bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues
Authors: Sharp Swee Y. , Prodromou Chrisostomos , Boxall Kathy , Powers Marissa V. , Holmes Joanna L. , Box Gary , Matthews Thomas P. , Cheung Kwai-Ming J. , Kalusa Andrew , James Karen , Hayes Angela , Hardcastle Anthea , Dymock Brian , Brough Paul A. , Barril Xavier , Cansfield Julie E. , Wright Lisa , Surgenor Allan , Foloppe Nicolas , Hubbard Roderick E. , Aherne Wynne , Pearl Laurence , Jones Keith , McDonald Edward , Raynaud Florence , Eccles Sue , Drysdale Martin , Workman Paul
Published: April 2007

Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (Kd) of VER-50589 was 4.5 ± 2.2 nmol/L compared with 78.0 ± 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC50 of 21 ± 4 nmol/L for VER-50589 compared with 47 ± 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI50 values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 ± 15 and 685 ± 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI50 for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors. [Mol Cancer Ther 2007;6(4):1198–211]
Neurosurgical Management of Intramedullary Spinal Cord Tumors in Children
Authors: Kothbauer Karl F.
Published: April 2007

The majority of intramedullary spinal cord tumors in children are low-grade glial tumors. They become symptomatic with pain, neurologic deficits or spinal deformity. The diagnosis is most readily obtained using magnetic resonance imaging. The natural history is significant for slow progression of symptoms. Surgery is the best treatment and is also indicated to confirm the histological diagnosis. In case of a low-grade tumor or a vascular lesion such as hemangioblastoma or cavernoma, a total or near-total resection is attempted. For astrocytomas the resection almost always remains biologically incomplete, but a near-total resection is still associated with a long progression-free survival. Neurologic morbidity is relatively low during long-term follow-up but can be up to 30% for transient motor deficits. The risk for neurologic deterioration is higher for patients with pronounced dysfunction preoperatively. This is an important argument for early surgical resection. Surgery is performed using the spectrum of microsurgical techniques as well as advanced technology, e.g. lasers and intraoperative neurophysiological monitoring with motor evoked potentials. High-grade tumors are resected conservatively and treated with radiation and chemotherapy. The prognosis of high-grade glial tumors remains poor.
Utility Technology in the Assessment of the Cut-Off between a Negative and a Positive Test in a Caries Prediction Model
Authors: van Palenstein Helderman W.H. , van’t Hof M.A. , van Loveren C. , Bronkhorst E.
Published: April 2007

The methodology for the assessment of a negative or positive test in caries prediction models has not received much attention. This study aims to explain how utility technology could be applied in a caries prediction model for the assessment of the cut-off between a negative and a positive test. In this study loss of utilities was assigned to false outcomes of the prediction test. A regression equation with past caries experience variables of 11-year-old children and caries increment in the 11- to 15-year forecast period as outcome was computed. The adjusted explained variance for caries increment was 0.45. Formulas were constructed for the loss of utilities for false-negative tests whereas false-positive tests were corrected with a fixed loss of utilities. Each 11-year-old child of the 252 children was screened at various points of the regression equation. Loss of utilities was calculated for each child on the basis of the validation criterion, the outcome of the test and the actual caries increment of the child. The point on the regression equation with the least loss of utilities for the whole group was taken as the cut-off between a negative and a positive test. If the validation criterion for the prediction period was set on no caries, the prediction model resulted in a sensitivity of 84% and a specificity of 73%. This prediction model has potential when caries incidence is low and resources limited.
Risk Factors for a False Positive Test Outcome in Diagnosis of Caries in Approximal Surfaces: Impact of Radiographic Modality and Observer Characteristics
Authors: Wenzel A. , Haiter-Neto F. , Gotfredsen E.
Published: April 2007

The aim of this study was to evaluate the impact of image modality and observer characteristics on radiographic caries diagnosis with particular emphasis on the false positive (FP) test outcome. Eighty human teeth were radiographed by eight digital modalities and film. Eight observers scored caries lesions in each approximal tooth surface. Their use of image enhancement and time spent in assessing an image was recorded. Microscopy served as validation for the presence/absence of a lesion. Of 160 approximal surfaces, 63% were sound and 37% had lesions. Multivariate logistic regression analysis was performed with the FP test outcome as the dependent variable and the radiographic modality and observer’s gender, experience, employment, image enhancement, and time use as the independent variables. The significant risk factors for an FP test outcome were: (1) gender: males scored fewer FP than females (OR 0.26, CI 0.18–0.36); (2) experience: observers with no experience with digital radiography had a six times higher risk for an FP (OR 6.09, CI 4.9–8.1); (3) radiographic modality: two of the digital systems had a significantly lower risk for an FP [a phosphor plate system (OR 0.55, CI 0.37–0.73) and a sensor-based system (OR 0.65, CI 0.46–0.93)] and one phosphor plate system had a higher risk (OR 1.57, CI 1.17–2.13) than film; (4) time use: more time was spent when scoring an FP (OR 1.05, CI 1.03–1.05) than for any other test outcome. Type of employment and the use of image enhancement had no significant impact on the risk for an FP diagnosis.
Reliability of Quantitative Laser Fluorescence Analysis of Smooth Surface Lesions Adjacent to the Gingival Tissues
Authors: Yin W. , Feng Y. , Hu D. , Ellwood R.P. , Pretty I.A.
Published: April 2007

The aim of this study was to determine the impact of analysis patch border inclusion or exclusion on the reliability of quantitative laser fluorescence (QLF) analyses of lesions close to the gingival margin. Ninety-three lesions on the maxillary anterior teeth were imaged using a fluorescent capturing system. All the lesions were located on the gingival third of the teeth. One examiner undertook two analyses of the images 1 week apart and another examiner undertook a single analysis. Analyses were undertaken using QLF 2.00 g with four patch borders. Each border was assessed as active or inactive. QLF metrics ΔF, ΔQ and area were exported. Kappa statistics were used to measure the agreement of border inclusion between all three analyses, and intra-class correlation coefficients (ICCs) were used to determine the intra- and inter-examiner reliability of the QLF metrics. Agreement on border exclusion was poor; with intra-examiner kappa of 0.48 and inter-examiner at 0.20. However, despite the inconsistencies in border exclusions the ICCs for each QLF metric were high; intra-examiner ΔQ 0.91, ΔF 0.80 and area 0.92; inter-examiner ΔQ 0.86, ΔF 0.68, area 0.88. Lesions adjacent to the gingival margin will often require a patch analysis border to be excluded in order to ensure a satisfactory reconstruction and thus accurate analysis. The decision to include or exclude a border and, if excluded, which border to select appears to be highly variable between examiners. Nevertheless, the QLF metrics appear to be robust as demonstrated by the high ICCs noted in this study.
Applicability of the Dyes CFSE, CM-DiI and PKH26 for Tracking of Human Preadipocytes to Evaluate Adipose Tissue Engineering
Authors: Hemmrich Karsten , Meersch Melanie , von Heimburg Dennis , Pallua Norbert
Published: April 2007

Adipose tissue engineering with preadipocyte-loaded scaffolds requires adequate tracking of preadipocytes to allow evaluation and quantification of cell proliferation, expansion and differentiation in three-dimensional systems. To differentiate between graft and host cells, labeling of preadipocytes before implantation and tracking of these cells until harvest would be useful. Immunohistochemistry enables the differentiation between cells of different species but is time-consuming, expensive, elaborate, and not applicable for autologous transplantation. So far, there is no published method to use externally applied dyes for tracking of human preadipocytes in adipose tissue engineering. We tested the cell dyes PKH26, CM-DiI, and CFSE to analyze their applicability for labeling human preadipocytes. CM-DiI had toxicity levels of 45–70%, while 3–4% proliferating cells were stained on day 35. CFSE revealed clear cytoplasmic coloring in proliferating cells with 5–6% stained cells after 35 days and toxicity ranging from 55 to 90% dead cells. PKH26 demonstrates lowest levels of toxicity and best labeling results after 4 weeks in proliferating preadipocytes in monolayer. Although none of the dyes showed long-lasting labeling during proliferation, all three dyes demonstrated permanent staining in differentiated cells. The results reveal the problems of preadipocyte tracking with fluorescent dyes but justify the dye application for limited time periods.
Digital Measurements: A Different Approach to Evaluate Bone Formation
Authors: Gordjestani M. , Dermaut L. , De Ridder L. , De Waele P. , De Leersnijder W. , Bosman F.
Published: April 2007

In this study a digital measurement technique has been proposed to quantify bone formation on histological images. Two standard parietal defects were created in 30 adult rabbits. The animals were divided into six groups. Four animals of each group were randomly chosen as experimental group in which osteopontin-coated hydroxyapatite (OPN-HA) and hydroxyapatite (HA) were inserted alternatively in created defects. To observe the spontaneous healing process of defects, one animal of each group was used as control animal and these created defects did not receive any implants. The animals were sacrificed after 1, 2, 6, 12, 18 and 30 weeks. The histological sections were magnified (×100) and scanned digitally. The newly formed bone surfaces within the healing area were indicated and quantified by means of Adobe Photoshop® 7 software. This measuring technique was found to be reliable and reproducible. The results of this study show no significant differences in bone formation between the OPN-HA and non-coated HA defects, although a significant difference in bone formation was measured at the margins of the defects treated with OPN-HA.
Immunohistochemical Study of Somatotrophs in Pituitary Pars Distalis of Male Viscacha (Lagostomus maximus maximus) in Relation to the Gonadal Activity
Authors: Filippa V. , Mohamed F.
Published: April 2007

Somatotrophs were identified and quantified in pituitary pars distalis of male viscachas (Lagostomus maximus maximus) during the annual reproductive cycle, after the administration of melatonin, after castration and in different growth stages by immunohistochemistry and morphometric analysis. In adult male viscachas, the somatotrophs were distributed throughout the pars distalis during the reproductive cycle. They were oval, pyramidal or round in shape with a large round nucleus. The percentage immunopositive area, the major cellular diameter and the number of cells decreased during the gonadal regression period in relation to the values found in the reproductive period. The administration of melatonin did not provoke any variations of the morphometric parameters studied. On the contrary, a significant decrease in the percentage immunopositive area, in the major cellular diameter and in the number of somatotrophs in castrated viscachas was observed. The study of different growth stages showed that these morphometric parameters increased from immature to adult animals in the reproductive period. The results obtained suggested that the variations of the morphometric parameters of somatotrophs are more related to the gonadal development and activity than to a direct effect of melatonin.
Which Panic Disorder Patients Benefit from Which Treatment: Cognitive Therapy or Antidepressants?
Authors: Dusseldorp Elise , Spinhoven Philip , Bakker Abraham , van Dyck Richard , van Balkom Anton J.L.M.
Published: April 2007

Background: Beliefs about the controllability of a disorder may be relevant in the causation, maintenance and treatment of disorders. We investigated whether congruence between patients’ beliefs about controllability of a panic disorder and the type of treatment provided predicted outcome. Methods: The differential effectiveness of cognitive therapy and antidepressant treatment (paroxetine or clomipramine) was investigated in a sample of 129 panic disorder patients in a 12-week, pretest posttest placebo-controlled study. Panic frequency, agoraphobic avoidance, anxiety, depression, and disability were measured with various validated interviewer and self-report measures. Beliefs about controllability were measured with the Multidimensional Anxiety Locus of Control Scale measuring an internal, chance, therapist and medication locus of control. In order to analyze aptitude-treatment interactions a new strategy called the Regression Trunk Approach was used in addition to classical hierarchical multiple regression analysis. Results: Using the Regression Trunk Approach we found that locus of control orientation (LOC) predicted the differential effectiveness of cognitive therapy. Those patients with a medium internal LOC who received cognitive therapy performed significantly better than all patients who received a placebo pill on 8 of the 10 outcome variables. We did not find a differential LOC effect for antidepressant treatment. No evidence for aptitude-treatment interactions using hierarchical multiple regression analysis was found. Conclusions: Moderately strong beliefs about self-control of panic disorder congruent with the cognitive intervention provided seem to moderate treatment effectiveness. Future studies must be more attentive to the nonlinear effects of patient characteristics on the outcome of different types of treatments.
WNT4 and RSPO1 Are Not Involved in a Case of Male-to-Female Sex Reversal with Partial Duplication of 1p
Authors: Wieacker P. , Volleth M.
Published: April 2007

Some studies suggest that WNT4 signaling acts to repress the male pathway and a single case of duplication of WNT4 located in 1p35 has been associated with ambiguous genitalia. Recently, RSPO1 located in 1p34.3 was shown to be essential in sex determination. We show that neither WNT4 nor RSPO1 are duplicated in another case of male-to-female sex reversal with partial duplication of 1p. Therefore, it can be assumed that in male-to-female sex reversal associated with duplication of 1p, other genetic factors may be involved.
Amyloid-β Aggregation
Authors: Finder Verena H. , Glockshuber Rudi
Published: April 2007

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-β (Aβ), a peptide of 39–42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that Aβ aggregates are ordered oligomers and the cause rather than a product of AD. The analysis of the assembly pathway of Aβ in vitro and biochemical characterization of Aβ deposits isolated from AD brains indicate that Aβ oligomerization occurs via distinct intermediates, including oligomers of 3–50 Aβ monomers, annular oligomers, protofibrils, fibrils and plaques. Of these, the most toxic species appear to be small Aβ oligomers. This article reviews the current knowledge of the mechanism of Aβ assembly in vivo and in vitro, as well as the influence of inherited amino acid replacements in Aβ and experimental conditions on Aβ aggregation. Challenges regarding the reproducible handling of the Aβ peptide for in vitro assembly studies are discussed.
Adenosine-Based Cell Therapy Approaches for Pharmacoresistant Epilepsies
Authors: Boison Detlev
Published: April 2007

Despite recent medical advances pharmacoresistant epilepsy continues to be a major health problem. The knowledge of endogenous protective mechanisms of the brain may lead to the development of rational therapies tailored to a patient’s needs. Adenosine has been identified as an endogenous neuromodulator with antiepileptic and neuroprotective properties. However, the therapeutic use of adenosine or its receptor agonists is largely precluded by strong peripheral and central side effects. Thus, local delivery of adenosine to a critical site of the brain may provide a solution for the therapeutic use of adenosine. The following rationale for the local augmentation of the adenosine system as a novel therapeutic principle in the treatment of epilepsy has been established: (1) Deficits in the adenosinergic system are associated with epileptogenesis and these deficits promote seizures. Thus, reconstitution of an inhibitory adenosinergic tone is a rational therapeutic approach. (2) The focal paracrine delivery of adenosine from encapsulated cells suppresses seizures in kindled rats without overt side effects. (3) The anticonvulsant activity of locally released adenosine is maintained in models of epilepsy which are resistant to major antiepileptic drugs. This review summarizes the rationale and recent approaches for adenosine-based cell therapies for pharmacoresistant epilepsies.
Cortical Plasticity: A View from Nonhuman Primates
Authors: Kiper Daniel , Martin Kevan A.C. , Scherberger Hansjörg
Published: April 2007

The primate’s large brain-to-body weight ratio and high complexity are unusual in the animal kingdom. There is compelling evidence that it is an evolutionary adaptation that allows its owner to live a long life because of its competence in solving a wide range of problems. How primates use their brain to achieve such competence is of course of central interest to us. Here we review some key aspects of the neocortex that can be explored in nonhuman primates. Studies of the cortical circuits in the visual cortex reveal that the two major types of pathways, called feedforward and feedback, involve a very small fraction of the total synapses that any area contains. Nevertheless these pathways may be critical for some important forms of cortical plasticity, like perceptual learning and tasks involving perception and action.
Inhibition of Angiotensin-Converting Enzyme Activity by a Partially Purified Fraction of Gynura procumbens in Spontaneously Hypertensive Rats
Authors: Hoe See-Ziau , Kamaruddin Mohd Yusof , Lam Sau-Kuen
Published: April 2007

Objectives: To investigate the hypotensive and angiotensin-converting enzyme (ACE) inhibitory activities of a partially purified fraction (FA-I) of the leaves of Gynura procumbens and to qualitatively analyse the putative compounds present in the fraction. Materials and Methods: The hypotensive effect of FA-I was tested in both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) by an intravenous administration of 0–10 mg/kg of the FA-I. Administration of captopril (20 µg/kg) served as the control. In vitro 0.0–2.0 mg/ml FA-I was added to a mixture of ACE and hippuryl-L-histidyl-L-leucine and assayed by a modification of the colourimetric method of Hurst and Lovell-Smith. All blood pressure measurements were monitored by the Macintosh MacLab set-up. ACE activity was measured by an in vitro assay in which the enzymatic cleavage of hippuryl-L-histidyl-L-leucine to form histidyl-leucine and hippurate was determined colourimetrically by a cyanuric chloride/dioxane reagent. Results: The FA-I produced a marked dose-dependent reduction in mean arterial pressure (MAP) in SHR and WKY rats, with an ED50 of 1.09 and 1.05 mg/kg, respectively (p < 0.01). Furthermore, FA-I at 10 mg/kg strongly inhibited the angiotensin I-induced rise in MAP (p < 0.01). This response was comparable to that of captopril at 20 µg/kg. In the in vitro assay, ACE activity was inhibited with an IC50 of 0.8 mg/ml. The qualitative phytochemical analysis of FA-I indicated the presence of glycoconjugates and peptides. Conclusion: These results suggest that the hypotensive effect of G. procumbens may be due, in part, to the glycoconjugated or peptidal substances found in FA-I that exhibit an inhibitory effect on ACE.
Is Transcranial Doppler for the Detection of Venous-to-Arterial Circulation Shunts Reproducible?
Authors: Sastry S. , Daly K. , Chengodu T. , McCollum C.
Published: April 2007

Background: We investigated the reproducibility of contrast transcranial Doppler (TCD), a safe non-invasive test for investigation of venous-to-arterial circulation shunts (v-aCS), usually patent foramen ovale, in young stroke patients. We also investigated whether microbubble contrast was reproducible and whether the addition of blood to agitated saline contrast affected the number of microbubbles produced. Methods: TCD investigation for v-aCS was repeated in 42 patients using a standardised protocol (i) by the same investigator and (ii) by a different investigator. Agitated saline was produced by mixing saline and 1 ml of air between two 10-ml syringes. The effect of adding blood and increasing the number of agitations was evaluated by microscopy examination using a haemocytometer to assess bubble numbers and sizes. Results: TCD: no difference was found in the highest microbubble count for the same investigator and between different investigators (p > 0.05). Reproducibility for the detection of v-aCS consistent with a patent foramen ovale was also good (ĸ values >0.8). Contrast: both the number of contrast mixes before injection and the presence of blood significantly increased the number of bubbles counted. On average, 18 agitations produced 1.86 (95% CI 1.62–2.13) times more bubbles than 6 agitations. Mixtures with blood produced on average 3.8 times more bubbles (3.08–4.69). The size of the bubbles was similar for all mixtures. Conclusions: Contrast TCD is reproducible and reliable for the detection of v-aCS. The addition of blood and 18 mixes rather than 6 significantly increased the number of microbubbles produced and may increase the effectiveness of microbubble contrast.
C-Reactive Protein Level in Severe Stenosis of Cerebral Arteries
Authors: Flegar-Meštrić Zlata , Vrhovski-Hebrang Danijela , Preden-Kereković Vlatka , Perkov Sonja , Hebrang Andrija , Grga Ante , Januš Dragutin , Vidjak V.
Published: April 2007

Background: C-reactive protein (CRP) as a non-specific inflammatory biomarker has been demonstrated to actively contribute to all stages of atherogenesis. The aim of this study was to investigate the relation between CRP concentrations and the severity of stenosis of cerebral arteries. Methods: Lipid parameters and CRP levels were measured in the sera of 119 patients with stenosis of the extracranial cerebral arteries established by angiography and compared with the control group, with a normal appearance of the cerebral arteries on ultrasound examination. CRP concentrations were determined by a high-sensitivity assay. Results: CRP concentrations showed a statistically significant difference in the group of patients with cerebrovascular stenosis of more than 70% compared to the control group (median value 3.4 vs. 1.5 mg/l in the control group, p < 0.05). At logistic regression analysis, CRP was significantly associated with stenosis of more than 70%. Conclusion: In addition to traditional biochemical risk markers, an elevated CRP level measured on automated analysers using a high-sensitivity assay may be useful in the detection of patients with severe stenosis of the cerebral arteries.
Fibromuscular Dysplasia May Herald Symptomatic Recurrence of Cervical Artery Dissection
Authors: de Bray J.M. , Marc G. , Pautot V. , Vielle B. , Pasco A. , Lhoste P. , Dubas F.
Published: April 2007

Background: The prevalence of fibromuscular dysplasia (FMD) in patients with cervical artery dissection (CAD) is unknown. Our objectives were to assess the risk of CAD recurring as a stroke or a transient ischemic attack and the association of these events with FMD. Methods: We prospectively included and followed 103 consecutive patients who had been admitted for a CAD. The median follow-up was 4 years (range 4 months to 10 years). The main criteria for inclusion were a mural hematoma demonstrated by cervical magnetic resonance imaging and/or signs suggesting CAD on 2 other investigations. FMD was diagnosed on the so-called string of beads pattern by digital subtraction angiography. Results: Five patients had CAD recurrence (60% occurred late). Four of these 5 patients had FMD. In 4 patients, CAD recurrence involved another cervical artery. Conclusion: The rate of symptomatic CAD recurrence was 1% per year and was often related to FMD.
Assessment and Clinical Aspects of Health-Related Quality of Life in Dialysis Patients and Patients with Chronic Kidney Disease
Authors: Molsted Stig , Prescott Lotte , Heaf James , Eidemak Inge
Published: April 2007

Background/Aims: It is relevant to investigate health-related quality of life (HRQOL) in dialysis and chronic kidney disease (CKD) patients in order to optimise treatment. The aim of this study was to investigate HRQOL in dialysis and CKD patients, to compare results from patients treated with hemodialysis (HD) and peritoneal dialysis (PD) and to investigate the prediction of dialysis quality control parameters (blood hemoglobin, plasma albumin, and Kt/V) and tobacco smoking in disease-specific HRQOL. Methods: Seventy-one HD, 59 PD, and 63 CKD patients participated in the study. Dialysis quality control parameters were measured and the patients completed the questionnaire Kidney Disease Quality Of Life. Results: PD patients rated Dialysis Staff Encouragement and Patient Satisfaction better than HD patients (p≤ 0.05). Dialysis patients scored significant lower than the general population in all generic HRQOL scales (p ≤ 0.01), whereas CKD patients scored lower than the general population in 5 of 8 scales (p ≤ 0.05). The dialysis quality parameters did not predict dialysis patients’ disease specific HRQOL, but tobacco consumption was independently associated with low scores on a number of HRQOL scales. Conclusion: Based on the results, it is suggested to include elements of HRQOL as a supplement to standard quality control parameters. It is also suggested routinely to include information of the beneficial effects of physical activity already in the predialysis program, and to focus on smoking as a very important risk factor.
The Limbic System in Mammalian Brain Evolution
Authors: Reep R.L. , Finlay B.L. , Darlington R.B.
Published: April 2007

Previous accounts of mammalian brain allometry have relied largely on data from primates, insectivores and bats. Here we examine scaling of brain structures in carnivores, ungulates, xenarthrans and sirenians, taxa chosen to maximize potential olfactory and limbic system variability. The data were compared to known scaling of the same structures in bats, insectivores and primates. Fundamental patterns in brain scaling were similar across all taxa. Marine mammals with reduced olfactory bulbs also had reduced limbic systems overall, particularly in those structures receiving direct olfactory input. In all species, a limbic factor with olfactory and non-olfactory components was observed. Primates, insectivores, ungulate and marine mammals collectively demonstrate an inverse relationship between isocortex and limbic volumes, but terrestrial carnivores have high relative volumes of both, and bats low relative volumes of both. We discuss developmental processes that may provide the mechanistic bases for understanding these findings.
Depressive Symptoms, Major Depressive Episode and Cognition in the Elderly: The Three-City Study
Authors: Godin Ophélia , Dufouil Carole , Ritchie Karen , Dartigues Jean-François , Tzourio Christophe , Pérès Karine , Artero Sylvaine , Alpérovitch Annick
Published: April 2007

Objectives: The relationship between depression and dementia in the elderly has been extensively studied but the tools used to define depressed subjects are heterogeneous between studies. The objective of this study was to examine the relationship between depression and cognitive performances by using multiple measures of depressive state. Methods: A sample of 7,869 nondemented community-dwelling persons aged ≧65 years participated in the study. Depressive symptoms were evaluated by the Center for Epidemiological Study Depression Scale and the Mini-International Neuropsychiatric Interview was used to assess history of major depressive episodes (MDE). Cognitive function was evaluated by several tests including the Mini-Mental State Examination (MMSE), Trail Making Test, Isaacs Set Test and Benton Visual Retention Test. Results: When studied in separate models, depressive symptoms were significantly related to lower cognitive performances for all neuropsychological tests after adjusting for potential confounders (p < 0.0001), whereas subjects with current MDE had significantly lower performances in MMSE and Isaacs Set Test. When studied concomitantly, only high levels of depressive symptoms were related to lower cognitive performance, whereas existence of MDE (past or current) was no longer associated with cognitive performances. Conclusions: These data suggest that once current depressive symptoms are taken into account, major depression (past or current) is not associated with lower cognitive performances in a community-based sample of elderly people aged ≧65 years.
Age and Risk of Stroke in Atrial Fibrillation: Evidence for Guidelines?
Authors: Frost Lars , Vukelic Andersen Ljubica , Godtfredsen John , Mortensen Leif Spange
Published: April 2007

Aim: Guidelines for the clinical management of patients with atrial fibrillation suggest that treatment strategies for prescribing oral anticoagulant therapy should implicate change at age 60, 65 and 75 years. We examined if there is any threshold concerning risk of stroke by age. Methods: We identified 141,493 subjects, aged 40–89 years, with an incident hospital diagnosis of nonvalvular atrial fibrillation or flutter and no previous or concomitant diagnosis of stroke in the Danish National Registry of Patients from January 1, 1980, to December 31, 2002. The subjects were followed in the Danish National Registry of Patients for the occurrence of an incident diagnosis of stroke of any nature and in the Danish Civil Registration System for emigration and vital status. We examined the risk of stroke by age in men and women using Cox regression models, which included age categorized in intervals, linear splines of age with cut points at age 60 and 75 years, or at age 65 and 75 years. We also analyzed age as a continuous variable in linear and polynomial regression models. Results: During follow-up 15,964 incident strokes were reported to the Danish National Registry of Patients. The risk of stroke increased by increasing age at baseline. We did not find any evidence for a threshold concerning risk of stroke by age, and the best model fit was obtained in a third-order polynomial regression model. Conclusion: The risk of stroke increased gradually by increasing age, and we could not detect any threshold concerning risk of stroke by age.
Current Approaches to the Diagnosis and Treatment of Polycystic Ovarian Syndrome in Youth
Authors: Harwood Katerina , Vuguin Patricia , DiMartino-Nardi Joan
Published: April 2007

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in reproductive-age women. It often presents during late adolescence but in some cases certain features are evident even before menarche. PCOS is a spectrum of disorders with any combination of oligo/anovulation, clinical and/or biochemical evidence of androgen excess, obesity, insulin resistance and polycystic ovaries on ultrasound. The pathogenesis is unknown; however, it is a complex multigenetic disorder where disordered gonadotropin release, dysregulation of steroidogenesis, hyperinsulinism and insulin resistance play a role. The diagnosis is based on a typical physical exam (acne, hirsutism, obesity, and acanthosis nigricans) and laboratory evidence of hyperandrogenism, such as elevated free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS), decreased sex hormone-binding globulin (SHBG) and increased luteinizing hormone (LH). An ovarian ultrasound may detect the multiple cysts. Secondary causes of PCOS need to be excluded. There are several classes of medications correcting different parameters of PCOS that can be used alone or in combination. Oral contraceptive therapy is used to reduce androgen and LH levels with resultant improvement in acne and hirsutism, and the induction of regular menses. Antiandrogens are usually required for a substantial improvement in hirsutism score. Insulin sensitizers such as metformin are a new class of drugs utilized in treatment of PCOS. By improving insulin sensitivity and decreasing insulin levels, they improve the unfavorable metabolic profile of patients with PCOS. Metformin also helps to increase SHBG, decrease androgen levels and induce ovulation. Despite all the available medications, life-style changes are the mainstay of therapy as weight loss and exercise improve all parameters of PCOS without the potential side effects of medication.
The Role of High-Resolution Magnetic Resonance in Atypical and Intractable Benign Paroxysmal Positional Vertigo: Our Preliminary Experience
Authors: Dallan Iacopo , Bruschini Luca , Neri Emanuele , Nacci Andrea , Segnini Giovanni , Rognini Ferdinando , Casani Augusto Pietro
Published: April 2007

Background: The diagnosis of benign paroxysmal positional vertigo (BPPV) is easy when typical nystagmus is present. However, diagnostic doubts arise when faced with cases presenting atypical features of the positional paroxysmal nystagmus as well as the clinical course and disease evolution. Methods: A morphological evaluation of inner ear structures via high-resolution magnetic resonance (HR-MR) studies has been performed in 2 patients that did not respond to traditional therapeutic manoeuvres. Results: In 1 patient, a filling defect at the level of the middle portion of the right lateral semicircular canal (LSC) has been demonstrated, while in the second one, a geometric-architectural abnormality – a ‘fold’ in the LSC – has been observed. Conclusion: HR-MR study of the inner ear offers a meaningful contribution to interpreting the physiopathogenesis of atypical cases of BPPV. HR-MR of the inner ear is a safe and useful tool to investigate patients with atypical and intractable BPPV.
Downregulation of Fanconi Anemia Genes in Sporadic Head and Neck Squamous Cell Carcinoma
Authors: Wreesmann Volkert B. , Estilo Cherry , Eisele David W. , Singh Bhuvanesh , Wang Steven J.
Published: April 2007

Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.
Risk Factors for Auditory Neuropathy/Auditory Synaptopathy
Authors: Beutner Dirk , Foerst Astrid , Lang-Roth Ruth , von Wedel Hasso , Walger Martin
Published: April 2007

Aims: It was the aim of this study to describe risk factors in auditory neuropathy/auditory synaptopathy (AN/AS). Methods: Between 1997 and 2005, we diagnosed 37 children with AN/AS. They underwent a critical chart review for risk factors and etiological coincidences in this idiosyncratic disorder. Results: Eighteen neonates had a history of prematurity and low birth weight. Hyperbilirubinaemia was present in 13 children. Three patients had evidence of infection during pregnancy, and AN/AS was associated with complex syndromal diseases in 2 cases. A congenital, familial pattern was seen in 2 siblings. Seven patients had idiopathic AN/AS. Conclusion: Rather than being a single etiological entity, AN/AS comprises a spectrum of risk factors and associated problems affecting the cochlea and the auditory pathway. This study shows that the majority of AN/AS in children is the result of perinatal problems and is not genetic in origin. Hyperbilirubinaemia is a common and etiologically significant finding in infants suffering from AN/AS. Thus, early hearing screening for AN/AS including transient evoked otoacoustic emissions and auditory brainstem response assessment among neonates with risk factors for AN/AS is crucial in order to better manage patients suffering from this disorder.
Prevalence of Human Papillomavirus DNA in Cholesteatomas
Authors: Franz P. , Teschendorf M. , Wohlschläger J. , Fischer M.
Published: April 2007

Cholesteatomas show histomorphological features like papillary growth and koilocytosis, which are characteristic of lesions induced by human papillomaviruses (HPV). Two previous studies investigating the possible role of HPV in the development of cholesteatoma had detected HPV-6 and HPV-11 DNA with a prevalence differing from 3 to 36%. The aim of the presented study was to evaluate the prevalence of different HPV types in cholesteatomas using a sensitive detection system for HPV DNA. Twenty-nine biopsies from cholesteatomas were screened for HPV DNA with a 2-step broad-spectrum PCR (PCR and nested PCR). HPV-positive products were directly sequenced by means of a cycle sequencing approach. Sensitivity of the applied broad-spectrum PCR was 0.1 copy/genome. One out of 29 biopsies showed a positive signal on the nested PCR level. Considering the low prevalence (1/29 biopsies) of detected HPV DNA in cholesteatomas, infections with common HPV types are unlikely to be a causative factor.
Helicobacter pylori and Gastric Cancer: The Causal Relationship
Authors: Peter Shajan , Beglinger Christoph
Published: April 2007

Gastric cancer has been recognized as an important cause of morbidity and mortality all over the world. Helicobacter pylori has been shown to have a causal relationship to gastric cancer. The knowledge into the mechanisms related to this has advanced considerably over the last few years thereby unarguably defining the role of this host-pathogen interaction. Epidemiological studies, research in animal models, molecular pathways involving host and bacterial factors, environmental factors and recent work on stem cells have contributed to understanding the origin and progress of this neoplasia. These form part of the myriad of interplaying factors resulting in the causal relationship. Nevertheless, current evidence is insufficient to accurately identify a definitive population where prevention or treatment strategies have to be targeted. Future trials will have to define the people at risk and shed more light in these areas.
Electromyography in Evaluation of Pain after Different Types of Tonsillectomy: Prospective Randomized Study
Authors: Vaiman Michael , Gavrieli Haim , Krakovski Daniel
Published: April 2007

Background: Combined surface electromyography (sEMG) and visual analogue scale (VAS) pain assessment was performed on randomly assigned adults following tonsillectomy to research the effect of fibrin sealant (Group 1, n = 25), CO2 laser (Group 2, n = 18) and electrocoagulation (Group 3, n = 40) on postsurgical pain. Methods: Timing and amplitude of sEMG activity of masseter, infrahyoid and submandibular muscles were measured during swallowing simultaneously with VAS assessment and compared to normative database. Results: Postsurgical electric activity of masseter and infrahyoid was significantly higher in comparison with normative database. sEMG and VAS data showed that tonsillectomy ended with fibrin sealant caused less pain than laser or electrocoagulation techniques with no correlation between the VAS score and duration of swallows. Conclusion: Tonsillectomy affects muscle activity significantly by involving additional muscles (infrahyoid) in swallowing. Combined sEMG and VAS data indicated electrocautery as the most painful, laser as less painful, and fibrin sealant as the least painful technique.
Stereotactic Surgery in the Rhesus Monkey (Macaca mulatta) Utilizing Intracerebral Landmarks
Authors: Ilinsky I.A. , Kultas-Ilinsky K.
Published: April 2007

A stereotactic method utilizing an intracerebral coordinate system and ventricular radiography was developed and applied in rhesus monkeys. The intercommissural line (CA-CP) and two perpendiculars to this line served as the main references for the coordinate system. Surgical placements with the use of this technique were made in various deep cerebral and cerebellar nuclei in 12 Macaca mulatta and the accuracy of the surgery was evaluated histologically. In 11 of the 12 monkeys, the intended targets were achieved precisely. The advantages and pitfalls of the proposed method are discussed.
Anticonvulsant Activation of Pain-Suppressive Systems
Authors: Hitchcock Edward , Teixeira Manuel
Published: April 2007

The effect of diphenylhydantoin, sodium valproate and carbamezepine on the enzymatic activity of the anterior mesencephalic periaqueductal grey matter was examined by a histochemical technique using density phase measurement. Diphenylhydantoin caused the greatest reduction in glutamate dehydrogenase and GABA. Only sodium valproate increased glutamate dehydrogenase and GABA and only diphenylhydantoin an increase in semi-aldehyde dehydrogenase activity. Central pain suppressive systems can be activated by certain anticonvulsants.
Adenovirus Transmission in a Nursing Home: Analysis of an Epidemic Outbreak of Keratoconjunctivitis
Authors: Domínguez-Berjón M.F. , Hernando-Briongos P. , Miguel-Arroyo P.J. , Echevarría J.E. , Casas I.
Published: April 2007

Background: An epidemic outbreak of keratoconjunctivitis occurred in a nursing home in Madrid from August to December 2005. Objective: This article reports the outbreak, the infection control measures taken, and risk factors for keratoconjunctivitis. Methods: A cohort study was conducted on the nursing home staff and residents. Specific attack rates and relative risks with their 95% confidence intervals were estimated. A multivariate analysis (logistic regression) was performed proving odds ratios (OR) of becoming ill. Conjunctival swab samples were taken and tested for viral infection. More stringent infection control measures were implemented following the occurrence of the initial cases. Results: Forty-six cases were identified in the nursing home (infection rates of 30.5% in residents and 8.3% in workers). Total duration of the outbreak was 120 days. Corneal ulcer occurred in 3 cases. The factors appearing as independent risk factors were age (OR = 5.7 in people aged ≧90 years compared to those aged <80 years), cognitive impairment (OR = 2.64) and nursing home floor (OR = 2.74 for the first floor, where the outbreak started). Adenoviral DNA was amplified in 10 samples, and 8 of them could be typed as adenovirus serotype 8. Conclusions: Early adoption of adequate hygiene measures is essential to control these outbreaks. In nursing homes with a high number of people with cognitive impairment, an additional effort should be made when the first cases occur to provide such people an increased and improved care and monitoring.
Transient Receptor Potential Channel TRPM8 Agonists Stimulate Calcium Influx and Neurotensin Secretion in Neuroendocrine Tumor Cells
Authors: Mergler Stefan , Strowski Mathias Z. , Kaiser Simone , Plath Thomas , Giesecke Yvonne , Neumann Marleen , Hosokawa Hiroshi , Kobayashi Shigeo , Langrehr Jan , Neuhaus Peter , Plöckinger Ursula , Wiedenmann Bertram , Grötzinger Carsten
Published: April 2007

TRPM8 is a member of the melastatin-type transient receptor potential ion channel family. Activation by cold or by agonists (menthol, icilin) induces a transient rise in intracellular free calcium concentration ([Ca2+]i). Our previous study demonstrated that Ca2+-permeable cation channels play a role in IGF-1-induced secretion of chromogranin A in human neuroendocrine tumor (NET) cell line BON [Mergler et al.: Neuroendocrinology 2006;82:87–102]. Here, we extend our earlier study by investigating the expression of TRPM8 and characterizing its impact on [Ca2+]i and the secretion of neurotensin (NT). We identified TRPM8 expression in NET BON cells by RT-PCR, Western blotting and immunofluorescence staining. Icilin increased [Ca2+]i in TRPM8-transfected human embryonic kidney cells (HEK293) but not in mock-transfected cells. Icilin and menthol induced Ca2+ transients in BON cells as well as in primary NET cell cultures of two different pancreatic NETs as detected by single cell fluorescence imaging. Icilin increased non-selective cation channel currents in BON cells as detected by patch-clamp recordings. This activation was associated with increased NT secretion. Taken together, this study demonstrates for the first time the expression TRPM8 in NET cells and its role in regulating [Ca2+]i and NT secretion. The regulation of NT secretion in NETs by TRPM8 may have a potential clinical implication in diagnosis or therapy.