bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular β-Tubulin/Chaperonin Containing TCP1-β Complex Serves as a Novel Chemotherapeutic Target against Drug-Resistant Tumors
Authors: Lin Yuan-Feng , Tsai Wen-Ping , Liu Hon-Ge , Liang Po-Huang
Published: August 2009

In the present study, treatment of HEK-293 cells with the synthetic small molecule N-iodoacetyl-tryptophan (I-Trp) at submicromolar concentrations efficiently induced cell apoptosis as judged from the accumulation of sub-G0 cells and intracellular DNA fragmentation. Activation of all intracellular caspases, except caspase-1, was detected in I-Trp–treated cells. Proteomic analysis revealed that β-tubulin acted as a specific intracellular target of I-Trp. Protein fingerprinting analysis indicated that the Cys354 residue in the peptide fragment TAVCDIPPR of β-tubulin, which is located at the binding interface with chaperonin containing TCP1-β (CCT-β), was alkylated by I-Trp. Moreover, site-directed mutagenesis of Cys354 (Cys-Ala) abolished the incorporation of I-Trp into β-tubulin, suggesting Cys354 is indeed the targeting site of I-Trp. Immunoprecipitation showed that the β-tubulin/CCT-β complex was constitutively formed but disrupted after treatment with I-Trp. Overexpression of the truncated β-tubulin (T351-S364) or treatment with I-Trp or the synthetic peptide Myr-TAVCDIPPRG caused more severe cell apoptosis in multidrug-resistant MES-SA/Dx5 cancer cells due to higher levels of CCT-β relative to wild-type MES-SA cancer cells. Silencing the expression of CCT-β rendered MES-SA/Dx5 cells less sensitive to I-Trp–induced apoptotic cell death. These findings suggest that the β-tubulin/CCT-β complex may serve as an effective chemotherapeutic target for treating clinical tubulin-binding agent-resistant or CCT-β–overexpressing tumors. [Cancer Res 2009;69(17):6879–88]
Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases
Authors: Mueller James , Gazzoli Isabella , Bandipalliam Prathap , Garber Judy E. , Syngal Sapna , Kolodner Richard D.
Published: August 2009

An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). Here, we have extended the analysis of 71 CRC cases suspected to be Lynch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects. All cases were screened for mutations in MSH2, MLH1, and MSH6, and all cases where tumors were available were screened for microsatellite instability (MSI) and expression of MSH2 and MLH1. Subsequently, mutation-negative cases were screened for MLH1 methylation and mutations in PMS2. Of the MSI-high (MSI-H) cases, 96% had a mismatch repair (MMR) gene defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutations were found. Four of the 28 MSI-H cases, including one Amsterdam criteria case, had biallelic tumor MLH1 methylation, indicating that sporadic cases can be admixed in with Lynch syndrome cases, even those meeting the strongest criteria for Lynch syndrome. MMR gene defects were found in similar frequency in cases where tumors were and were not available. One MLH1 and one MSH2 deletion mutation were found in MSI–stable/low cases, indicating that MSI testing can exclude cases with pathogenic mutations. Our analysis supports a diagnostic algorithm where cases are selected for analysis based on clinical criteria or prediction models; isolated sporadic young-onset cases can be prescreened by tumor testing, whereas familial cases may be directly subjected to molecular analysis for mutations in MMR genes followed by MSI, protein expression, and DNA methylation analysis to aid in the resolution of mutation-negative cases. [Cancer Res 2009;69(17):7053–61]
Human Multiple Myeloma Cells Are Sensitized to Topoisomerase II Inhibitors by CRM1 Inhibition
Authors: Turner Joel G. , Marchion Douglas C. , Dawson Jana L. , Emmons Michael F. , Hazlehurst Lori A. , Washausen Peter , Sullivan Daniel M.
Published: August 2009

Topoisomerase IIα (topo IIα) is exported from the nucleus of human myeloma cells by a CRM1-dependent mechanism at cellular densities similar to those found in patient bone marrow. When topo IIα is trafficked to the cytoplasm, it is not in contact with the DNA; thus, topo IIα inhibitors are unable to induce DNA-cleavable complexes and cell death. Using a CRM1 inhibitor or a CRM1-specific small interfering RNA (siRNA), we were able to block nuclear export of topo IIα as shown by immunofluorescence microscopy. Human myeloma cell lines and patient myeloma cells isolated from bone marrow were treated with a CRM1 inhibitor or CRM1-specific siRNA and exposed to doxorubicin or etoposide at high cell densities. CRM1-treated cell lines or myeloma patient cells were 4-fold more sensitive to topo II poisons as determined by an activated caspase assay. Normal cells were not significantly affected by CRM1-topo II inhibitor combination treatment. Cell death was correlated with increased DNA double-strand breaks as shown by the comet assay. Band depletion assays of CRM1 inhibitor–exposed myeloma cells showed increased topo IIα covalently bound to DNA. Topo IIα knockdown by a topo IIα–specific siRNA abrogated the CRM1-topo II therapy synergistic effect. These results suggest that blocking topo IIα nuclear export sensitizes myeloma cells to topo II inhibitors. This method of sensitizing myeloma cells suggests a new therapeutic approach to multiple myeloma. [Cancer Res 2009;69(17):6899–905]
MicroRNA Expression, Chromosomal Alterations, and Immunoglobulin Variable Heavy Chain Hypermutations in Mantle Cell Lymphomas
Authors: Navarro Alba , Beà Sílvia , Fernández Verónica , Prieto Miriam , Salaverria Itziar , Jares Pedro , Hartmann Elena , Mozos Anna , López-Guillermo Armando , Villamor Neus , Colomer Dolors , Puig Xavier , Ott German , Solé Francesc , Serrano Sergi , Rosenwald Andreas , Campo Elías , Hernández Luis
Published: August 2009

The contribution of microRNAs (miR) to the pathogenesis of mantle cell lymphoma (MCL) is not well known. We investigated the expression of 86 mature miRs mapped to frequently altered genomic regions in MCL in CD5+/CD5− normal B cells, reactive lymph nodes, and purified tumor cells of 17 leukemic MCL, 12 nodal MCL, and 8 MCL cell lines. Genomic alterations of the tumors were studied by single nucleotide polymorphism arrays and comparative genomic hybridization. Leukemic and nodal tumors showed a high number of differentially expressed miRs compared with purified normal B cells, but only some of them were commonly deregulated in both tumor types. An unsupervised analysis of miR expression profile in purified leukemic MCL cells revealed two clusters of tumors characterized by different mutational status of the immunoglobulin genes, proliferation signature, and number of genomic alterations. The expression of most miRs was not related to copy number changes in their respective chromosomal loci. Only the levels of miRs included in the miR-17-92 cluster were significantly related to genetic alterations at 13q31. Moreover, overexpression of miR-17-5p/miR-20a from this cluster was associated with high MYC mRNA levels in tumors with a more aggressive behavior. In conclusion, the miR expression pattern of MCL is deregulated in comparison with normal lymphoid cells and distinguishes two subgroups of tumors with different biological features. [Cancer Res 2009;69(17):7071–8]
Circulating Galectin-3 Promotes Metastasis by Modifying MUC1 Localization on Cancer Cell Surface
Authors: Zhao Qicheng , Guo Xiuli , Nash Gerard B. , Stone Philip C. , Hilkens John , Rhodes Jonathan M. , Yu Lu-Gang
Published: August 2009

Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the “protective shield” of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (Galβ1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis. [Cancer Res 2009;69(17):6799–806]
Ectopic Runx2 Expression in Mammary Epithelial Cells Disrupts Formation of Normal Acini Structure: Implications for Breast Cancer Progression
Authors: Pratap Jitesh , Imbalzano Karen M. , Underwood Jean M. , Cohet Nathalie , Gokul Karthiga , Akech Jacqueline , van Wijnen Andre J. , Stein Janet L. , Imbalzano Anthony N. , Nickerson Jeffrey A. , Lian Jane B. , Stein Gary S.
Published: August 2009

The transcription factor Runx2 is highly expressed in breast cancer cells compared with mammary epithelial cells and contributes to metastasis. Here we directly show that Runx2 expression promotes a tumor cell phenotype of mammary acini in three-dimensional culture. Human mammary epithelial cells (MCF-10A) form polarized, growth-arrested, acini-like structures with glandular architecture. The ectopic expression of Runx2 disrupts acini formation, and electron microscopic ultrastructural analysis revealed the absence of lumens. Characterization of the disrupted acini structures showed increased cell proliferation (Ki-67 positive cells), decreased apoptosis (Bcl-2 induction), and loss of basement membrane formation (absence of β4 integrin expression). In complementary experiments, inhibition of Runx2 function in metastatic MDA-MB-231 breast cancer cells by stable expression of either short hairpin RNA-Runx2 or a mutant Runx2 deficient in subnuclear targeting resulted in reversion of acini to more normal structures and reduced tumor growth in vivo. These novel findings provide direct mechanistic evidence for the biological activity of Runx2, dependent on its subnuclear localization, in promoting early events of breast cancer progression and suggest a molecular therapeutic target. [Cancer Res 2009;69(17):6807–14]
Identification of a Stat3-Dependent Transcription Regulatory Network Involved in Metastatic Progression
Authors: Ranger Jill J. , Levy David E. , Shahalizadeh Solmaz , Hallett Michael , Muller William J.
Published: August 2009

High levels of activated Stat3 are often found in human breast cancers and can correlate with poor patient outcome. We employed an activated ErbB2 mouse model of breast cancer to investigate the in vivo role of Stat3 in mammary tumor progression and found that Stat3 does not alter mammary tumor initiation but dramatically affects metastatic progression. Four-fold fewer animals exhibited lung metastases in the absence of Stat3 and a 12-fold reduction in the number of lung lesions was observed in animals bearing Stat3-null tumors when compared with the wild-type cohort. The decreased malignancy in Stat3-deficient tumors is attributed to a reduction in both angiogenic and inflammatory responses associated with a Stat3-dependent transcriptional cascade involving CCAAT/enhancer binding protein δ. [Cancer Res 2009;69(17):6823–30]
Gene Expression Profiling of Bone Marrow Endothelial Cells in Patients with Multiple Myeloma
Authors: Ria Roberto , Todoerti Katia , Berardi Simona , Coluccia Addolorata Maria Luce , De Luisi Annunziata , Mattioli Michela , Ronchetti Domenica , Morabito Fortunato , Guarini Attilio , Petrucci Maria Teresa , Dammacco Franco , Ribatti Domenico , Neri Antonino , Vacca Angelo
Published: August 2009

Purpose: To determine a “gene/molecular fingerprint” of multiple myeloma endothelial cells and identify vascular mechanisms governing the malignant progression from quiescent monoclonal gammopathy of undetermined significance.

Experimental Design: Comparative gene expression profiling of multiple myeloma endothelial cells and monoclonal gammopathy of undetermined significance endothelial cells with the Affymetrix U133A Arrays was carried out in patients at diagnosis; expression and function of selective vascular markers was validated by real-time reverse transcriptase-PCR, Western blot, and small interfering RNA analyses.

Results: Twenty-two genes were found differentially expressed (14 down-regulated and eight up-regulated) at relatively high stringency in multiple myeloma endothelial cells compared with monoclonal gammopathy of undetermined significance endothelial cells. Functional annotation revealed a role of these genes in the regulation of extracellular matrix formation and bone remodeling, cell adhesion, chemotaxis, angiogenesis, resistance to apoptosis, and cell-cycle regulation. Validation was focused on six genes (DIRAS3, SERPINF1, SRPX, BNIP3, IER3, and SEPW1) not previously found to be functionally correlated to the overangiogenic phenotype of multiple myeloma endothelial cells in active disease. The small interfering RNA knockdown of BNIP3, IER3, and SEPW1 genes affected critical multiple myeloma endothelial cell functions correlated with the overangiogenic phenotype.

Conclusions: The distinct endothelial cell gene expression profiles and vascular phenotypes detected in this study may influence remodeling of the bone marrow microenvironment in patients with active multiple myeloma. A better understanding of the linkage between plasma cells and endothelial cells in multiple myeloma could contribute to the molecular classification of the disease and thus pinpoint selective gene targets for more effective antiangiogenic treatments. (Clin Cancer Res 2009;15(17):5369–78)
Tissue Biomarker Development in a Multicentre Trial Context: a Feasibility Study on the PETACC3 Stage II and III Colon Cancer Adjuvant Treatment Trial
Authors: Bosman Fred T. , Yan Pu , Tejpar Sabine , Fiocca Roberto , Van Cutsem Eric , Kennedy Richard D. , Dietrich Daniel , Roth Arnaud
Published: August 2009

Purpose: We evaluated the feasibility of biomarker development in the context of multicenter clinical trials.

Experimental Design: Formalin-fixed, paraffin-embedded (FFPE) tissue samples were collected from a prospective adjuvant colon cancer trial (PETACC3). DNA was isolated from tumor as well as normal tissue and used for analysis of microsatellite instability, KRAS and BRAF genotyping, UGT1A1 genotyping, and loss of heterozygosity of 18 q loci. Immunohistochemistry was used to test expression of TERT, SMAD4, p53, and TYMS. Messenger RNA was retrieved and tested for use in expression profiling experiments.

Results: Of the 3,278 patients entered in the study, FFPE blocks were obtained from 1,564 patients coming from 368 different centers in 31 countries. In over 95% of the samples, genomic DNA tests yielded a reliable result. Of the immmunohistochemical tests, p53 and SMAD4 staining did best with reliable results in over 85% of the cases. TERT was the most problematic test with 46% of failures, mostly due to insufficient tissue processing quality. Good quality mRNA was obtained, usable in expression profiling experiments.

Conclusions: Prospective clinical trials can be used as framework for biomarker development using routinely processed FFPE tissues. Our results support the notion that as a rule, translational studies based on FFPE should be included in prospective clinical trials. (Clin Cancer Res 2009;15(17):5528–33)
Assessment of Health-Related Quality of Life and Patient Satisfaction in Children and Adolescents with Growth Hormone Deficiency or Idiopathic Short Stature – Part 1: A Critical Evaluation of Available Tools
Authors: Brütt Anna Levke , Sandberg David E. , Chaplin John , Wollmann Hartmut , Noeker Meinolf , Kołtowska-Häggström Maria , Bullinger Monika
Published: August 2009

The concept of health-related quality of life (HrQoL) reflects the subjective perception of health and includes aspects of well-being and functioning in physical, emotional, mental and social life domains. Nowadays, HrQoL has become a relevant treatment outcome from epidemiological and clinical perspectives and is also broadly employed in health economic analyses. To assess HrQoL generic as well as condition-specific instruments are used. The former are applicable to a wide range of health conditions and aim at measuring HrQoL across different conditions. The latter focus on capturing the impact of a specific disease. Although HrQoL research in adults is now well-advanced, there are still open questions regarding how to assess HrQoL in pediatric conditions, such as short stature. Eight generic (one chronic-generic) and seven condition-specific (one treatment-specific) instruments used in HrQoL research in short stature of youth are described. Additionally, this mini review identifies a need for further research and indicates potential directions.
Health-Related Quality of Life of Children and Adolescents with Growth Hormone Deficiency or Idiopathic Short Stature – Part 2: Available Results and Future Directions
Authors: Bullinger Monika , Kołtowska-Häggström Maria , Sandberg David , Chaplin John , Wollmann Hartmut , Noeker Meinolf , Brütt Anna Levke
Published: August 2009

Research on the health-related quality of life (HrQoL) impact of short stature and its treatment in children and adolescents has developed recently. Based on a PubMed literature search, studies addressing this issue were identified and considerable methodological problems mainly related to the HrQoL instruments used and conflicting results are discussed in this mini review. Additionally, this mini review identifies a need for further research and indicates potential directions.
The Interrelationships between Abdominal Adiposity, Leptin and Bone Mineral Content in Overweight Latino Children
Authors: Afghani Afrooz , Goran Michael I.
Published: August 2009

Background/Aims: The link between abdominal fat and bone mineral content (BMC), independent of weight, has not been extensively studied. In Latino children, the contributions of abdominal subcutaneous and visceral fat to BMC have not been examined. Research on the effect of leptin on BMC has also been inconclusive. Methods: The present study included 256 overweight Latino children (111 girls, 145 boys; mean BMI 28.2; age 11.1 ± 1.7 years) from Los Angeles, California. Subcutaneous abdominal adipose tissue (SAAT) and intra-abdominal adipose tissue (IAAT) were determined by single-slice magnetic resonance imaging. BMC was measured using dual-energy X-ray absorptiometry. Results: Independent of age, Tanner stage and weight, abdominal adipose tissue (SAAT + IAAT) was inversely correlated with BMC (r = –0.46, p < 0.0001; n = 256). In girls, there was an inverse correlation between SAAT and BMC (r = –0.38, p < 0.05), between IAAT and BMC (r = –0.32, p < 0.05) and between leptin and BMC (r = –0.39, p < 0.05). In boys, SAAT and BMC were inversely correlated (r = –0.26, p < 0.05), but the correlation between IAAT and BMC was not significant (p = 0.22). Leptin was also inversely correlated with BMC (r = –0.38, p < 0.05) in boys and contributed to the variances in BMC in both girls and boys. Conclusion: Total abdominal adipose fat and leptin are negatively associated with BMC in Latino children. The correlation between SAAT and BMC is stronger in girls than boys. IAAT and BMC are negatively associated in girls but not correlated in boys.
Dose-Dependent Effects of Triiodothyronine on the Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cells
Authors: Boeloni J.N. , Ocarino N.M. , Melo A.B. , Silva J.F. , Castanheira P. , Goes A.M. , Serakides R.
Published: August 2009

Background/Aims: The aim of this study was to investigate the dose-dependent effects of triiodothyronine (T3) on the osteogenic differentiation of mesenchymal stem cells(MSCs). Methods: MSCs that express CD73, CD54 (intercellular adhesion molecule-1) and CD90 were cultured in triplicate (1 × 105/well) in osteogenic medium with T3 (1, 10, 103 or 105 pM) or without T3 (control) for 7, 14 and 21 days. Alkaline phosphatase activity, conversion of MTT into formazan crystals, collagen synthesis, collagen maturation, the number of mineralized nodules and their diameters were all determined, and the means were compared by the Student-Newman-Keuls test. Results: A dose of 105 pM T3 resulted in a negative effect on MSC osteogenic differentiation, with less collagen synthesis. The 1 pM T3 dose resulted in greater collagen synthesis and alkaline phosphatase activity and more mineralized nodules than in the control group, similar to the 10 pM dose. Nevertheless, the 10 pM dose demonstrated better results than the 1 pM dose with regard to MSC osteogenic differentiation, with greater MTT reduction, better collagen maturation and a larger mean diameter of mineralized nodules. Conclusions: The effect of T3 on MSC differentiation is dose-dependent, with the 10 pM dose promoting better bone marrow MSC osteogenic differentiation.
Comparison of Adolescents with Klinefelter Syndrome according to the Circumstances of Diagnosis: Amniocentesis versus Clinical Signs
Authors: Girardin Céline M. , Lemyre Emmanuelle , Alos Nathalie , Deal Cheri , Huot Céline , Van Vliet Guy
Published: August 2009

Aims: We compared the phenotype of adolescents with Klinefelter syndrome diagnosed by amniocentesis or postnatally to the general population with a view to evidence-based genetic counselling. Methods: The charts of 28 patients seen between ages 12 and 18 years were reviewed. Physical and neurodevelopmental data were compared between patients diagnosed by chance (amniocentesis, group A, n = 11) or on the basis of symptoms (group B, n = 17) and the general population. Our hypothesis was that group A would have a more heterogeneous and less severe phenotype than group B. Results: All patients had spontaneous puberty. The 2 patient groups were similar in physical development. Mean testosteronemia became lower than the normal mean from age 14 years. Compared to the general population, the prevalence of gynecomastia and school delay in group A was not significantly different (gynecomastia 33 vs. 40%, p = 0.70; school delay 40 vs. 20%, p = 0.25). In contrast, gynecomastia (77%) and school delay (56%) were significantly more frequent in group B than in the general population (p = 0.01 for both). Conclusions: Although they are based on a small number of patients, our data provide the groundwork for cautious optimism in prenatal counselling for Klinefelter syndrome.
Subcutaneous Gonadotropin-Releasing Hormone Agonist (Triptorelin) Test for Diagnosing Precocious Puberty
Authors: Poomthavorn Preamrudee , Khlairit Patcharin , Mahachoklertwattana Pat
Published: August 2009

Background: A test involving 100 μg of intravenous gonadotropin-releasing hormone (GnRH) is a gold standard for confirming the diagnosis of central precocious puberty (CPP). However, intravenous GnRH for testing is commercially limited. Objective: To develop subcutaneous GnRH agonist (GnRH-A) testing and define a peak luteinizing hormone (LH) cutoff value in diagnosing CPP. Methods: A retrospective study of 101 girls with sexual precocity was undertaken. All girls underwent 100 μg subcutaneous GnRH-A (triptorelin) testing. Blood samples before and 30, 60, 90 and 120 min after GnRH-A injection were analyzed for LH and follicle-stimulating hormone levels. Criteria for diagnosing CPP include accelerated height, advanced bone age and pubertal-sized uterus and ovaries. Results: Fifty-five girls were documented as having CPP. The remaining 46 girls were diagnosed with premature thelarche (PT). Peak LH concentration in the CPP group was significantly greater than that of the PT group with a median (range) of 10.0 IU/l (2.93–65.39) and 3.04 IU/l (0.19–8.82), respectively. Peak LH was achieved within 60 min following GnRH-A injection. Peak LH of 6 IU/l provided the most appropriate cutoff level in diagnosing CPP with a sensitivity of 89.1% and a specificity of 91.3%. Conclusion: Subcutaneous GnRH-A can be used as an alternative to confirm the diagnosis of CPP.
TSH Levels in Relation to Gestation, Birth Weight and Sex
Authors: Korada Murthy , Pearce Mark S. , Avis Enid , Turner Steve , Cheetham Tim
Published: August 2009

Aims: Low birth weight is associated with hypothyroidism and an adverse metabolic profile in later life. Our aim was to examine the relationship between neonatal TSH and birth weight, gestational age and sex. Methods: We compared blood spot filter paper TSH levels with birth weight, gestational age and sex in a 10% sample of infants screened for congenital hypothyroidism at a single centre in Northern England. All gestational ages were included with infants suspected of having congenital hypothyroidism excluded. Results: Data on 1,728 male and 1,662 female infants were analysed. The distribution of TSH was significantly different between males and females, with males having a higher median TSH (0.7 vs. 0.6). Correlations were shown between TSH and birth weight (ρ = –0.07, p = 0.0001) and gestational age (ρ = –0.05, p = 0.008), with the birth weight association remaining independent of gestational age. The functional form of the model suggested that higher TSH in the lowest birth weight categories was responsible for the association between TSH and birth weight. Conclusions: Low birth weight is related to neonatal TSH levels. Further research is required to assess whether this association explains the relationship between higher TSH and an adverse metabolic profile in later life.
Episodic Spontaneous Hypothermia Potentially Triggered by Hyperinsulinemia
Authors: Capanna R. , Marcovecchio M.L. , Verrotti A. , Trotta D. , Chiarelli F. , Mohn A.
Published: August 2009

Episodic spontaneous hypothermia is an infrequent disorder, the pathogenic mechanisms of which have not been completely clarified, although alterations in the serotoninergic system have been suggested. We report the history of a girl with episodes of dizziness and shivering associated with a body temperature lower than 35°C since the age of 10 months. At the age of 11 years, she was admitted to a local hospital and an oral glucose tolerance test showed high total insulin levels. Hypoglycemia secondary to hyperinsulinemia was suspected, and a low-carbohydrate (simple) diet was proposed without results. Due to the recurrence of the episodes, episodic spontaneous hypothermia triggered by hyperinsulinemia was suspected, and treatment with flunarizine, a drug considered the first line in the treatment of migraine-related disorders, was started with a resulting reduction in the episodes. A new endocrinological evaluation showed decreased insulin secretion. In our patient, the success of the therapy might be due to the well-known effect of calcium antagonists in inhibiting serotonin uptake and thereby regulating serotonin levels after hyperinsulinism. This case suggests hyperinsulinemia as a potential mechanism for episodic spontaneous hypothermia, probably mediated by an interaction between insulin and the serotoninergic system.
Cognitive Characteristics Associated with Mild Cognitive Impairment in Parkinson’s Disease
Authors: McKinlay A. , Grace R.C. , Dalrymple-Alford J.C. , Roger D.
Published: August 2009

Background: Cognitive deficits are common in Parkinson’s disease (PD), but the range of deficits is variable. The aim of this study was to identify different cognitive subgroups associated with PD. Methods: A broad range of neuropsychological measures and cognitive domains were used in a cluster analysis to identify subgroups of patients. Results: Three subgroups of patients were identified. Compared to controls, one PD subgroup showed no or minimal cognitive impairment (PD-NCI), a second group showed a variable or uncertain pattern of mild to severe cognitive impairments (PD-UCI), and a third group had evidence of severe cognitive impairment across most cognitive domains (mild cognitive impairment; PD-MCI). The subgroups did not differ with regard to age, motor impairment, or disease duration. Conclusions: Patients with PD are heterogeneous with regard to cognitive presentation and it may be possible to identify patients in the preclinical stage of dementia. The identification of preclinical dementia in PD patients (PD-MCI) provides an opportunity to understand cognitive decline in PD and its progression to dementia.
Characterization of a 2,4-Dinitrochlorobenzene-Induced Chronic Dermatitis Model in Rats
Authors: Fujii Y. , Takeuchi H. , Sakuma S. , Sengoku T. , Takakura S.
Published: August 2009

Although many mouse models of atopic dermatitis have been reported, few rat models have been studied. In this study, a rat chronic allergic dermatitis model was developed and evaluated as a pharmacological model of atopic dermatitis. Prominent ear thickening and scratching were induced after the application of 2,4-dinitrochlorobenzene to the right ear of Brown Norway rats 3 times per week for 3 weeks. Histopathologically, infiltration of T cells in the ear was observed on day 7, and eosinophils and mast cells were found in addition to T cells on day 21. The expression of interferon-γ and interleukin-4 was increased on day 7 when compared with normal rats. However, interferon-γ expression had disappeared by day 21. Tacrolimus ointment applied after ear tissue thickening fully developed, suppressed chronic dermatitis in a dose-dependent manner. This model has some symptomatic and histopathological similarities to atopic dermatitis and might be useful in pharmacological studies.
Influence of Bathing or Washing on Skin Barrier Function in Newborns during the First Four Weeks of Life
Authors: Garcia Bartels N. , Mleczko A. , Schink T. , Proquitté H. , Wauer R.R. , Blume-Peytavi U.
Published: August 2009

Background and Objectives: After birth, skin barrier function is in state of flux and at risk of dysfunction. In a prospective clinical study, we compared the effects of 2 standard cleansing procedures on skin barrier function in newborns. Methods: Fifty-seven healthy full-term neonates aged ≤48 h were randomly assigned to either a bathing group (group B; n = 29), who were bathed with clear water twice weekly, or to a washing group (group W; n = 28), who were washed with a washcloth moistened with clear water twice weekly. Transepidermal water loss (TEWL), skin pH, stratum corneum hydration (SCH) and sebum production were measured at days 2, 7 and 28 of life on the forehead, abdomen, upper leg and buttock. Results: Group B showed significantly lower TEWL on the buttock and higher SCH on the abdomen and forehead compared to group W at day 28. Conclusions: Both skin care regimens do not harm the adaptation of the skin barrier in healthy neonates within the first 4 weeks of life. Skin barrier function differentiates after birth in a regionally specific fashion.
Stratum Corneum Is an Effective Barrier to TiO2 and ZnO Nanoparticle Percutaneous Absorption
Authors: Filipe P. , Silva J.N. , Silva R. , Cirne de Castro J.L. , Marques Gomes M. , Alves L.C. , Santus R. , Pinheiro T.
Published: August 2009

Background: There is increasing concern over the local and systemic side effects of TiO2 and ZnO coated nanoparticles widely used in sun blockers. Objective: To determine the localization and possible skin penetration of TiO2 and ZnO nanoparticles, dispersed in 3 sunscreen formulations, under realistic in vivo conditions in normal and altered skin. Methods: Nuclear microscopy techniques provided spatially resolved quantitative analysis of Ti and Zn nanoparticle distributions in transversal cryosections of skin obtained by biopsy with no further treatment. A test hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and 2 commercial sunscreen formulations containing TiO2 alone or in combination with ZnO were tried, taking into account realistic use conditions by consumers and compared with the recommended standard condition for the sun protection factor test. The protocols consisted of an open test. Results: Following a 2-hour exposure period of normal human skin to TiO2- and ZnO-containing sunscreens, detectable amounts of these physical blockers were only present at the skin surface and in the uppermost stratum corneum regions. Layers deeper than the stratum corneum were devoid of TiO2 or exogenous ZnO, even after 48 h of exposure to the sunscreen, under occlusion. Deposition of TiO2 and ZnO nanoparticles in the openings of the pilosebaceous follicles was also observed, suggesting a preferential fixation area. Penetration of nanoparticles into viable skin tissue could not be detected. Conclusions: TiO2 or ZnO nanoparticles are absent or their levels are too low to be tested under the stratum corneum in human viable epidermal layers. Therefore, significant penetration towards the underlying keratinocytes is unlikely.
Idiopathic Sclerosing Orbital Inflammation – A Case Series Study
Authors: Chen Yan-Ming , Hu Fung-Rong , Liao Shu-Lang
Published: August 2009

Aims: It was the aim of this study to perform a review of the clinical features, treatments and outcomes of patients with idiopathic sclerosing orbital inflammation (ISOI) in Taiwan. Methods: All patients with histologically confirmed ISOI from 1995 to 2007 at the National Taiwan University Hospital were included. We reviewed the medical charts to see the clinical presentation, treatment modalities, treatment efficacy and final clinical status of these patients. Results: Six male and 3 female patients ranging in age from 33 to 82 years were included. The most common symptoms were pain and blurred vision (both 77.8%). Reduced visual acuity and proptosis were the most common signs (both 89%). Five patients received oral steroid treatment with/without pulse therapy combined with tissue removal, the response to which was good in 1 patient and partially effective in the other 4 patients. One patient received oral steroids and surgery, followed by radiotherapy, with only partial response. Patients with oral prednisolone or surgery only all had poor responses. Conclusion: ISOI is rare and also difficult to diagnose and manage. Early intervention with steroids/immunosuppressants combined with surgical debulking procedures may result in control or regression of this recalcitrant disease.
Ultra-Short-Term Heart Rate Variability for Early Risk Stratification following Acute ST-Elevation Myocardial Infarction
Authors: Karp Erez , Shiyovich Arthur , Zahger Doron , Gilutz Harel , Grosbard Aviva , Katz Amos
Published: August 2009

Objectives: To evaluate the prognostic significance of early ultra-short-term heart rate variability (HRV) measurement in patients admitted for ST-elevation myocardial infarction (STEMI). Methods: HRV was calculated retrospectively from the standard admission and discharge 10-second ECG of 196 consecutive patients with STEMI. Reduced HRV was defined as standard deviation of N-N intervals (SDNN) <9.5 (25th percentile). Data regarding all end points were obtained 2 years after discharge for all patients. Results: Patients’ age was 60.9 ± 13 years and 21% were female. Admission SDNN was lower than discharge SDNN (20.2 ± 18 vs. 34.2 ± 31.1, respectively; p = 0.001). Admission and discharge SDNN positively correlated with survival (r = 0.16, p = 0.03 and r = 0.15, p = 0.04, respectively), but were not predictive of other cardiovascular end points. Reduced admission SDNN was associated with increased mortality at 1 and 6 months, and 1 and 2 years after admission, while discharge SDNN was associated only with 1- and 2-year mortality. Using multivariate analysis, adjusted for potential confounders, admission SDNN <9.5 was found to be an independent risk factor for 2-year mortality (odds ratio = 2.9, 95% confidence interval = 1.12–7.56; p = 0.028). Conclusions: Reduced HRV, recorded from admission and discharge ECG, appears to be a significant and independent predictor of all-cause mortality in patients with STEMI.
Revisiting Brain Reserve Hypothesis in Frontotemporal Dementia: Evidence from a Brain Perfusion Study
Authors: Borroni B. , Premi E. , Agosti C. , Alberici A. , Garibotto V. , Bellelli G. , Paghera B. , Lucchini S. , Giubbini R. , Perani D. , Padovani A.
Published: August 2009

Background: Literature data on Alzheimer’s disease suggest that years of schooling and occupational level are associated with a reserve mechanism. No data on patients with behavioral variant frontotemporal dementia (bvFTD) are available yet. Objective: To evaluate the impact of education, occupation, and midlife leisure activities on brain reserve in bvFTD. Methods: Fifty-four bvFTD patients entered the study and underwent neuropsychological and behavioral assessment, including the FTD-modified Clinical Dementia Rating for FTD (FTD-modified CDR), and SPECT imaging. We tested for the linear correlation of educational and occupational level, and midlife leisure activities with regional cerebral blood flow (rCBF), controlling for demographic variables (age and gender) and for cognitive performance (FTD-modified CDR) (statistical parametric mapping). Results: A significant relationship between higher educational and occupational attainments and lower rCBF in medial frontal cortex and dorsolateral frontal cortex, bilaterally, was found (p < 0.005). When midlife leisure activities were considered, no correlation was found. The correlation between a reserve index, accounting for both educational and occupational level, and rCBF showed the same pattern of hypoperfusion. Conclusions: This study suggests that education and occupation act as proxies for reserve capacity in bvFTD. These lifestyle attainments may counteract the onset of this genetic-based disease in at-risk individuals.
Ethnic Disparities in the Treatment of Dementia in Veterans
Authors: Kalkonde Yogeshwar V. , Pinto-Patarroyo Gineth P. , Goldman Tatiana , Strutt Adriana M. , York Michele K. , Kunik Mark E. , Schulz Paul E.
Published: August 2009

Objectives: To test for ethnic disparities in the evaluation and treatment of dementia. Methods: We reviewed 1,401 charts of patients from 4 veteran clinics that routinely evaluate dementia patients. A total of 410 patients met criteria for dementia or mild cognitive impairment (MCI) and their charts were reviewed in detail. Results: Regarding their evaluation, laboratory and imaging testing did not differ between ethnic groups (p > 0.05). Depression screening was more common in African-American (AA) patients (p = 0.03). Significantly more Caucasian patients underwent neuropsychologic testing (p = 0.001). Regarding management, in a multivariate analysis, AA patients with Alzheimer’s disease (AD) (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.02–0.5) or ‘all dementia types’ (OR 0.6, 0.3–0.9) were significantly less likely to receive acetylcholinesterase inhibitors (CHEIs). Other independent predictors of CHEI use were age ≥71 years (OR 5.2, 2.8–9.6), a diagnosis of AD (OR 3.1, 1.6–6.3) or MCI (OR 0.3, 0.1–0.7), and if their evaluation included imaging (head CT or MRI; OR 1.9, 1.05–3.3). Conclusions: AA patients underwent comparable evaluations for dementia and the percentage of CHEI-responsive diagnoses rendered was similar across ethnic groups. However, dementia management differed significantly: AAs were prescribed CHEIs at considerably reduced rates. The reasons for this great disparity warrant further investigation because it may produce significantly greater cognitive impairment and hence suffering amongst AA patients.
Speech Perception after Cochlear Implantation in 53 Patients with Otosclerosis: Multicentre Results
Authors: Rotteveel Liselotte J.C. , Snik Ad F.M. , Cooper Huw , Mawman Deborah J. , van Olphen Adriaan F. , Mylanus Emmanuel A.M.
Published: August 2009

Objectives: To analyse the speech perception performance of 53 cochlear implant recipients with otosclerosis and to evaluate which factors influenced patient performance in this group. The factors included disease-related data such as demographics, pre-operative audiological characteristics, the results of CT scanning and device-related factors. Methods: Data were reviewed on 53 patients with otosclerosis from 4 cochlear implant centres in the United Kingdom and the Netherlands. Comparison of demographics, pre-operative CT scans and audiological data revealed that the patients from the 4 different centres could be considered as one group. Speech perception scores had been obtained with the English AB monosyllable tests and Dutch NVA monosyllable tests. Based on the speech perception scores, the patients were classified as poor or good performers. The characteristics of these subgroups were compared. Results: There was wide variability in the speech perception results. Similar patterns were seen in the phoneme scores and BKB sentence scores between the poor and good performers. The two groups did not differ in age at onset of hearing loss, duration of hearing loss, progression, age at onset of deafness, or duration of deafness. Conclusions: The clinical presentation of the otosclerosis (rapid or slow progression) did not influence speech perception. Better performance was related to less severe signs of otosclerosis on CT scan, full insertion of the electrode array, little or no facial nerve stimulation and little or no need to switch off electrodes.
Major Cerebral Events in Staphylococcus Aureus Infective Endocarditis: Is Anticoagulant Therapy Safe?
Authors: Rasmussen Rasmus V. , Snygg-Martin Ulrika , Olaison Lars , Buchholtz Kristine , Larsen Carsten T. , Hassager Christian , Bruun Niels E.
Published: August 2009

Objectives: To study the impact of anticoagulation on major cerebral events in patients with left-sided Staphylococcus aureus infective endocarditis (IE). Methods: A prospective cohort study; the use of anticoagulation and the relation to major cerebral events was evaluated separately at onset of admission and during hospitalization. Results: Overall, 70 out of 175 patients (40%; 95% CI: 33–47%) experienced major cerebral events during the course of the disease, cerebral ischaemic stroke occured in 59 patients (34%; 95% CI: 27–41%), cerebral infection in 23 patients (14%; 95% CI: 9–19%), and cerebral haemorrhage in 5 patients (3%; 95% CI: 0.5–6%). Patients receiving anticoagulation were less likely to have experienced a major cerebral event at the time of admission (15%) compared with those without anticoagulation (37%, p = 0.009; adjusted OR: 0.27; 95% CI: 0.075–0.96; p = 0.04). In-hospital mortality was 23% (95% CI: 17–29%), and there was no significant difference between those with or without anticoagulation. Conclusions: We found no increased risk of cerebral haemorrhage in S. aureus IE patients receiving anticoagulation. Anticoagulation was associated with a reduced risk of cerebral events before initiation of antibiotics. Data support the continuance of anticoagulation in S. aureus IE patients when indicated.
Association between Dental Caries and Fluorosis among South Australian Children
Authors: Do L.G. , Spencer A.J. , Ha D.H.
Published: August 2009

There is an ongoing debate whether early exposure to fluoride is necessary. The effect of early exposure to fluoride needs to be understood to inform the appropriate population oral health policy. This study aimed to evaluate the effects of systemic fluoride intake in early childhood on caries experience of the permanent dentition observed at the age of 8 or 9 years, controlling for the effects of topical exposures to fluoride at the age of 5 years. The fluorosis experience of children was used as a proxy indicator for early exposure to fluoride, while exposures to fluoride at the age of 5 years, which were collected retrospectively, were used to control for the topical effect on permanent caries experience of the same children. Caries experience recorded at 8 or 9 years of age of 571 children was compared between groups with or without fluorosis. Bivariate analysis and multivariate analysis controlling for exposures to fluoride at the age of 5 years and other potential contributory factors were conducted. A quarter of the sample had very mild to mild fluorosis, while 15% had caries experience in the permanent dentition. Multivariate models showed that children who did not have fluorosis had a higher prevalence and severity of caries compared to those with fluorosis after controlling for other factors. In conclusion, there was a significant negative association between fluorosis status and caries experience in the permanent dentition.
From Alienism to the Birth of Modern Psychiatry: A Neurological Story?
Authors: Bogousslavsky Julien , Moulin Thierry
Published: August 2009

The interactions between developing neurology and psychiatry in Paris are of interest, in a city which was the main center for studies on the nervous system and its disorders during the nineteenth century. Contrary to a common view, and in spite of an established tradition for mental diseases, emerging neurology had a much stronger influence on psychiatry (‘alienism’) than the reverse. This was largely due to the school built up by Jean-Martin Charcot, which was organized around the study and management of hysteria. Although Charcot himself always claimed his disinterest in mental medicine, he stimulated the development of an original scientific approach to nervous system conditions, along with a structured academic teaching, while alienism paradoxically remained stuck in organicism, after Antoine Bayle’s report in 1822 of ‘arachnitis’ as the substratum of general paresis of the insane. Contrary to alienism, the young neurological school was able of self-criticism, and progressively underscored mental factors in hysteria. This led to the paradox that neurologists were active in a disease with a recognized lack of organic lesion, while alienists were postulating brain lesions in all mental disorders. The neurological activity thus indirectly and involuntarily led to the first developments of psychodynamic concepts in mental diseases. The academic evolution led to the launch of a faculty chair of mental and brain diseases in 1875, which was taken over for nearly half a century by direct pupils of Charcot: Benjamin Ball, Alix Joffroy, and Gilbert Ballet held the position until 1916, supporting the development of modern psychiatry in general hospitals, while alienism progressively disappeared at the turn of the century.
Issues Related to Deep Brain Stimulation for Treatment-Refractory Tourette’s Syndrome
Authors: Porta Mauro , Sevello Domenico , Sassi Marco , Brambilla Arianna , Defendi Stefano , Priori Alberto , Robertson Mary
Published: August 2009

Deep brain stimulation (DBS) has been used in a small number of patients with Tourette’s syndrome and results on tics and comorbidities have been promising. The choice of the DBS target appears to influence the effectiveness; preliminary studies and case reports suggest that certain target areas may be more effective than others in patients with specific symptoms and comorbidities. Clinical data on the effect of DBS on tics and behavioral symptoms support its use in patients with severe, refractory Tourette’s syndrome, particularly in younger adults who have a greater severity and prevalence of tics and comorbidities, and are more likely to experience social impairment. Although DBS has shown potential as an ‘add-on’ therapy for Tourette’s syndrome patients failing to show adequate improvement with conventional conservative treatments, several issues remain to be resolved, including patient selection, choice of target, and adverse effects. Successful DBS requires an experienced multidisciplinary team for the management of these complex pre-, peri- and postoperative issues. Future studies should include establishment of consistent inclusion criteria and specific practical requirements for clinical trials, evaluation of the impact of DBS on non-tic symptoms and their influence on outcome, social impairment and quality of life, and the identification of optimum neurophysiologically based DBS targets for improved efficacy in specific patient subtypes.