bluuebunny/crossref_metadata_2025 huggingface dataset:
When Tinnitus Loudness and Annoyance Are Discrepant: Audiological Characteristics and Psychological Profile
Authors: Hiller Wolfgang , Goebel Gerhard
Published: July 2007

This study evaluates sociodemographic and clinical characteristics of patients reporting discrepant levels of tinnitus loudness and annoyance. 4958 subjects recruited from a national tinnitus association completed a comprehensive screening questionnaire including Klockhoff and Lindblom’s loudness grading system and the psychometric Mini-TQ (Tinnitus Questionnaire). There was a moderate correlation of 0.45 between loudness and annoyance. Of the subjects reporting very loud tinnitus, about one third had only mild or moderate annoyance scores. They were not different from those with high annoyance regarding age, gender and tinnitus duration, but annoyance was increased when subjects had additional hearing loss (OR = 1.71), vertigo/dizziness (OR = 1.94) or hyperacusis (OR = 4.96). Another significant predictor was history of neurological disease (OR = 3.16). Subjects reported low annoyance despite high loudness more often if not feeling low/depressed and not considering themselves as victims of their noises. A specific psychological profile was found to characterize annoyed tinnitus sufferers. Permanent awareness of the noises, decreased ability to ignore them and concentration difficulties were reported frequently even when overall annoyance scores were comparatively low. It is concluded that the coexistence of tinnitus with hearing loss, vertigo/dizziness and hyperacusis as complicating otological conditions seems to be of clinical relevance for the prediction of high annoyance levels. Tinnitus loudness and annoyance are not necessarily congruent and should be assessed separately.
Conditional Targeting in the Kidney
Authors: Wu Fiona
Published: July 2007

Conditional gene targeting utilising the Cre/loxP system, which allows spatial and temporal control of gene expression, has been increasingly used to study gene function in vivo. The ability to limit gene disruption to a particular cell type and/or to control the timing of gene targeting overcomes some of the limitations associated with conventional targeting and total knockout of a gene, namely, potential embryonic lethality and complicated phenotype affecting multiple tissues. Although the application of this approach to the kidney is relatively recent, it has already proven to enhance our ability to study the developmental, physiological, and pathological processes in the kidney: dissecting the roles of several proteins in complex homeostatic systems, uncovering novel actions of proteins, and establishing models of kidney diseases. As the number of kidney-specific Cre mouse strains increases, this strategy will allow increasingly specific and complicated biological questions in the kidney to be addressed.
Pimecrolimus Cream 1% for Treatment of Vulvar Lichen Simplex Chronicus: An Open-Label, Preliminary Trial
Authors: Goldstein Andrew T. , Parneix-Spake Anne , McCormick Calogera L. , Burrows Lara J.
Published: July 2007

Background: To evaluate efficacy and safety of pimecrolimus cream 1% twice daily for treatment of vulvar lichen simplex chronicus (LSC). Methods: Patients in this 12-week, open-label study had biopsy-proven vulvar LSC. Inclusion criteria were patient-reported Visual Analog Scale for Pruritus Relief ≧3 (VAS-PR, 0 cm = no itching to 10 cm = severe itching) and Investigator’s Global Assessment ≧2 (IGA, 0 = no disease to 3 = severe disease). Safety was evaluated by adverse event reports and pimecrolimus blood level measurements. Results: Twelve women aged 25–53 years were enrolled. The median pruritus score (VAS-PR) decreased from 6 (min. 4.9, max. 9.0) at baseline to 0 cm at week 4 (max. 4.2), week 8 (max. 3.1) and week 12 (max. 2.1). Seven patients reported complete resolution of pruritus by week 4. Median IGA decreased from 2.5 (min. 2, max. 3) at baseline to 0 (min. 0, max. 2) at week 12. Erythema, excoriation, and lichenification improved for all patients. Pimecrolimus blood concentration for all samples was below the limit of quantification, 0.3 ng/ml. No adverse events were reported. Conclusions: In this exploratory study, signs and symptoms of vulvar LSC improved for all women and pimecrolimus cream showed a favorable safety profile. Larger prospective studies are needed to further evaluate pimecrolimus for treatment of vulvar LSC.
Intersegmental Arterial Communication between the Medial and Left Lateral Segments of the Liver
Authors: Cho Akihiro , Gunji Hisashi , Koike Naoto , Narumoto Souichi , Asano Takehide , Yamamoto Hiroshi , Kainuma Osamu , Ryu Munemasa , Mori Chisato , Murakami Gen , Okazumi Shinichi , Ochiai Takenori
Published: July 2007

Background/Aims: Although the interlobar arterial collateral of the liver has been thoroughly analyzed, few reports have described the intersegmental arterial collateral between the medial and left lateral segments. Methods: The hepatic arterial system of the left liver was evaluated using 12 latex resin cast specimens in which latex resin was injected into the left hepatic artery after ligation of the right hepatic artery. Results: In all 12 livers, an intersegmental collateral between the medial and left lateral segments was detected. These collaterals were extrahepatically located in the umbilical plate and gave rise to branches traveling to the bile duct of the left liver. Conclusions: The present study showed that the communicating arcade between the middle and left lateral hepatic arteries was consistently present in the umbilical plate and played an important role not only in the intersegmental arterial collateral system of the left liver but also in the blood supply to the bile ducts.
Free Radical and Antioxidant Levels in Patients with Secondary Peritonitis and Their Prognostic Significance
Authors: Kumar Yogesh , Singh Gurpreet , Davidson Brian R.
Published: July 2007

Background: The clinical outcome of patients with secondary bacterial peritonitis depends on the production of superoxides involved in bacterial killing and the endogenous level of antioxidants. The prognostic significance of their levels has not previously been investigated. Patients and Methods: Forty-five patients undergoing surgery for secondary peritonitis were prospectively evaluated. Severity of illness at admission (APACHE II score) was correlated with admission levels of superoxide radicals and antioxidants (superoxide dismutase (SOD), catalase and glutathione peroxidase). Levels were compared with general surgery controls (n = 10). Superoxide and antioxidant levels at admission (day 1) and post-operative days 3 and 5/7 were then correlated with outcome. Results: Nine of the 45 patients died (20% mortality) and 17 patients had complications (47% morbidity). The mean APACHE II score on admission was significantly higher among non-survivors than survivors (p < 0.01). The APACHE II score on admission correlated with the level of free radicals (r = 0.477, p < 0.01), catalase (r = –0.489, p < 0.01) and SOD (r = –0.357, p < 0.05). Admission superoxide levels were higher and antioxidant levels lower in peritonitis patients than controls. Levels did not significantly change following surgical intervention and post-operative levels did not correlate with outcome. Conclusion: The levels of superoxide and antioxidants correlate with the severity of illness on admission in patients with secondary peritonitis, but serial levels following surgical intervention do not predict outcome.
Proteinuria Is a Determinant of Quality of Life in Diabetic Nephropathy: Modeling Lagged Effects with Path Analysis
Authors: Kelley Ken , Aricak O. Tolga , Light Robert P. , Agarwal Rajiv
Published: July 2007

Background: Diabetic nephropathy with overt proteinuria often progresses relentlessly to end-stage renal disease (ESRD). Material and Methods: To answer the question whether it is impaired glomerular filtration rate (GFR) or its precursor proteinuria which is more related with multiple domains of health-related quality of life (HRQOL), we measured GFR and proteinuria in 44 patients with type 2 diabetes and overt nephropathy and repeated the measurements after 4 months. 38 patients with ESRD due to diabetic nephropathy served as a control group. We used path analysis to examine the association of baseline proteinuria and GFR with baseline and subsequent HRQOL scales. Results: Compared to patients with ESRD, patients with non-dialysis CKD had Kidney Disease Burden (KDB) that was, on a scale from 0 to 100, 19.8 better (95% CI 6.9–32.8) (p = 0.003). Mental component score (MCS) did not differ and physical component score (PCS) was worse in non-dialysis CKD patients by 8.5 (p < 0.001). Proteinuria at baseline was a predictor of PCS, MCS and KDB score at 4 months, suggesting a lagged effect of proteinuria on HRQOL after controlling for the autoregressive effects. GFR was not shown to have a significant impact on HRQOL. One log unit increase in proteinuria was associated with 3.8 (p = 0.011) fall in PCS, 3.3 (p = 0.043) fall in MCS and 10.6 (p = 0.006) fall in KDB. Conclusion: In patients with advanced diabetic nephropathy, we found that proteinuria has a lagged and profound effect on multiple domains of HRQOL.
EEG Frequency Analysis in Demented and Nondemented Parkinsonian Patients
Authors: Neufeld M.Y. , Blumen S. , Aitkin I. , Parmet Y. , Korczyn A.D.
Published: July 2007

In an attempt to evaluate EEG changes associated with dementia in Parkinson''s disease (PD), we performed frequency analysis in three groups of 10 subjects each; two with PD, and one normal control group. The PD patient groups were matched for age, sex, severity and duration of disease, but were discordant for the existence of dementia. Normals were age- and sex-matched healthy volunteers. The relative alpha amplitude was significantly decreased in the demented PD patients, unrelated to motor disability. There was a non-significant but consistent trend of increased amplitude in the delta and theta range in the demented PD patients as compared to nondemented PD subjects and normal controls, as well as increased amplitude in the theta and delta range with more severe motor disability in the nondemented PD patients.
Detection of an Alzheimer Disease Pattern of Cerebral Metabolism in Down Syndrome
Authors: Azari N.P. , Pettigrew K.D. , Pietrini P. , Horwitz B. , Schapiro M.B.
Published: July 2007

Correlational analysis of cerebral metabolic (rCMRglc) data obtained with positron emission tomography (PET) assesses group differences and has demonstrated reduced frontal-parietal rCMRglc interdependencies in Alzheimer''s disease (AD). A multivariate analysis of rCMRglc data assesses individual differences. We recently identified discriminant functions, reflecting frontal-parietal rCMRglc interdependencies, that separated AD from control subjects. To test if the functions would identify an AD rCMRglc pattern in older Down syndrome (DS) adults with (DS DAT+) or without (DS DAT–) dementia, we applied the functions to longitudinal rCMRglc data in: young DS (n = 15), DS DAT– (n = 10), DS DAT+ (n = 4), and young controls (n = 15). All DS DAT+ and some of the later DS DAT– scans were classified as AD. The results provide additional validation of the functions and suggest their utility for the early detection of AD.
Synaptophysin Immunoreactivity of the Cortical Neuropil in Vascular Dementia of Binswanger Type Compared with the Dementia of Alzheimer Type and Nondemented Controls
Authors: Zhan S.-S. , Beyreuther K. , Schmitt H.P.
Published: July 2007

It has been shown recently that in Alzheimer''s disease the degree of dementia is strongly correlated with a reduction of the synaptophysin reactivity of the cortical neuropil as a measure of synapse density, while counts of neuritic plaques showed a weak correlation. This suggests that mechanisms acting at the synaptic level, finally resulting in a numerical decline of synapses, may represent an important factor in the pathogenesis of dementia. Under these aspects, we wanted to examine whether changes of synaptophysin immunoreactivity may also occur in dementia of vascular origin such as Binswanger''s disease, where the white matter atrophy is usually conceived to be the main morphologic correlate of dementia. However, infrequently patients with morphologically typical Binswanger''s subcortical encephalopathy including white matter atrophy are not demented. We found in 9 cases of vascular dementia of Binswanger type a significant reduction in synaptophysin immunoreactivity of the cortical neuropil (9.1 %), the magnitude of which was not much less than in Alzheimer type dementia (10.9 %). These results suggest that a reduction in cortical synaptic population density may also play a significant role in the pathogenesis of dementia in Binswanger''s disease. In view of the fact that similar conditions have been shown to occur in neurodegenerative disorders with dementia other than Alzheimer type dementia, there seems to be evidence for a possible common pathogenetic link between these forms of dementia at the synaptic level, where different etiologic factors may result in similar changes.
Alzheimer's Disease in the NAS-NRC Registry of Aging Twin Veterans
Authors: Breitner J.C.S. , Welsh K.A. , Robinette C.D. , Gau B.A. , Folstein M.F. , Brandt J.
Published: July 2007

Over 3 years we followed 8 pairs of male twins one or both of whom had suspected Alzheimer''s disease (AD) including ''mild/ambiguous'' changes suggestive of incident AD. These pairs were screened in 1988 and 1989 from 339 pairs in the (US) National Academy of Sciences – National Research Council Registry (NASR) of aging veteran twins, then 61–72 years of age. Most of the suspected cases (10 of 12) had mild/ambiguous changes. Including these subjects, we had estimated the prevalence of AD in the NASR as about 2%. We now describe briefly the longitudinal evaluation of these 8 pairs. Only 1 of the 10 individuals with mild/ambiguous changes has progressed to show well-defined clinical symptoms of AD. Two others remain in their original research category, while 7 clearly do not have AD. Thus, we now estimate the 1988–1989 prevalence of AD in the NASR as 0.5%. These results contrast with other follow-up studies of mild cases from a university-based Alzheimer''s clinic. We suggest that the contrasting findings reflect the nature of the samples studied, and we show that the present results are predicted by Bayesian reasoning.
Pathology and Pathophysiology of Cerebrovascular Dementia: Pure Subgroups of Obstructive and Hypoperfusive Etiology
Authors: Brun Arne
Published: July 2007

The brains of 175 consecutive autopsy cases of dementia, clinically studied prospectively, were analyzed pathoanatomically with regard to type, size and site of lesions. Pure groups of vascular dementia caused by large or small vessel disease and by hypoperfusion could be defined. The infarcts were either complete with a more or less pronounced incomplete perifocal component or of an incomplete type only. Incomplete infarction appears to be an important and yet little appreciated cause of brain dysfunction. These groups could be used as a basis for a pathoanatomical classification of vascular dementias. Vascular dementia is much more common than generally assumed.
Pathogenesis of Vascular Dementia: The Possible Role of Hypertension
Authors: Johansson Barbro B.
Published: July 2007

In spite of the fact that hypertension is the main risk factor for cerebrovascular disease, retrospective studies have not given a clear answer concerning the role of hypertension in vascular dementia. Hypertension predisposes to intracerebral and extracerebral arterial alterations which may cause cerebrovascular events by a number of mechanisms. In addition to the established association between hypertension and stroke, the role of hypertension for silent white matter hyperintensities (WMHIs) observed on magnetic resonance imaging is debated. Data are presented indicating that WMHIs are rare below the age of 55 in normotensive individuals but are not infrequent when the blood pressure is moderately or markedly increased. It is proposed that the possible role of hypertension in vascular dementia should be evaluated in prospective studies of hypertensive populations.
Clinical Criteria for Vascular Dementia: The NINDS-AIREN Criteria
Authors: Erkinjuntti Timo
Published: July 2007

Vascular dementia (VAD) is the second most common cause of dementia. In addition, cerebrovascular disease (CVD) coexists with other causes, including Alzheimer''s disease. Cognitive impairment related to CVD may be preventable, and these patients could benefit from therapy. This emphasizes the need for early detection, diagnostic consistency and accuracy of the clinical diagnosis of VAD. A number of current limitations in our knowledge about VAD have restricted the construction of clinical criteria, especially the concept of a behavioral syndrome due to vascular factors affecting the brain, and the main pathophysiological factors related to VAD. The latter include the type, extent, location and tempo of vascular brain lesions, as well as the causality between brain lesions and cognitive impairment. However, relevant information on VAD is beginning to emerge. The NINDS-AIREN Workshop on VAD made an attempt to facilitate international discussion and cooperation by defining consequences of CVD and the criteria for the VAD syndrome, for epidemiological and clinical studies. Here the concepts, pathophysiological factors, current conceptual barriers, and the criteria for the clinical diagnosis are reviewed.
Cambridge Neuropsychological Test Automated Battery (CANTAB): A Factor Analytic Study of a Large Sample of Normal Elderly Volunteers
Authors: Robbins T.W. , James M. , Owen A.M. , Sahakian B.J. , McInnes L. , Rabbitt P.
Published: July 2007

The CANTAB battery was administered to a large group (n = 787) of elderly volunteers in the age range from 55 to 80 years. This battery, which is based on tests used to identify the neural substrates of learning and memory in non-human primates, has now been extensively used in the assessment of various forms of dementia and also validated on patients with neurosurgical lesions of the frontal and temporal lobes. The tests employed were pattern and spatial recognition, simultaneous and delayed matching to sample, learning of visuo-spatial paired associates, a matching to sample, reaction time task and a test of spatial working memory. The sample was banded into different IQ bands based on performance on 5 standard tests of intelligence. The MMSE was also administered to exclude cases of possible dementia (n = 16) in the normal sample. In general, performance declined with age and IQ, but these factors did not interact. A factor analysis (with varimax rotation) identified 4 factors with eigenvalues greater than 1, which accounted for over 60% of the variance. Factor 1 was equated with general learning and memory ability and loaded significantly with the Intelligence scores; factor 2 was related to speed of responding and loaded most heavily with Age. Comparisons were also made of performance on CANTAB of those subjects with dementing scores on the MMSE and the lowest 5th percentile of the population sample. The results are discussed in terms of the utility of the CANTAB battery for the assessment of dementia and of the implications for theories of changes in cognitive function during normal aging.
The Diagnosis and Grading of Dementia in Population Surveys: Measuring Disability
Authors: Kay D.W.K
Published: July 2007

Comparability in respect of severity of dementia and determination of the nature and degree of disabilities in daily living due to dementia are important in population-based surveys. In physical diseases impairment of a system or organ may be established independently of disability using the ICIDH frame-work but there are problems in measuring cognitive abilities apart from the characteristic behavioural limitations and aberrations that constitute the dementia syndrome. Both DSM-III-R and ICD-10 require as a criterion of dementia that social activities are interfered with, and the degree of dependency is the measure of severity. This suggests that assessment of disability should be the first objective, and the mental or physical causes uncovered next. A suitable informant may be the best judge of the nature of the disability. This procedure would show what services demented persons actually require, clarify the implications of dementia for estimates of active life-expectancy, and increase comparability between studies. Problems associated with this approach and the role of cognitive testing are briefly discussed.
Transcranial Doppler Sonography in Dementia of Alzheimer Type
Authors: Heun R. , Knappertz V. , Kraemer G.
Published: July 2007

The intention of this study was to examine the relation of clinical variables and cognitive dysfunction to cerebrovascular blood flow in a sample of patients with Alzheimer''s disease without any sign or symptom of cardiovascular or cerebrovascular disease. The patients met DSM-III-R criteria for dementia of Alzheimer type. Blood flow velocities in the anterior, middle (MCA) and posterior cerebral arteries were recorded using transcranial Doppler sonography. Several psychometric tests including the Mini-Mental State Examination (MMSE) were performed. The patients’ age correlated significantly with the systolic flow velocity in the left MCA (r = –0.57) explaining 24% of the total variance; there was a reduction of the mean flow velocity of 0.7 ± 0.2 mm/s for every additional year. The MMSE correlated significantly with the systolic flow velocity in the left MCA (r = 0.62) explaining 29% of the total variance. The correlations of flow velocities with age indicate that even in very old patients there is a progressive reduction of cerebral blood flow velocities. The independent negative correlations of flow velocities with cognitive dysfunction indicate that there are progressive cerebrovascular flow reductions in the course of Alzheimer''s disease. Both facts should be taken into account when Alzheimer patients are compared with other samples.
Evaluation of the Triple Tibial Osteotomy. A new technique for the management of the canine cruciate-deficient stifle
Authors: Rose A. , Tuke J. , Robins G. M. , Bruce W. J.
Published: July 2007

The triple tibial osteotomy (TTO) is a technique which combines the features of tibial tuberosity advancement and wedge osteotomy for the treatment of complete and partial cruciate ligament injuries in dogs. In this paper, the technique is described and the results of a prospective study of 64 consecutive cases are presented. TTO provided a satisfactory clinical outcome in a very high percentage of cases. The technique is relatively easy to learn and has a low post-operative complication rate.
Phenotypic maintenance of articular chondrocytes in vitro requires BMP activity
Authors: Oshin A. O. , Caporali E. , Byron C. R. , Stewart A. A. , Stewart M. C.
Published: July 2007

Articular chondrocytes are phenotypically unique cells that are responsible for the maintenance of articular cartilage. The articular chondrocytic phenotype is influenced by a range of soluble factors. In particular, members of the bone morphogenetic protein (BMP) family support the articular chondrocytic phenotype and stimulate synthesis of cartilaginous matrix. This study was carried out to determine the importance of BMPs in supporting the differentiated phenotype of articular chondrocytes in vitro. Exogenous BMP-2 supported expression of collagen type II and aggrecan in monolayer chondrocyte cultures, slowing the dedifferentiation process that occurs under these conditions. In contrast, BMP-2 had little effect on expression of these genes in three-dimensional aggregate cultures. Endogenous BMP-2 expression was lost in monolayer cultures, coincident with the down-regulation of collagen type II and aggrecan mRNAs, whereas BMP-2 mRNA levels were stable in aggregate cultures. Antagonism of endogenous BMP activity in aggregate cultures by Noggin or a soluble form of the BMP receptor resulted in reduced expression of collagen type II and aggrecan mRNAs, reduced collagen type II protein and sulfated glycosaminoglycan (GAG) deposition into the aggregate matrices and reduced secretion of GAGs into the culture media. These results indicate that endogenous BMPs are required for maintenance of the differentiated articular chondrocytic phenotype in vitro. These findings are of importance to cell-based strategies designed to repair articular cartilage. Articular chondrocytes require conditions that will support endogenous expression of BMPs to maintain the specialized phenotype of these cells.
Avulsion of the triceps tendon insertion in a cat
Authors: Jermyn K. , Carmichael S. , Clarke S. P.
Published: July 2007

Avulsion of the insertion of the triceps tendon, which had a pre-existing tendinopathy, is described in a cat. The tendon was re-attached to the olecranon and the repair was immobilised using a type Ia trans-articular external skeletal fixator. The treatment was successful, however, mild and intermittent lameness persisted. Although it is an uncommon condition in small animals, the diagnosis should be based on careful clinical and radiographic examination.
Measurement of velocity with a kinematic system versus a photocell system in the collection of canine ground reaction forces
Authors: Punke J. P. , Andrews C. M. , Speas A. L. , Reynolds L. R. , Budsberg S. C.
Published: July 2007

Velocities obtained from a five photocell system were compared to velocities of nine anatomical points on a handler and canine subject as reported by a kinematic system over the same distance. There was not a statistically significant difference between the velocities of the markers on the dogs’ occipital protuberance and interscapular region compared with the velocity as reported by the photocell system. The average velocities of the three markers on the forelimb of the dogs and three markers on the handler's leg and one on the sacrum had statistically different values than the photocell system. Given these results, photocell systems with the same configuration in this study can be trusted to report accurate trunk velocities of canine subjects during the collection of ground reaction forces.
Tibial segmental bone defect treated with bone plate and cage filled with either xenogeneic composite or autologous cortical bone graft
Authors: Teixeira C. R. , Volpi R. S. , Taga R. , Cestari T. M. , Granjeiro J. M. , Vulcano L. C. , Correa M. A. , Rahal S. C.
Published: July 2007

Tibia segmental defect healing in sheep were clinically, radiographically and histologically evaluated. Twelve young sheep aged four to five months were divided into two groups, G1 and G2. A 3.5 cm long segmental defect was created in the right tibial diaphysis with maintenance of the periosteum. The bone defects in both groups were stabilized with a bone plate combined with a titanium cage. In G1 the cage was filled with pieces of autologous cortical bone graft. In G2 it was filled with a composite biomaterial which consisted of inorganic bovine bone, demineralized bovine bone, a pool of bovine bone morphogenetic proteins bound to absorbable ultra-thin powdered hydroxyapatiteand bonederived denaturized collagen. Except for one G1 animal, all of them showed normal limb function 60 days after surgery. Radiographic examination showed initial formation of periosteal callus in both groups at osteotomy sites, over the plate or cage 15 days postoperatively. At 60 and 90 days callus remodeling occurred. Histological and morphometric analysis at 90 days after surgery showed that the quantity of implanted materials in G1 and G2 were similar, and the quantity of new bone formation was less (p=0.0048) and more immature in G1 than G2, occupying 51 ± 3.46% and 62 ± 6.26% of the cage space, respectively. These results suggest that the composite biomaterial tested was a good alternative to autologous cortical bone graft in this experimental ovine tibial defect. However, additional evaluation is warranted prior to its clinical usage.
Pathogenic Sequence for Dissecting Aneurysm Formation in a Hypomorphic Polycystic Kidney Disease 1 Mouse Model
Authors: Hassane Sabrine , Claij Nanna , Lantinga-van Leeuwen Irma S. , Van Munsteren J. Conny , Van Lent Natascha , Hanemaaijer Roeland , Breuning Martijn H. , Peters Dorien J.M. , DeRuiter Marco C.
Published: July 2007

Objective—

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a multi-system disorder characterized by progressive cyst formation in the kidneys. Serious complications of ADPKD are intracranial and aortic aneurysms. The condition is mainly caused by mutations in the
PKD1
or
PKD2
gene. We have carefully analyzed vascular remodeling in hypomorphic
Pkd1

nl/nL

mouse model with dissecting aneurysms in the aorta.

Methods and Results—

Quantitative real-time polymerase chain reaction revealed that in the aorta the expression of normal
Pkd1
is reduced to approximately 26%. Using (immuno)histochemistry we have characterized the pathogenetic sequence for dissecting aneurysm formation. The aorta shows regions with accumulation of matrix components between the elastin lamellae. This is followed by increased numbers of smooth muscle cells and locally weakening of the media. In the intima, accumulation of matrix components and detachment of endothelial cells from the elastin lamellae results in a tear. The combination of weak media and a tear in the intima leads to rupture of the vessel wall resulting in intramural bleeding.

Conclusions—

The
Pkd1

nl/nl

mouse reveals that polycystin1 is implicated in maintenance of the vessel wall structural integrity, and it is a useful model for dissecting aneurysm formation studies.
Estrogen-Mediated Endothelial Progenitor Cell Biology and Kinetics For Physiological Postnatal Vasculogenesis
Authors: Masuda Haruchika , Kalka Christoph , Takahashi Tomono , Yoshida Miyoko , Wada Mika , Kobori Michiru , Itoh Rie , Iwaguro Hideki , Eguchi Masamichi , Iwami Yo , Tanaka Rica , Nakagawa Yoshihiro , Sugimoto Atsuhiko , Ninomiya Sayaka , Hayashi Shinichiro , Kato Shunichi , Asahara Takayuki
Published: July 2007

Estrogen has been demonstrated to promote therapeutic reendothelialization after vascular injury by bone marrow (BM)–derived endothelial progenitor cell (EPC) mobilization and phenotypic modulation. We investigated the primary hypothesis that estrogen regulates physiological postnatal vasculogenesis by modulating bioactivity of BM-derived EPCs through the estrogen receptor (ER), in cyclic hormonally regulated endometrial neovascularization. Cultured human EPCs from peripheral blood mononuclear cells (PB-MNCs) disclosed consistent gene expression of ER α as well as downregulated gene expressions of ER β. Under the physiological concentrations of estrogen (17β-estradiol, E2), proliferation and migration were stimulated, whereas apoptosis was inhibited on day 7 cultured EPCs. These estrogen-induced activities were blocked by the receptor antagonist, ICI182,780 (ICI). In BM transplanted (BMT) mice with ovariectomy (OVX) from transgenic mice overexpressing β-galactosidase (lacZ) regulated by an endothelial specific Tie-2 promoter (Tie-2/lacZ/BM), the uterus demonstrated a significant increase in BM-derived EPCs (lacZ expressing cells) incorporated into neovasculatures detected by CD31 immunohistochemistry after E2 administration. The BM-derived EPCs that were incorporated into the uterus dominantly expressed ER α, rather than ER β in BMT mice from BM of transgenic mice overexpressing EGFP regulated by Tie-2 promoter with OVX (Tie-2/EGFP/BMT/OVX) by ERs fluorescence immunohistochemistry. An in vitro assay for colony forming activity as well as flow cytometry for CD133, CD34, KDR, and VE-cadherin, using human PB-MNCs at 5 stages of the female menstrual-cycle (early-proliferative, pre-ovulatory, post-ovulatory, mid-luteal, late-luteal), revealed cycle-specific regulation of EPC kinetics. These findings demonstrate that physiological postnatal vasculogenesis involves cyclic, E2-regulated bioactivity of BM-derived EPCs, predominantly through the ERα.
Increased Severity of Hemorrhage in Transgenic Mice Expressing Cerebral Protease Nexin-2/Amyloid β-Protein Precursor
Authors: Xu Feng , Previti Mary Lou , Van Nostrand William E.
Published: July 2007

Background and Purpose—

Secreted isoforms of amyloid β-protein precursor (AβPP) that contain the Kunitz proteinase inhibitor domain, also known as protease nexin-2 (PN2), are enriched in brain. Although little is known of its physiological function, the potent inhibition of certain prothrombotic proteinases by PN2/AβPP suggests that it may function to regulate cerebral thrombosis during vascular injury events.

Methods—

To examine the antithrombotic function of cerebral PN2/AβPP in vivo, we performed measurements of carotid artery thrombosis and experimental intracerebral hemorrhage in transgenic mice with specific and modest overexpression of PN2/AβPP in brain. Comparisons were made with wild-type mice and Tg-rPF4/APP mice, a model that possesses specific and modest overexpression of PN2/AβPP in platelets and exhibits reduced thrombosis in vivo.

Results—

Modest overexpression of PN2/AβPP in transgenic mouse brain had no effect on intraluminal carotid arterial thrombosis but resulted in larger hematoma volumes and hemoglobin levels (23.1±2.7 mm
3
[n=6;
P
<0.01] and 1411±202 μg/hemisphere [n=12;
P
<0.01], respectively), compared with wild-type mice (15.9±2.2 mm
3
[n=6] and 935±418 μg/hemisphere [n=12], respectively).

Conclusions—

These findings indicate that cerebral PN2/AβPP plays a significant role in regulating thrombosis in brain and that modest age-related increases in the cerebral levels of this protein could markedly enhance the extent of cerebral hemorrhage.
Prevalence of Subcortical Vascular Lesions and Association With Executive Function in Mild Cognitive Impairment Subtypes
Authors: Bombois Stéphanie , Debette Stéphanie , Delbeuck Xavier , Bruandet Amélie , Lepoittevin Samuel , Delmaire Christine , Leys Didier , Pasquier Florence
Published: July 2007

Background and Purpose—

Subcortical hyperintensities (SH) have not been systematically evaluated in mild cognitive impairment (MCI). We sought to describe their frequency and distribution, and to test their association with cognitive characteristics in MCI patients.

Methods—

We performed standardized neuropsychological tests and an MRI scan in 170 consecutive MCI patients. Medial temporal lobe atrophy and SH, including periventricular, lobar white matter, basal ganglia and infratentorial hyperintensities, were assessed with visual semiquantitative scales.

Results—

The median age was 68.1 years (range: 45.5 to 87.0), and the median Mini-Mental State Examination score 28.0 (range: 26.0 to 30.0). MCI subtypes were amnestic single domain (21.2%), amnestic multiple domain (52.3%), nonamnestic single domain (21.8%), and nonamnestic multiple domain (4.7%). SH were found in 157 patients (92.6%); periventricular hyperintensities (80.6%) and lobar white matter hyperintensities (83.5%) were the most prominent locations. There was no association between SH and MCI subtypes. Executive dysfunction was independently associated with SH (odds ratio=2.53, 95% CI: 1.20 to 5.32), periventricular hyperintensities (odds ratio=2.51, 95% CI: 1.13 to 5.55), and white matter hyperintensities (odds ratio=2.08, 95% CI: 1.01 to 4.25).

Conclusions—

The prevalence of SH is high in MCI patients, irrespective of MCI subtypes. SH (especially periventricular hyperintensities, and lobar white matter hyperintensities) are associated with executive dysfunction.
Therapeutic Benefit of Low-Dose Clopidogrel in Patients Undergoing Carotid Surgery Is Linked to Variability in the Platelet Adenosine Diphosphate Response and Patients’ Weight
Authors: Payne David A. , Jones Chris I. , Hayes Paul D. , Naylor A. Ross , Goodall Alison H.
Published: July 2007

Background and Purpose—

We have previously shown that a single 75-mg tablet of clopidogrel, taken before carotid endarterectomy, significantly reduces postoperative embolization, a marker of thromboembolic stroke. This study explores the antiplatelet effect of this submaximal dose.

Methods—

Fifty-six patients on long-term aspirin (150 mg) were randomized to 75 mg clopidogrel or placebo before carotid endarterectomy. Blood samples were taken pre- and postdrug administration and at the end of surgery to measure platelet activation and adenosine diphosphate (ADP) response by flow cytometry and aggregometry.

Results—

Surgery produced a significant rise in platelet activation in vivo as evidenced by a rise in the percentage of monocyte–platelet aggregates in patients given placebo, but this was not seen in patients receiving clopidogrel. Before surgery, clopidogrel produced a significant reduction in the platelet response to ADP; for example, with 10
−6
M ADP, 77.32±2.3% bound fibrinogen in placebo group compared with 67.16±3.1% after clopidogrel (
P
=0.01). This was accentuated after surgery when the percentage of platelets binding fibrinogen in response to ADP was 76.53±2.2% in patients given placebo and 62.84±3.3% in the clopidogrel group (
P
=0.002). Similar differences were seen over a range of ADP concentrations and by aggregometry. Platelet responsiveness before treatment was highly variable and was positively correlated with the inhibitory effect of clopidogrel; patients with the highest baseline response to ADP showed the greatest response to clopidogrel. A negative correlation was seen between the effect of clopidogrel and patients’ weight (
r
=0.57;
P
=0.002).

Conclusions—

These results explain how a single 75-mg dose of clopidogrel produces a significant clinical impact on embolization.
Estimating Surface Damage of Composite Panels with Inverse Analysis
Authors: Ramanujam Narayanan , Nakamura Toshio
Published: July 2007

When composite structures are exposed to harsh environmental conditions or impacted by foreign objects, their surfaces may degrade or damage. Damage evaluations of composite panels often demand expensive tools and time-consuming processes. The aim of this work is to introduce a versatile inverse analysis based method that requires less measurement efforts than those of conventional techniques. In this procedure, first, strains are measured on a surface opposite to damaged surface. Then, general functions relating damage conditions to strain fields are established. These functions reduce computational efforts required during the damage identification. With the measured strains and functions, an error objective function is minimized via iterations to estimate the damage extent. To verify the effectiveness of this proposed procedure, a detailed simulation study is performed with cross-ply composite laminates possessing various damage. The results show excellent matches between the estimated damage fields and the specified conditions imposed on the models. Following this promising outcome, the proof of concept study is extended to several real cross-ply composite panels that are damaged by either sand-blasting or environmental exposure. In the latter case, the composites were exposed to combined ultraviolet radiation and moisture absorption. On composite specimens, spatial variations of strain fields are measured with strip strain-gauges. Then they are used to identify surface damage distributions with either the quadratic formulation or the B-spline method. The latter approach is suitable when the functional change of strains due to damage is not smooth. The results estimated the variation of damage extent in each specimen. This feasibility study clearly supports the possibility of using strain sensor-network or optical method to quantify surface damage.
Demobilization and Reintegration
Authors: Humphreys Macartan , Weinstein Jeremy M.
Published: July 2007

Since 1989, international efforts to end protracted conflicts have included sustained investments in the disarmament, demobilization, and reintegration (DDR) of combatants. Yet while policy analysts have debated the factors that contribute to successful DDR programs and scholars have reasoned about the macro conditions that facilitate successful peace building, little is known about the factors that account for successful reintegration at the micro level. Using a new dataset of ex-combatants in Sierra Leone, this article analyzes the individual-level determinants of demobilization and reintegration. Past participation in an abusive military faction is the strongest predictor of difficulty in achieving social reintegration. On economic and political reintegration, we find that wealthier and more educated combatants face greater difficulties. Ideologues, men, and younger fighters are the most likely to retain strong ties to their factions. Most important, we find little evidence at the micro level that internationally funded programs facilitate demobilization and reintegration.
Modeling of In Vitro Drug Activity and Prediction of Clinical Outcome in Acute Myeloid Leukemia
Authors: Quartino Angelica , Karlsson Mats O. , Freijs Agneta , Jonsson Niclas , Nygren Peter , Kristensen Jörgen , Lindhagen Elin , Larsson Rolf
Published: July 2007

The objectives of this study were to develop a population pharmacodynamic model describing the in vitro drug sensitivity of tumor cells and to relate in vitro parameters to clinical outcome. Cell samples from 179 patients with acute myelocytic leukemia were exposed to cytosine arabinoside and daunorubicin, and cytotoxicity was analyzed using the fluorometric microculture cytotoxicity assay. A sigmoid Emax‐model for daunorubicin and an Emax‐model for cytosine arabinoside described the data. The model predicted drug potency (EC50) adequately from 1 concentration measurement. A logistic regression on individual in vitro parameters of 46 patients treated with the daunorubicin plus cytosine arabinoside regimen showed that the probability of complete response was significantly (P <.05) related to the product of the Emax/EC50 ratio of the two drugs. The findings demonstrate the value of population pharmacodynamic modeling of in vitro drug sensitivity data and a significant relationship between the in vitro parameters and clinical outcome.
Single‐ and Multiple‐Dose Administration of Caspofungin in Patients With Hepatic Insufficiency: Implications for Safety and Dosing Recommendations
Authors: Mistry Goutam C. , Migoya Elizabeth , Deutsch Paul J. , Winchell Gregory , Hesney Michael , Li Susan , Bi Sheng , Dilzer Stacy , Lasseter Kenneth C. , Stone Julie A.
Published: July 2007

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single‐dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple‐dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration‐time profile over the interval of last quantifiable point to infinity (AUC0‐∞) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32–1.86) in the single‐dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04–1.39) for day 14 area under the concentration– time profile calculated over the interval 0 to 24 hours (AUC0‐24h) following multidose. The AUC0‐∞ GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51–2.06) following 70 mg; AUC0‐24h GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90–1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70‐mg loading dose is recommended for patients with moderate hepatic insufficiency.
Pharmacokinetics of 852A, an Imidazoquinoline Toll‐Like Receptor 7‐Specific Agonist, Following Intravenous, Subcutaneous, and Oral Administrations in Humans
Authors: Harrison Lester I. , Astry Calvin , Kumar Sandeep , Yunis Carla
Published: July 2007

852A is an imidazoquinoline Toll‐like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de‐escalation), and to 6 subjects as a 2.0‐mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0‐mg oral dose because of hypotension. The 2.0‐mg subcutaneous dose had 80.5% ± 12.8% (mean ± SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon‐α dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0‐mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% ± 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.
An Informatics Approach to Assess Pediatric Pharmacotherapy: Design and Implementation of a Hospital Drug Utilization System
Authors: Zuppa Athena , Vijayakumar Sundararajan , Jayaraman Bhuvana , Patel Dimple , Narayan Mahesh , Vijayakumar Kalpana , Mondick John T. , Barrett Jeffrey S.
Published: July 2007

Drug utilization in the inpatient setting can provide a mechanism to assess drug prescribing trends, efficiency, and cost‐effectiveness of hospital formularies and examine subpopulations for which prescribing habits may be different. Such data can be used to correlate trends with time‐dependent or seasonal changes in clinical event rates or the introduction of new pharmaceuticals. It is now possible to provide a robust, dynamic analysis of drug utilization in a large pediatric inpatient setting through the creation of a Web‐based hospital drug utilization system that retrieves source data from our accounting database. The production implementation provides a dynamic and historical account of drug utilization at the authors' institution. The existing application can easily be extended to accommodate a multi‐institution environment. The creation of a national or even global drug utilization network would facilitate the examination of geographical and/or socioeconomic influences in drug utilization and prescribing practices in general.
Development of a Community-Based Diabetes Management Program for Pacific Islanders
Authors: Wang Chen-Yen , Abbott Lisa , Goodbody Angela K. , Hui Wai-Ting Y. , Rausch Clair
Published: July 2007

PURPOSE

his study examined the perception of diabetes among a sample of Pacific Islanders in Honolulu, Hawaii. All 23 participants were diagnosed with type 2 diabetes, ranged in age from 21 to 70 years, and had glycosylated hemoglobin levels of 5.8% to 13.9%.

METHODS

Four focus groups were held in English and audiotaped. Outreach workers served as translators and comoderators. The content of transcripts was analyzed with Ethnograph software by investigators. The priority issues were confirmed by the comoderators and participants.

RESULTS

Participants perceived diabetes as full of complications, emotions, symptoms, and behavior changes. Responses to hyperglycemia were fear, frustration, and uncertainty. Barriers to staying on the prescribed diet were habit, cultural ritual, ideal body image, and limited budget.

CONCLUSIONS

Participants suggested that helpful activities would include walking/support group, cooking class, community healthy food store, translated material, and family participation. A community-based diabetes program has been developing as a result of the focus group findings.