissues for p53 protein labeling. Only two diffuse astrocytomas exhibited p53 genetic abnormalities, and both tumors behaved aggressively. Two tumors exhibited p53 protein immuno labeling, including one of the cases with genetic changes. p53 genetic alterations are only rarely involved in the pathogenesis of low-grade gliomas. The authors speculate that they occur late in the transition from low-grade to high-grade tumors. Int J Surg Pathol 1 (3):163-170, 1994
Rhabdomyosarcoma of the Long Bone in an Adult
Authors: Rashid Asif , Dickersin G. Richard , Rosenthal Daniel I. , Mankin Henry , Rosenberg Andrew E.
Published: November 2007

Rhabdomyosarcoma is one of the most common sarcomas of childhood. It usually arises in the soft tissues but may involve bone by several different mechanisms, includ ing direct extension, metastatic spread, as a component of dedifferentiated chondrosar coma or malignant mesenchymoma, or as a primary tumor. Only nine cases of primary rhabdomyosarcoma of bone have been previously reported, many of them not well documented. The histologic, immunohistochemical, and ultrastructural findings of a primary rhabdomyosarcoma of the femur in a 68-year-old woman are presented. Also discussed are the different aspects of skeletal muscle differentiation in bone tumors and the possible explanation for the rarity of primary skeletal rhabdomyosarcoma. Int J Surg Pathol 1(4):253-260, 1994
Primary Pigmented Neuroectodermal Tumor of the Uterine Cervix
Authors: Sobel N. , Carcangiu M.L.
Published: November 2007

A primary pigmented neuroectodermal tumor of the uterine cervix is described. The patient was 57 years old when she presented with vaginal bleeding. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph adenectomy, followed by chemotherapy. Histologically, the tumor was characterized by the concomitant presence of two neural crest derivatives, neuroblasts and melano cytes. The latter cells were arranged in a tubulopapillary fashion and contained abun dant melanin. Histochemical, immunohistochemical, and electron microscopic exami nation confirmed the diagnosis. The patient was alive without evidence of disease 5 years later. An origin of this tumor from abnormally migrated neural crest cells is suggested. Int J Surg Pathol 2(1):31-36, 1994
Neuroendocrine Carcinoma Arising in Barrett's Esophagus
Authors: Slavin John , Pitson Graham , Dowling John P.
Published: November 2007

There is a well-established association between Barrett's esophagus and esophageal adenocarcinoma. Primary esophageal neuroendocrine carcinoma is a rare tumor and has not previously been reported in association with Barrett's esophagus. We report such a case with immunohistochemical and electron microscopic findings. Int J Surg Pathol 2(1):43-46, 1994
Transitional Cell Carcinoma Metastatic to Lung, With Dedifferentiation Into Small Cell Undifferentiated Carcinoma
Authors: Todd David L. , Laucirica Rodolfo , Ostrowski Mary L. , Brown Richard , Truong Luan D.
Published: November 2007

Small-cell undifferentiated carcinoma (SCUC) has been increasingly recognized in the urinary tract. 1,2,3 Up to 66% of SCUCs in this location are associated with a minor component of a more differentiated carcinoma that most frequently represents transi tional-cell carcinoma (TCC), but adenocarcinoma, squamous-cell carcinoma, spindle- cell carcinoma, and carcinoid carcinoma have all been described. We report a case of low-grade TCC of the urinary tract metastasizing to a distant location and therein dedifferentiating into an SCUC and discuss the clinical and biologic implication of the process of dedifferentiation. Int J Surg Pathol 2(2):157-162, 1994
Periosteal Myxoma of the Tibia
Authors: Magro G. , Lanzafame S. , Grasso S.
Published: November 2007

Myxoma is one of the rarest benign primary tumors of the long bones. A case of periosteal myxoma of the diaphysis of tibia with a benign course after 7 years, is reported in a 69-year-old man. Radiographic appearance of the lesion showed ero sion of the cortex of bone and extension into soft tissue, suggesting an initial diag nosis of malignancy. A limited biopsy showing benign myxoid tissue was not con sidered specific for diagnosis of myxoma. Histologic examination of the entire lesion was essential to make definitive diagnosis. Differential diagnosis with benign and malignant bone lesions containing myxoid features is discussed. Int J Surg Pathol 2(4) :333-336, 1995
Hydrochlorothiazide Increases Efferent Glomerular Arteriolar Resistance in Spontaneously Hypertensive Rats
Authors: Komatsu Kazutoshi , Numabe Atsushi , Ono Yuko , Frohlich Edward D.
Published: November 2007

Background: Micropuncture studies were performed to determine the intrarenal hemody namic effects of two conventional antihypertensive agents, hydrochlorothiazide (HCTZ) and hydralazine (HYDR) alone and in combination.

Methods and Results: Male spontaneously hypertensive and normotensive Wistar Kyoto rats (19 weeks old) were treated for 3 weeks with vehicle (control), HCTZ (80 mg/kg/d), HYDR (5 mg/kg/d), or combined therapy (HCTZ 30 mg/kg/d and HYDR 2 mg/kg/d). Each treatment significantly reduced arterial pressure while effective renal plasma flow, glomerular filtration rate and single nephron glomerular filtration rate were unaffected by any treatment in either strain. In spontaneously hypertensive rats HCTZ decreased single nephron plasma flow (11 ± 8 to 84 ± 4 nL/min; P < .05) but, despite this reduction, glomerular pressure remained unchanged (51.4 ± 0.7 to 52.1 ± 0.8 mmHg) attributable to increased efferent glomerular resistance (1.58 ± 0.14 to 2.11 ± 0.12 10 U; P < .05). By contrast, HYDR increased single nephron plasma flow (to 147 ± 8 nL/min; P < .01) and decreased efferent glomerular resis tance (to 1.09 ± 0.09 U; P < .05). Combined treatment produced responses similar to HCTZ when used alone, thereby nullifying the beneficial efferent glomerular resistance effects: sin gle nephron plasma flow ± fell (to 89 ± 7 nL/min; P < .05) and efferent glomerular resistance increased (to 2:05 ± 0.17 U; P < .05). In Wistar Kyoto rats, HCTZ and combined treatment had no-effect. HCTZ alone induced glomerular ischemia that was associated with efferent glomerular arteriolar constriction in these spontaneously hypertensive rats.

Conclusions: These findings provide a possible explanation for the lack of improved renal target-organ damage in controlled multicenter trials employing thiazide diuretics.
Efficacy and Safety of Nifedipine Coat-Core versus Amlodipine in Patients With Mild to Moderate Essential Hypertension: Comparison of 24-Hour Mean Ambulatory Diastolic Blood Pressure
Authors: Byyny Richard L. , Shannon Timothy , Schwartz Lawrence A. , Rotolo Christa , Jungerwirth Steven
Published: November 2007

Background: Calcium channel blockers have been successfully used for the treatment of hypertension. In this study, the antihypertensive efficacy and safety of the dihydropyridine calcium channel blockers nifedipine coat-core 30 mg and amlodipine 5 mg were evaluated. Methods: This multicenter, double-blind, prospective, randomized, parallel-arm study com pared once daily administration of nifedipine coat-core 30 mg with once daily amlodipine 5 mg in subjects with mild-to-moderate essential hypertension. A 4-week placebo run-in period was followed by an 8-week active treatment period. Blood pressure reduction was measured by ambulatory blood pressure monitoring and casual office blood pressure measured by mer cury sphygmomanometer.

Results: Nifedipine coat-core and amlodipine produced equivalent reductions in mean dias tolic blood pressure, as determined by 24-hour ambulatory blood pressure monitoring. Mean reduction in diastolic blood pressure was 5.4 mmHg and 5.8 mmHg for nifedipine coat-core and amlodipine, respectively. Both drugs were well tolerated and neither treatment resulted in a significant change in heart rate.

Conclusions: Nifedipine coat-core 30 mg once-daily is comparable to amlodipine 5 mg once-daily for blood pressure reduction.
Differential Effects of Protein Kinase C Activators and Inhibitors on α- and β-Adrenoceptor-mediated Positive Inotropic Effect in Isolated Rabbit Papillary Muscle
Authors: Hassan Talukder M.A. , Endoh Masao
Published: November 2007

Background: A number of novel agents that activate or inhibit protein kinase C (PKC) in vitro have been developed to evaluate the physiologic role of PKC in regulation of cellular function. However, most of the PKC inhibitors also affect the protein kinase A, and the effects of these agents in intact myocardium remain still controversial. The present study was carried out to examine the effects of these agents on the positive inotropic effect (PIE) medi ated by α- and β-adrenoceptors in isolated rabbit papillary muscle.

Methods and Results: A potent PKC activator, phorbol 12, 13-dibutyrate (PDBu) at 10 and 30 nM, induced a significant PIE. PDBu at 3 nM and higher inhibited the α-mediated PIE and abolished it at 100 nM without affecting the β-mediated PIE. Phorbol 12-myristate 13- acetate (PMA) and 1-oleyl-2-acetyl-sn-glycerol (OAG) elicited a similar selective inhibitory action on the α-mediated PIE. The PIE of PDBu was abolished by chelerythrine and partially inhibited by staurosporine, but H-7 or calphostin-C did not affect the PIE. These PKC inhibitors consistently inhibited the α-mediated PIE by 20-30% at concentrations that they did not affect the β-mediated PIE. None of the PKC inhibitors influence the PDBu-induced inhibitory action on the α-mediated PIE, an indication that they failed to reach the site of the inhibitory action of PDBu.

Conclusion: Selective modulation by the PKC activators and inhibitors of the α-mediated PIE with little effect on the β-mediated PIE implies that the activation of PKC has a physiological relevance to the α-mediated PIE. However, the externally administered PKC activators do not mimic the effect of diacylglycerol that is generated endogenously by α-stimulation. By con trast, externally applied PKC inhibitors selectively antagonize the α-adrenoceptor-mediated PIE in rabbit ventricular myocardium.
Local Delivery of an Ultra-short-acting Nitric Oxide- releasing Compound, DMHD/NO, Is Highly Effective in Inhibiting Acute Platelet-Thrombus Formation on Injured Arterial Strips
Authors: Kaul Sanjay , Naqvi Tasneem Z. , Fishbein Michael C. , Cercek Bojan , Badimon Juan J. , Hutsell Thomas C. , Thomas Sasha , Molloy Mia , Shah Prediman K.
Published: November 2007

Background: Nitric oxide (NO) plays an important role in modulating platelet-vessel wall interaction following vascular injury. We examined the effects of local infusion of an ultra- short-acting NO-releasing compound: NO adduct of N, N'-dimethylhexanediamine (DMHD/NO), sodium nitroprusside, intravenous nitroglycerin, and aspirin on acute platelet-thrombus formation under conditions of high-shear blood flow in a rabbit extracor poreal perfusion model.

Materials and Methods: Strips of porcine aortic media were perfused in a Badimon cham ber with arterial blood from 20 New Zealand White rabbits for 10 minutes at a shear rate of 1700 s-1. Thrombus formation was quantified by morphometric analysis of thrombus area. Effects on collagen-induced platelet aggregation, blood pressure, bleeding time, and acti vated clotting time were also examined.

Results: DMHD/NO inhibited thrombus area and platelet aggregation in a dose-dependent manner with a 90% reduction in thrombus area (0.018 ± 0.039 vs 0.215 ± 0.085 mm 2/mm control, P < .001) and a 50% reduction in platelet aggregation (4.8 ± 4.4 vs 9.9 ± 4.1 Ω con trol, P = .04) at the highest dose of 1.0 nM/kg and 100 μM/L, respectively, without any effects on blood pressure, bleeding time, or activated clotting time. In contrast, equimolar concentrations of sodium nitroprusside and intravenous nitroglycerin had significantly reduced effects on thrombus area compared to DMHD/NO and were associated with signifi cant reductions in blood pressure and prolongation of bleeding time. Aspirin had no effect on thrombus area at 1 μM/kg but reduced thrombus area and prolonged bleeding time at 2 and 5 μM/kg.

Conclusions: Local delivery of DMHD/NO produced a 90% inhibition of experimental acute platelet-thrombosis under high-shear flow conditions without producing adverse systemic hemodynamic or hemostatic effects. Thus, inhibition of thrombus formation by local delivery of a rapidly acting NO donor may be an effective strategy for prevention of arterial injury- induced thrombosis.
Molecular Delivery System for Antisense Oligonucleotides: Enhanced Effectiveness of Antisense Oligonucleotides by HVJ-liposome Mediated Transfer
Authors: Morishita Ryuichi , Gibbons Gary H. , Horiuchi Masatsugu , Nakajima Masatoshi , Ellison Kristin E. , Lee Wendy , Kaneda Yasufumi , Ogihara Toshio , Dzau Victor J.
Published: November 2007

Background: The effectiveness of antisense oligodeoxynucleotides for in vitro and in vivo studies is limited by a low efficiency of cellular uptake and instability due to degradation by nucleases. To overcome some of these problems, we recently developed a transfer method that utilizes inactivated Sendai virus (hemagglutinating virus of Japan [HVJ]) complexed with liposomes to deliver antisense oligodeoxynucleotides. In this study, we compared the effectiveness of the HVJ-liposome method versus a cationic liposome method versus passive uptake to deliver antisense oligodeoxynucleotides against basic fibroblast growth factor on angiotensin (Ang) II-induced rat vascular smooth muscle cell growth.

Methods and Results: Twenty to twenty-eight hours after transfection, antisense fibroblast growth factor oligodeoxynucleotides introduced by passive uptake and HVJ-liposome method decreased basal DNA synthesis significantly as compared to the sense, control, and scrambled oligodeoxynucleotides groups; however, 60-68 hours after transfection, only anti sense fibroblast growth factor oligodeoxynucleotides transduced by the HVJ-liposome method resulted in a significant inhibition of DNA synthesis under basal and Ang II-(10-6M) stimulated conditions. The IC25 of oligodeoxynucleotides assessed by the inhibition of thymidine incorporation was significantly lower using the HVJ-liposome method than those using the other transfer methods. To clarify the mechanisms of cellular uptake of olibodeoxynucleotides with the HVJ-liposome method, we studied the cellular fate of fluo rescein isothiocyanate (FITC)-labeled oligodeoxynucleotides FITC-oligodeoxynucleotides was localized in nuclei at 5 minutes after transfection with the HVJ-liposome method. In contrast, FITC-oligodeoxynucleotides introduced by passive uptake was detected in nonnu clear cellular compartments, possibly endosomes, but not the nuclei. Cellular fluorescence of oligodeoxynucleotides introduced by passive uptake disappeared within 24 hours, while that introduced by the HVJ-liposome method could be observed up to 72 hours.

Conclusion: These results demonstrate that the HVJ-liposome transfer enhanced the effec tiveness of AS-fibroblast growth factor via its specific molecular mechanisms of transfer.
Platelet-Mediated Cardioprotective Effect Against Ischemia-Reperfusion Injury in Isolated Rat Hearts: Role of Platelet Number and Contribution of Supernatant of Aggregated Platelets
Authors: Yang Baichun , Mehta Paulette , Mehta Jawahar L.
Published: November 2007

Background: Previous studies have documented cardioprotective effects of circulating platelets after reperfusion injury. The present study was designed to examine the role of platelet number and the contribution of platelet-released mediators in the platelet superna tant in cardioprotection against ischemia-reperfusion-induced myocardial dysfunction.

Methods and Results: Isolated buffer-perfused (constant volume) Sprague-Dawley rat hearts were subjected to 25 minutes of global ischemia followed by 30 minutes of reperfu sion. Ischemia-reperfusion resulted in myocardial dysfunction, indicated by an increase in coronary perfusion pressure and left ventricular end-diastolic pressure, and a decrease in de veloped left ventricular pressure. Perfusion of hearts with washed rat platelets (103-2.2 × 107 cells/mL) significantly ( P < .01) attenuated these indices of myocardial dysfunction upon ischemia-reperfusion in a concentration-dependent manner. A cardioprotective effect of platelets was observed at a concentration as low as 105 platelets/mL. Similar cardioprotec tion was seen in hearts perfused with the supernatant of aggregated platelets.

Conclusions: These observations indicate that the platelet-mediated cardioprotective effect against ischemia-reperfusion in vitro is concentration dependent, and platelet-released mediators in the platelet supernatant are protective against ischemia-reperfusion injury.
Double-Blind Comparison of Apolipoprotein and Lipoprotein Particle Lowering Effects of Atorvastatin and Pravastatin Monotherapy in Patients With Primary Hypercholesterolemia
Authors: Dallongeville Jean , Fruchart Jean-Charles , Maigret Pascal , Bertolini Stefano , Bittolo Bon Gabriele , Campbell M. Malcom , Farnier Michel , Langan John , Mahla Gerhard , Pauciullo Paolo , Sirtori Cesare
Published: November 2007

Methods and Results: A total of 305 subjects with primary hypercholesterolemia were ran domized in a 3:1 ratio to receive either atorvastatin 10 mg daily or pravastatin 20 mg daily according to a 16-week double-blind comparative study of the effect on apolipoprotein and lipoprotein particle levels. All patients had low-density lipoprotein (LDL)-cholesterol levels between 4.2 and 6.6 mM and triglyceride concentrations below 4.5 mM at baseline. After 16 weeks of treatment, apoB (-27% and -16%; P < .001), apoE (-13.3% and -5.6%; P < .05) and the triglyceride-rich LpC-III:B particle (-33% and -26%; P < .05) levels were reduced to a significantly greater extent in the atorvastatin than in the pravastatin treatment group. Both atorvastatin and pravastatin increased apoA-I levels, an effect that was more pronounced in the pravastatin group (+7% and + 11 %; P < .002). The increased apoA-I levels predominated on LpA-I in the atorvastatin group (+11%) and on LpA-I:A-II in the pravastatin group (+13%). ApoA-II levels were decreased with atorvastatin to a greater extent than with pravastatin (-1% and +2.8%; P <.05).

Conclusions: Although atorvastatin and pravastatin belong to the same therapeutic family, they produce different effects in apolipoprotein concentrations in hypercholesterolemic patients. Atorvastatin, an agent of the new generation, appears to efficiently reduce apoB- containing lipoprotein particles containing apoC-III.
Clonidine-Induced Heat-Shock Protein Expression in Rat Aorta
Authors: Moen R.J. , LaVoi Kathleen P. , Zhang Mingyu , Blake Michael J.
Published: November 2007

Background: Restraint-stress and administration of drugs that precipitate hypertension induce heat-shock protein (HSP) expression in the aorta. The exact mechanism supporting this hypertension-related HSP response is unclear because HSP induction is blocked by receptor-selective and nonselective antihypertensive agents.

Methods and Results: To identify mechanisms contributing to the pharmacological/physio logical regulation of the HSP response in cardiovascular tissues, we administered clonidine to awake and freely moving animals to determine its effect on HSP expression in vivo. Inconsistent with previous work, we found that clonidine produced a dose-dependent and transient increase in HSP70 mRNA levels in the aorta. No other tissue examined displayed an HSP response after clonidine administration. Clonidine-induced HSP expression was not restricted to the HSP70 family; HSP89α, HSP89β, and HSP60 were also induced. Interest ingly, no heat-shock element-binding activity was observed after clonidine administration, suggesting that unusual transcriptional regulatory mechanisms mediate this response. Yohimbine and nifedipine blocked HSP70 mRNA expression, whereas isoproterenol, mecamylamine, and reserpine had no effect.

Conclusions: The functional consequence of HSP expression in cardiovascular tissues may be to alter the responsiveness of cells in these tissues to subsequent drug or stress exposures, thereby implicating the HSP response as an important component of cardiovascular homeo stasis. If so, treatment of mammalian organisms with drugs capable of inducting selective HSP expression in vascular tissue may alter the progression of cardiovascular disease processes.
The Effect of Chloroquine on Circulating Platelet Survival in the Rat
Authors: Osim Eme , Mudzingwa Shepherd , Musabayane Cephas , Mbajiorgu Felix , Munjeri Owen
Published: November 2007

Background: Chloroquine inhibits platelet aggregation. Because platelet aggregation may lead to the lysis of platelets, the effect of chloroquine administration on circulating platelet survival was studied.

Methods and Results: Platelets harvested from the blood of male inbred (WAG) rats were labeled with 111Indium oxine and returned to other inbred rats. At timed intervals, blood samples were drawn from the rats and taken for radioactivity estimation. In some experi ments, the rats (n = 10) received chloroquine (10 mg/kg) intraperitoneally daily for 3 days. Control rats (n = 10) received normal saline. Indium-labeled platelets disappeared expo nentially in control and test rats. The fraction of indium disappearing/h was significantly less in chloroquine-treated rats than in control rats (0.0368 ± 0.0016 vs 0.0520 ± 0.0016, mean ± SEM; P < .001). In all, 99% of the labeled platelets disappeared in 5.3 days in chloro quine-treated rats and 3.7 days in control rats.

Conclusions: Chloroquine administration increases the life span of circulating platelets in rats. If the results are confirmed in humans, chloroquine may prevent the shortened platelet survival and thrombocytopenia common in malarial infection and other thrombotic disorders.
Intravenous Amiodarone in the Management of Atrial Fibrillation
Authors: Reiffel James A.
Published: November 2007

Background: Although approved only for therapy of life-threatening ventricular tachy arrhythmias, intravenous amiodarone is also being used for the treatment of atrial fibrilla tion (AF), generally in the intensive care unit setting and most often after cardiac surgery. When used for AF, dosing regimens and clinical experience have varied.

Methods and Results: This article summarizes representative reports in hopes of clarifying the role of intravenous amiodarone for practitioners who prescribe it for the management of AF. The most immediate and most predictable response is reduction of the ventricular rate, which generally is noted after the first 300-400 mg. Restoration of sinus rhythm (car dioversion) may occur, but the precise incidence in a placebo-controlled, blinded study has not been determined. When present, it often takes 24 hours, and a total dose of 1,000 mg or more. Least certain is the efficacy of the drug in preventing the appearance (when used pro phylactically) or reappearance of AF.

Conclusions: More data are required with regard to patient characterization, electrical sys tem status, and dosing regimen to better characterize intravenous amiodarone for this role.