bluuebunny/crossref_metadata_2025 huggingface dataset:
Augmentation Controls the Fast Rebound From Depression at Excitatory Hippocampal Synapses
Authors: Garcia-Perez Elizabeth , Wesseling John F.
Published: January 2008

Short-term plasticity occurs at most central chemical synapses and includes both positive and negative components, but the principles governing interaction between components are largely unknown. The residual Ca2+ that persists in presynaptic terminals for several seconds after repetitive use is known to enhance neurotransmitter release under artificial, low probability of release conditions where depression is absent; this is termed augmentation. However, the full impact of augmentation under standard conditions at synapses where depression dominates is not known because of possibly complicated convolution with a variety of potential depression mechanisms. This report shows that residual Ca2+ continues to have a large enhancing impact on release at excitatory hippocampal synapses recovering from depression, including when only recently recruited vesicles are available for release. No evidence was found for gradual vesicle priming or for fast refilling of a highly releasable subdivision of the readily releasable pool (RRP). And decay of enhancement matched the clearance of residual Ca2+, thus matching the behavior of augmentation when studied in isolation. Because of incomplete RRP replenishment, synaptic strength was not typically increased above baseline when residual Ca2+ levels were highest. Instead residual Ca2+ caused single pulse release probability to rebound quickly from depression and then depress quickly during subsequent bursts of activity. Together, these observations can help resolve discrepancies in recent timing estimates of recovery from depression. Additionally, in contrast to results obtained under reduced release conditions, augmentation could be driven to a maximal level, occluding paired-pulse facilitation and other mechanisms that increase release efficiency.
Role of Hog1 and Yaf9 in the transcriptional response ofSaccharomyces cerevisiaeto cesium chloride
Authors: Del Vescovo Valerio , Casagrande Viviana , Bianchi Michele M. , Piccinni Eugenia , Frontali Laura , Militti Cristina , Fardeau Vivienne , Devaux Frédéric , Sanza Claudio Di , Presutti Carlo , Negri Rodolfo
Published: January 2008

We analyzed the global transcriptional response of Saccharomyces cerevisiae cells exposed to different concentrations of CsCl in the growth medium and at different times after addition. Early responsive genes were mainly involved in cell wall structure and biosynthesis. About half of the induced genes were previously shown to respond to other alkali metal cations in a Hog1-dependent fashion. Western blot analysis confirmed that cesium concentrations as low as 100 mM activate Hog1 phosphorylation. Another important fraction of the cesium-modulated genes requires Yaf9p for full responsiveness as shown by the transcriptome of a yaf9-deleted strain in the presence of cesium. We showed that a cell wall-restructuring process promptly occurs in response to cesium addition, which is dependent on the presence of both Hog1 and Yaf9 proteins. Moreover, the sensitivity to low concentration of cesium of the yaf9-deleted strain is not observed in a strain carrying the hog1/ yaf9 double deletion. We conclude that the observed early transcriptional modulation of cell wall genes has a crucial role in S. cerevisiae adaptation to cesium.
Genome-wide discovery of Pax7 target genes during development
Authors: White Robert B. , Ziman Melanie R.
Published: January 2008

Pax7 plays critical roles in development of brain, spinal cord, neural crest, and skeletal muscle. As a sequence-specific DNA-binding transcription factor, any direct functional role played by Pax7 during development is mediated through target gene selection. Thus, we have sought to identify genes targeted by Pax7 during embryonic development using an unbiased chromatin immunoprecipitation (ChIP) cloning assay to isolate cis-regulatory regions bound by Pax7 in vivo. Sequencing and genomic localization of a library of chromatin-DNA fragments bound by Pax7 has identified 34 candidate Pax7 target genes, with occupancy of a selection confirmed with independent chromatin enrichment tests (ChIP-PCR). To assess the capacity of Pax7 to regulate transcription from these loci, we have cloned alternate transcripts of Pax7 (differing significantly in their DNA binding domain) into expression vectors and transfected cultured cells with these constructs, then analyzed target gene expression levels using RT-PCR. We show that Pax7 directly occupies sites within genes encoding transcription factors Gbx1 and Eya4, the neurogenic cytokine receptor ciliary neurotrophic factor receptor, the neuronal potassium channel Kcnk2, and the signal transduction kinase Camk1d in vivo and regulates the transcriptional state of these genes in cultured cells. This analysis gives us greater insight into the direct functional role played by Pax7 during embryonic development.
p53-Dependent and p53-Independent Activation of Autophagy by ARF
Authors: Abida Wassim M. , Gu Wei
Published: January 2008

The ARF tumor suppressor is a crucial component of the cellular response to hyperproliferative signals, including oncogene activation, and functions by inducing a p53-dependent cell growth arrest and apoptosis program. It has recently been reported that the ARF mRNA can produce a smARF isoform that lacks the NH2-terminal region required for p53 activation. Overexpression of this isoform can induce autophagy, a cellular process characterized by the formation of cytoplasmic vesicles and the digestion of cellular content, independently of p53. However, the level of this isoform is extremely low in cells, and it remains unclear whether the predominant form of ARF, the full-length protein, is able to activate autophagy. Here, we show that full-length ARF can induce autophagy in 293T cells where p53 is inactivated by viral proteins, and, notably, expression of the NH2-terminal region alone, which is required for nucleolar localization, is sufficient for autophagy activation, independently of p53. Given the reported ability of p53 to induce autophagy, we also investigated the role of p53 in ARF-mediated autophagy induction. We found that full-length ARF expression induces p53 activation and promotes autophagy in a p53-positive cell line, and that ARF-mediated autophagy can be abrogated, at least in part, by RNAi-mediated knockdown of p53 in this cellular context. Thus, our findings modify the current view regarding the mechanism of autophagy induction by ARF and suggest an important role for autophagy in tumor suppression via full-length ARF in both p53-dependent and p53-independent manners, depending on cellular context. [Cancer Res 2008;68(2):352–7]
The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma
Authors: Shen Zan , Yang Zhen Fan , Gao Yi , Li Ji Cheng , Chen Hai Xiao , Liu Ching Chiu , Poon Ronnie T.P. , Fan Sheung Tat , Luk John M. , Sze Kong Hung , Li Tsai Ping , Gan Ren Bao , He Ming Liang , Kung Hsiang Fu , Lin Marie C.M.
Published: January 2008

The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G0-G1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and β fibroblast growth factor (bFGF)/β fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH2-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. [Cancer Res 2008;68(2):404–14]
Glioma Pathogenesis-Related Protein 1 Exerts Tumor Suppressor Activities through Proapoptotic Reactive Oxygen Species–c-Jun–NH2 Kinase Signaling
Authors: Li Likun , Abdel Fattah ElMoataz , Cao Guangwen , Ren Chengzhen , Yang Guang , Goltsov Alexei A. , Chinault A. Craig , Cai Wei-Wen , Timme Terry L. , Thompson Timothy C.
Published: January 2008

Glioma pathogenesis-related protein 1 (GLIPR1), a novel p53 target gene, is down-regulated by methylation in prostate cancer and has p53-dependent and -independent proapoptotic activities in tumor cells. These properties suggest an important tumor suppressor role for GLIPR1, yet direct genetic evidence of a tumor suppressor function for GLIPR1 is lacking and the molecular mechanism(s), through which GLIPR1 exerts its tumor suppressor functions, has not been shown. Here, we report that the expression of GLIPR1 is significantly reduced in human prostate tumor tissues compared with adjacent normal prostate tissues and in multiple human cancer cell lines. Overexpression of GLIPR1 in cancer cells leads to suppression of colony growth and induction of apoptosis. Mice with an inactivated Glipr1 gene had significantly shorter tumor-free survival times than either Glipr1+/+ or Glipr1+/− mice in both p53+/+ and p53+/− genetic backgrounds, owing to their development of a unique array of malignant tumors. Mechanistic analysis indicated that GLIPR1 up-regulation increases the production of reactive oxygen species (ROS) leading to apoptosis through activation of the c-Jun–NH2 kinase (JNK) signaling cascade. Thus, our results identify GLIPR1 as a proapoptotic tumor suppressor acting through the ROS-JNK pathway and support the therapeutic potential for this protein. [Cancer Res 2008;68(2):434–43]
Multiple Rare Nonsynonymous Variants in the Adenomatous Polyposis Coli Gene Predispose to Colorectal Adenomas
Authors: Azzopardi Duncan , Dallosso Anthony R. , Eliason Kristilyn , Hendrickson Brant C. , Jones Natalie , Rawstorne Edward , Colley James , Moskvina Valentina , Frye Cynthia , Sampson Julian R. , Wenstrup Richard , Scholl Thomas , Cheadle Jeremy P.
Published: January 2008

It has been proposed that multiple rare variants in numerous genes collectively account for a substantial proportion of multifactorial inherited predisposition to a variety of diseases, including colorectal adenomas (CRA). We have studied this hypothesis by sequencing the adenomatous polyposis coli (APC) gene in 691 unrelated North American patients with CRAs and 969 matched healthy controls. Rare inherited nonsynonymous variants of APC were significantly overrepresented in patients who did not carry conventional pathogenic mutations in the APC or MutY homologue genes [non–familial adenomatous polyposis (FAP) non–MUTYH-associated polyposis (MAP) patients; 81 of 480, 16.9%] compared with patients with FAP or MAP (20 of 211, 9.5%, P = 0.0113), and this overrepresentation was highest in those non-FAP non-MAP patients with 11 to 99 CRAs (30 of 161, 18.6%, P = 0.0103). Furthermore, significantly more non-FAP non-MAP patients carried rare nonsynonymous variants in the functionally important β-catenin down-regulating domain compared with healthy controls (32 of 480 versus 37 of 969, P = 0.0166). In silico analyses predicted that ∼46% of the 61 different variants identified were likely to affect function, and upon testing, 7 of 16 nonsynonymous variants were shown to alter β-catenin–regulated transcription in vitro. These data suggest that multiple rare nonsynonymous variants in APC play a significant role in predisposing to CRAs. [Cancer Res 2008;68(2):358–63]
Hypermethylation of theAKAP12Promoter is a Biomarker of Barrett's-Associated Esophageal Neoplastic Progression
Authors: Jin Zhe , Hamilton James P. , Yang Jian , Mori Yuriko , Olaru Alexandru , Sato Fumiaki , Ito Tetsuo , Kan Takatsugu , Cheng Yulan , Paun Bogdan , David Stefan , Beer David G. , Agarwal Rachana , Abraham John M. , Meltzer Stephen J.
Published: January 2008

The A-kinase anchoring protein 12 (AKAP12) is a kinase scaffold protein with known tumor suppressor activity. Recently, AKAP12 promoter hypermethylation was reported in gastric and colorectal cancers. We examined AKAP12 promoter hypermethylation using real-time methylation-specific PCR in 259 human esophageal tissues. AKAP12 hypermethylation showed highly discriminative receiver-operator characteristic (ROC) curve profiles, clearly distinguishing esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma and normal esophagus (P < 0.0001). AKAP12-normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's, and EAC than in normal esophagus (P < 0.0000001). AKAP12 hypermethylation frequency was zero in normal esophagus but increased early during neoplastic progression, to 38.9% in BE from patients with Barrett's alone, 52.5% in dysplastic Barrett's metaplasia, and 52.2% in EAC. AKAP12 hypermethylation levels were significantly higher in normal esophageal epithelia from patients with EAC (mean = 0.00082) than in normal esophagi from patients without Barrett's or esophageal cancer (mean = 0.00007; P = 0.006). There was a significant correlation between AKAP12 hypermethylation and BE segment length, a known clinical neoplastic progression risk factor. In contrast, only 2 (7.7%) of 26 esophageal squamous cell carcinomas exhibited AKAP12 hypermethylation. Treatment of BIC and OE33 EAC cells with 5-aza-2'-deoxycytidine reduced AKAP12 methylation and increased AKAP12 mRNA expression. AKAP12 mRNA levels in EACs with unmethylated AKAP12 (mean = 0.1663) were higher than in EACs with methylated AKAP12 (mean = 0.0668). We conclude that promoter hypermethylation of AKAP12 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker for the early detection of EAC. (Cancer Epidemiol Biomarkers Prev 2008;17(1):111–7)
Relationship between Menopausal Hormone Therapy and Risk of Ductal, Lobular, and Ductal-Lobular Breast Carcinomas
Authors: Li Christopher I. , Malone Kathleen E. , Porter Peggy L. , Lawton Thomas J. , Voigt Lynda F. , Cushing-Haugen Kara L. , Lin Ming Gang , Yuan Xiaopu , Daling Janet R.
Published: January 2008

Combined estrogen and progestin hormone therapy (CHT) increases breast cancer risk, but this risk varies by breast cancer type. Several studies indicate that CHT is more strongly related to lobular carcinoma risk than to ductal carcinoma risk, but these studies have been limited in their assessments of recency and duration of use, and none included a centralized pathology review. We conducted a population-based case-control study consisting of 324 lobular, 196 ductal-lobular, and 524 ductal cases diagnosed from 2000 to 2004 and 469 controls ages 55 to 74 years old. Tissue specimens were centrally reviewed for 83% of cases. Associations between hormone use and breast cancer risk were evaluated using polytomous logistic regression. Current CHT users had 2.7-fold [95% confidence interval (95% CI), 1.7-4.2] and 3.3-fold (95% CI, 2.0-5.7) elevated risks of lobular and ductal-lobular carcinomas, respectively, regardless of tumor stage, size, or nodal status. Elevations in risk were observed only among users of CHT for ≥3 years. Among ductal-lobular cases, CHT increased risk of tumors that were ≥50% lobular (odds ratio, 4.8; 95% CI, 2.1-11.1) but not tumors that were <50% lobular (odds ratio, 1.9; 95% CI, 0.9-4.1). Current CHT users for ≥3 years have a substantially increased risk of lobular carcinomas. Although lobular carcinomas are less common than ductal carcinomas (∼16% versus 70% of all invasive breast cancers in the United States), this duration is shorter than the 5 years of use widely cited to be needed to confer an increased risk of breast cancer overall. Further studies focusing on the etiology of lobular carcinomas are needed. (Cancer Epidemiol Biomarkers Prev 2008;17(1):43–50)
Association of Vitamin D–Related Information from a Telephone Interview with 25-Hydroxyvitamin D
Authors: Sahota Harleen , Barnett Heidi , Lesosky Maia , Raboud Janet M. , Vieth Reinhold , Knight Julia A.
Published: January 2008

Vitamin D may be associated with reduced risks of several types of cancer, including colon, prostate, and breast. We examined the relationship between vitamin D–related questions administered in a telephone interview and serum 25-hydroxyvitamin D [25(OH)D]. Three hundred and eight eligible women were randomly selected from controls in a breast cancer case-control study. Questions pertaining to sun exposure and dietary sources of vitamin D over the previous 4 weeks were asked in both summer and winter. We assessed the association between questionnaire-derived items and 25(OH)D using multiple linear regression. There were 217 participating women, 203 in summer and 213 in winter. Models were adjusted for age, body mass index, and skin color. Number of days when more than 0.5 hour was spent outdoors per week (“7” versus “<7” β = 11.12; P = 0.01), limb coverage (“no” β = 24.90 and “partial” β = 8.15 versus “yes”; P = 0.0001), and milk intake (glasses/wk; “>10” β = 18.94, “>5-10” β = 9.16, and “1-5” β = 7.90 versus “<1”; P = 0.02) best predicted 25(OH)D in the summer. The best predictors in the winter were sunlamp use (“yes” β = 27.97 versus “no”; P = 0.01), milk intake (glasses/wk; “>10” β = 14.54, “>5-10” β = 11.54, and “1-5” β = 2.15 versus “<1”; P = 0.01), and vitamin D–containing supplements (“high” β = 17.30 and “moderate” β = 13.82 versus “none”; P = 0.0006). The R2 was 0.29 for the summer model and was 0.21 for the winter model. Overall, there was evidence to suggest that questions designed to assess vitamin D exposure were in fact related to serum 25(OH)D. (Cancer Epidemiol Biomarkers Prev 2008;17(1):232–8)
Nine-Gene Molecular Signature Is Not Associated with Prostate Cancer Death in a Watchful Waiting Cohort
Authors: Mucci Lorelei A. , Pawitan Yudi , Demichelis Francesca , Fall Katja , Stark Jennifer R. , Adami Hans-Olov , Andersson Swen-Olof , Andrén Ove , Eisenstein Anna S. , Holmberg Lars , Huang Wei , Kantoff Philip W. , Perner Sven , Stampfer Meir J. , Johansson Jan-Erik , Rubin Mark A.
Published: January 2008

Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):249–51)
Body Mass and Endometrial Cancer Risk by Hormone Replacement Therapy and Cancer Subtype
Authors: McCullough Marjorie L. , Patel Alpa V. , Patel Roshni , Rodriguez Carmen , Feigelson Heather Spencer , Bandera Elisa V. , Gansler Ted , Thun Michael J. , Calle Eugenia E.
Published: January 2008

Epidemiologic studies unequivocally show that greater body mass increases the risk of endometrial cancer, but whether risk varies by use of postmenopausal hormone therapy (HT), location of fat deposition, or cancer subtype is still unclear. We examined these associations among 33,436 postmenopausal women in the Cancer Prevention Study II Nutrition Cohort, who completed questionnaires on diet, lifestyle, and medical history at baseline in 1992. A total of 318 cases were eligible through June 2003. Cox-proportional hazards analyses were used to estimate multivariate-adjusted rate ratios (RR). As expected, adult body mass index (BMI) was a strong predictor of risk [RR, 4.70; 95% confidence interval (CI), 3.12-7.07 for BMI 35+ versus 22.5-25.0, P trend < 0.0001]. Use of estrogen plus progestin postmenopausal HT modified the association. Among never-users, risk was significantly linear across the entire range of BMI examined (RR, 0.51; 95% CI, 0.29-0.92 for <22.5 versus 22.5-25.0; RR, 4.41; 95% CI, 2.70-7.20 for ≥35 versus 22.5-25.0, P trend < 0.0001), but among ever estrogen plus progestin users, the association was not significant (P trend = 1.0; P interaction < 0.0001). We observed no difference in risk according to tendency for central versus peripheral fat deposition. Greater BMI (≥30 versus <25.0) increased risk of both “type I” (classic estrogen pathway, RR, 4.22; 95% CI, 3.07-5.81) and “type II” (serous, clear cell, and all other high grade) cancers (RR, 2.87; 95% CI, 1.59-5.16). The increased risk of endometrial cancer across the range of BMI in women who never used postmenopausal HT stresses the need to prevent both overweight and obesity in women. (Cancer Epidemiol Biomarkers Prev 2008;17(1):73–9)
Serum Interleukin-6 Level but not Genotype Predicts Survival after Resection in Stages II and III Gastric Carcinoma
Authors: Liao Wei-Chih , Lin Jaw-Town , Wu Chun-Ying , Huang Shih-Pei , Lin Ming-Tsan , Wu Ariel Sing-Huei , Huang Yu-Jie , Wu Ming-Shiang
Published: January 2008

Purpose: It has been suggested that interleukin-6 (IL-6) is a prognostic indicator for survival in patients with gastric carcinoma, but this has not been proved using survival analysis. In Asians, the −634G allele is associated with increased IL-6 production. The objective of this study was to evaluate the association between serum IL-6 levels, −634G/C polymorphism, and overall survival after resection for gastric carcinoma.

Experimental Design: A total of 155 consecutive patients with gastric carcinoma were evaluated. Serum IL-6 levels were analyzed using an enzyme-linked immunoabsorbent assay. Genotype was determined by PCR and restriction fragment length polymorphism. Serum levels and survival were correlated with genotype and clinicopathologic factors.

Results: Age and stage, but not −634G/C genotype, were associated with serum IL-6 levels. The median survival for patients with stage II or stage III gastric carcinoma was 1,418 days in patients with low (≤13 pg/mL) versus 618 days in patients with high (>13 pg/mL) serum IL-6 levels (P = 0.038). Results of a multivariate analysis showed that serum IL-6 level of >13 pg/mL was a significant predictor of poor survival (hazard ratio, 1.77; 95% confidence interval, 1.07-2.92; P = 0.026).

Conclusions: Serum IL-6 level of >13 pg/mL correlates with tumor progression and is an independent predictor of poor survival after resection. In patients with stage II and III gastric carcinoma, serum IL-6 level is more effective than stage as a prognostic indicator. By measuring IL-6, these patients can be divided into two groups with significant differences in survival. The −634G/C polymorphism is not associated with serum IL-6 level or survival.
Diagnosis of Familial Hypercholesterolemia in General Practice Using Clinical Diagnostic Criteria or Genetic Testing as Part of Cascade Genetic Screening
Authors: Leren Trond P. , Finborud Tora Himle , Manshaus Turid E. , Ose Leiv , Berge Knut Erik
Published: January 2008

Background: Too few familial hypercholesterolemia (FH) patients are diagnosed. The most cost-effective strategy to diagnose FH is to examine first-degree relatives of already diagnosed patients. This is referred to as cascade genetic screening. Methods and Results: One thousand eight hundred and five first-degree relatives of index patients with molecularly defined FH consented to cascade genetic screening by the use of molecular genetic testing. Of these, 44.8% were mutation carriers and 55.2% were noncarriers. Only 44.2% of the mutation carriers were on lipid-lowering drugs at the time of genetic testing. Of these, only 9.4% had a value for total serum cholesterol below 5 mM. Among adult mutation carriers who were not on lipid-lowering treatment at the time of genetic testing, reductions in total serum cholesterol and low-density lipoprotein cholesterol of 18.4% (p < 0.0001) and 25.3% (p < 0.0001), respectively, were observed 6 months after genetic testing. It is assumed that this improvement in the lipid profile is due to a definite diagnosis obtained by molecular genetic testing. By using the results of genetic testing as the gold standard for diagnosis of FH, data from a questionnaire filled out by the relatives showed that the use of clinical criteria to diagnose FH in general practice had a sensitivity of 46.2% and a specificity of 88.0%. Conclusions: The use of clinical diagnostic criteria to diagnose FH in general practice identifies only approximately 50% of FH patients. Molecular genetic testing as part of cascade genetic screening is an efficient tool to diagnose patients, leading to significant improvement in the lipid profile. It should therefore be implemented in clinical medicine.
Genetic Testing for Familial Cancer
Authors: Eisinger François
Published: January 2008

Background: Since 2002, hereditary cancer gene testing has been funded at the national level in France. Here we report on the impact of this funding on the number of tests carried out and specify the genes/syndromes on which these tests focus. Methods: All French laboratory facilities funded had to submit a report on their activities to the French Health Ministry in March 2004. Results: Funding has led to an increase of >344% in the number of tests carried out between the years 2000 and 2003. For every 100,000 inhabitants, 16.02 cases with a familial cancer syndrome (index cases subjected to ‘diagnostic genetic testing’) and 4.44 relatives of an index case with a proven mutation were tested. The overall mutation detection rate was 15.2% in the case of breast cancer genes and 17.2% in that of mismatch repair genes. Conclusion: In France, the current mutation detection rate is high in comparison with the 10% benchmark level. A further increase can be expected to occur in the number of tests carried out in the future.
Prevention of β-Thalassemia in a Large Pakistani Family through Cascade Testing
Authors: Baig S.M. , Din M.A. , Hassan H. , Azhar A. , Baig J.M. , Aslam M. , Anjum I. , Farooq M. , Hussain M.S. , Rasool M. , Nawaz S. , Qureshi J.A. , Zaman T.
Published: January 2008

Background: We report cascade testing of a large Pakistani family for β-thalassemia alleles. The family was still practicing consanguineous marriages and was at risk of having more affected births. Objective: The objective of this study was to show that identification of disease carriers in families with index cases in order to create awareness about disease and provide genetic counseling would result in reduction of the frequency of β-thalassemia in Pakistan. Methods: In this large family with an index case, 27 available living members were tested for β-thalassemia. Carriers of the disease were detected by measuring hemoglobin indices, and amplification refractory mutation system polymerase chain reaction was used for mutation analysis. Genetic counseling was provided to members of this family. Results: There were already 3 marriages between the carrier members and 1 between a carrier and noncarrier in this large family; 12 (44.4%) members were found to carry the mutant gene, representing a very high carrier rate compared to the 5.4% carrier frequency of β-thalassemia in the general population of Pakistan. The family was counseled for prevention of affected births. The initially reluctant family gradually became cooperative and seriously attended the genetic counseling sessions. Conclusion: Cascade testing is more practical than general population screening in a country with limited health facilities where consanguineous marriages are practiced. This report emphasizes the need of extensive testing within families with index cases to identify the carriers of β-thalassemia in order to reduce disease occurrence through awareness and genetic counseling.
Public Perception of Prenatal Genetic Testing: Arguments Put forward by the Public during a Participatory Policy Project in the Netherlands
Authors: de Cock Buning Tjard , Broerse Jacqueline E.W. , Bunders Joske F.G.
Published: January 2008

In early 2002, the Dutch Ministry of Public Health, Welfare and Sport piloted the application of an interactive process to policy development in the field of medical biotechnology. In such an approach, relevant societal actors, including the public at large, are actively involved in an open exchange, planning, action and reflection process. This paper reports on the findings of one of the activities of the ministry within this initiative, the consultation of the public on dilemmas with respect to prenatal genetic testing by means of citizen panels. Participants were asked to reflect on questions with respect to whether and under which conditions pregnant women may have freedom of choice to use prenatal genetic testing. In a structured way, arguments in favour and against various positions were identified and prioritized. The paper closes with a discussion on the implications of the use of citizen panels and summarizes the 2 actual policy changes of the ministry that resulted from this process.
Successful Pregnancy following Insertion of a Levonorgestrel-Releasing Intrauterine System in Two Infertile Patients with Complex Atypical Endometrial Hyperplasia
Authors: Qi Xiujuan , Zhao Wencui , Duan Yuying , Li Yujun
Published: January 2008

Two infertile patients are presented with complex atypical endometrial hyperplasia becoming pregnant following conservative treatment with a levonorgestrel-releasing intrauterine system (LNG-IUS) insertion. Histological morphology of endometrial samples after 6 months’ exposure to LNG-IUS showed secretory or atrophic glands with decidualized stroma. Two healthy babies were born following ovulation induction after removal of the LNG-IUS.
Down Syndrome, Achondroplasia and Tetralogy of Fallot
Authors: Dabir Tabib , McCrossan Brian A. , Sweeney Louise , Magee Alex , Sands Andrew J.
Published: January 2008

This paper describes a female infant with achondroplasia, Down syndrome and tetralogy of Fallot. Down syndrome and achondroplasia were confirmed by karyotyping and presence of a common fibroblast growth factor receptor 3 mutation (Gly380Arg), respectively. The clinical course was complicated by pulmonary hypoplasia and subsequent intractable respiratory failure secondary to the combination of congenital conditions, which resulted in the patient’s death at 5 months.
Early Discriminatory Diagnosis of Dementia with Lewy Bodies
Authors: Aarsland Dag , Kurz Martin , Beyer Mona , Bronnick Kolbjørn , Piepenstock Nore Sabine , Ballard Clive
Published: January 2008

Background: The clinical diagnostic criteria for dementia with Lewy bodies (DLB) have a low sensitivity, and there are no generally accepted biomarkers to distinguish DLB from other dementias. Our aim was to identify biomarkers that may differentiate DLB from Alzheimer’s disease (AD). Method: We performed a systematic literature search for studies of EEG, imaging techniques and genetic and CSF markers that provide sensitivity and specificity in the identification of DLB. Results: The best evidence was for scintigraphy of the striatal dopamine transporter system using FP-CIT SPECT. Several small scintigraphy studies of cardiovascular autonomic function using metaiodobenzylguanidine SPECT have reported promising results. Studies exploring innovative techniques based on CSF have reported interesting findings for the combination of amyloid β (aβ) isoforms as well as α-synuclein, and there are interesting results emerging from preliminary studies applying proteomic techniques. Data from studies using structural MRI, perfusion SPECT, genetics and EEG studies show differences between DLB and AD but only at a group level. Conclusion: Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown good diagnostic accuracy in the research setting. Data from large multicentre studies and from studies with autopsy confirmation exist for scintigraphy of the dopamine transporter system. Future studies should explore its value in possible DLB and for clinical management and health economics.
Searching for Memories, Sudoku, Implicit Check Bits, and the Iterative Use of Not-Always-Correct Rapid Neural Computation
Authors: Hopfield J. J.
Published: January 2008

The algorithms that simple feedback neural circuits representing a brain area can rapidly carry out are often adequate to solve easy problems but for more difficult problems can return incorrect answers. A new excitatory-inhibitory circuit model of associative memory displays the common human problem of failing to rapidly find a memory when only a small clue is present. The memory model and a related computational network for solving Sudoku puzzles produce answers that contain implicit check bits in the representation of information across neurons, allowing a rapid evaluation of whether the putative answer is correct or incorrect through a computation related to visual pop-out. This fact may account for our strong psychological feeling of right or wrong when we retrieve a nominal memory from a minimal clue. This information allows more difficult computations or memory retrievals to be done in a serial fashion by using the fast but limited capabilities of a computational module multiple times. The mathematics of the excitatory-inhibitory circuits for associative memory and for Sudoku, both of which are understood in terms of energy or Lyapunov functions, is described in detail.
Familiarity between mates improves few aspects of reproductive performance in house sparrows
Authors: Westneat David , Hatch Margret
Published: January 2008

Many hypotheses have been proposed to account for the increased reproductive success with age documented in most birds. One, the mate familiarity hypothesis, suggests that older individuals are likely to have partners with whom they have bred before, which may enhance reproductive success. We found that pairs of house sparrows that bred together previously fledged more young than pairs that were newly formed. This was primarily due to newly-formed pairs with at least one yearling having fewer nesting attempts than continuing pairs. We also examined the possibility that continuing pairs were better coordinated in parental duties, but found no evidence for this in terms of amount of overlap at the nestbox or amount of time nestlings were unattended. Our results suggest the higher success of continuing pairs may be a matter of female age and quality and not due to benefits accrued by coordination with their mate.
Antiphonal exchanges in African elephants (Loxodonta africana): collective response to a shared stimulus, social facilitation, or true communicative event?
Authors: Savage Anne , Soltis Joseph , Leighty Katherine , Leong Kirsten
Published: January 2008

Female African elephants are thought to exchange 'rumble' vocalizations, but such temporally associated calls may not constitute communicative events. Affiliated females are more likely to engage in antiphonal calling, but affiliation is defined according to time spent in proximity. Affiliated partners may vocalize in sequence simply because their proximity causes them to collectively respond to shared external stimuli or due to a social facilitation effect. We used bi-variate and partial correlation analyses to test for the independent effects of the strength of the social relationship and distance between vocal partners on the likelihood of a vocal response. Female African elephants at Disney's Animal Kingdom were video-taped and outfitted with audio-recording collars that allowed for the individual identification of low-frequency rumbles. Affiliation had a strong influence on response likelihood, even after controlling for the effects of the distance between vocalizing partners. Further, the distance between vocalizing partners did not correlate with response likelihood, and factoring out the effects of affiliation did not significantly alter this result. These results suggest that rumble exchanges are communicative events that reflect social bonds, not simply artifacts of increased proximity and, therefore, provide support for functional hypotheses concerning rumble exchanges in wild African elephants.
Males respond differently than females to mate loss in the biparental convict cichlid fish
Authors: Itzkowitz  , Bockelman
Published: January 2008

Using the biparental convict cichlid fish, Archocentrus nigrofasciatus, we examined whether the loss of a mate prior to spawning influences pair re-formation and reproduction. We manipulated an individuals' "readiness to mate" by removing its mate within 24 h prior to spawning and immediately replacing it with a similar sized individual that had not been exposed to prior courtship. Most pairs with a replaced male showed an increase in aggression and courtship but, within 24 h, successfully spawned. We determined that resident females required the presence of a male before depositing their eggs and the likelihood of forming this new pair bond remained unchanged in spite of the abbreviated premating period. Pairs in which females were replaced (i.e., male is the resident) took longer to spawn than control pairs. Courtship behavior did not increase with the addition of the new female, further illustrating that spawning was not imminent. Here again we provide evidence that the likelihood of forming a pair bond remained unchanged. We suggest that unlike females that were provided with a new male, a male provided with new female delays spawning because of his prior pair bond attachment to the initial female.
Vertical Tracer Concentration Profiles Measured during the Joint Urban 2003 Dispersion Study
Authors: Flaherty Julia E. , Lamb Brian , Allwine K. Jerry , Allwine Eugene
Published: January 2008

An atmospheric tracer dispersion study known as Joint Urban 2003 was conducted in Oklahoma City, Oklahoma, during July of 2003. As part of this field program, vertical concentration profiles were measured at approximately 1 km from the downtown ground-level tracer gas release locations. These profiles showed that the urban landscape was very effective in mixing the plume vertically. In general, the lowest concentration measured along the profile was within 50% of the highest concentration in any given 5-min measurement period. The general slope of the concentration profiles was bounded by a Gaussian distribution with Briggs’s urban equations (stability classes D and E/F) for vertical dispersion. However, measured concentration maxima occurred at levels above the surface, which would not be predicted by Gaussian formulations. Variations in tracer concentration observed in the time series between different release periods were related to changes in wind direction as opposed to changes in turbulence. This was demonstrated using data from mobile analyzers that captured the width of the plume by traveling east to west along nearby streets. These mobile-van-analyzer data were also used to compute plume widths. Plume widths increased for wind directions at larger angles to the street grid, and a simple model comprising adjusted open-country dispersion coefficients and a street channeling component, were used to describe the measured widths. This dispersion dataset is a valuable asset not only for developing advanced tools for emergency-response situations in the event of a toxic release but also for refining air-quality models.
Culinary Tourism Supply Chains: A Preliminary Examination
Authors: Smith Stephen L. J. , Xiao Honggen
Published: January 2008

This article begins by defining culinary tourism as any tourism experience in which one learns about, appreciates, or consumes branded local culinary resources. The centrality of local ingredients and culinary resources to the culinary tourism experience means that an understanding of the issues and structures associated with accessing those resources can contribute to a deeper understanding of culinary tourism as a product and its linkages to other sectors of the economy. Supply chain theory is introduced and its relevance to culinary tourism discussed. A preliminary description of the supply chains for three culinary tourism products—farmers' markets, festivals, and restaurants—are identified on the basis of semistructured discussions with representatives from the three product sectors in Ontario, Canada. Key issues faced by producers in each sector are also described. The article concludes with recommendations for further research.
An Examination of Current Psychometric Assessments of Child Molesters' Offense-Supportive Beliefs Using Ward's Implicit Theories
Authors: Gannon Theresa A. , Keown Kirsten , Rose Mariamne R.
Published: January 2008

Are current questionnaire methods fit for the task of assessing offense-related schemas? Six published and unpublished questionnaire measures that assess child molesters' offense-related beliefs are evaluated and examined for evidence of the five implicit schemas proposed by Ward: children as sexual beings, nature of harm, uncontrollability, entitlement, and dangerous world. Current treatment approaches assume that child molesters hold some, if not all, of these implicit schemas—an assumption demonstrated through the use of appropriately modified schema-based treatment techniques. Coding the six questionnaires revealed that nonsexual offense-specific implicit theories are underrepresented on existing measures (i.e., uncontrollability, entitlement, and dangerous world) and that many questionnaire items could not be classified as tapping any implicit theories. Suggestions are made for the future design and revision of questionnaire assessments .
Brain Drain in the Rust Belt
Authors: Mitra Dana L. , Movit Marcela , Frick William
Published: January 2008

City leaders increasingly have hoped that school reform can spark a renaissance in struggling communities. Using the lens of building civic capacity, this article examines efforts to revitalize “Milltown”—a small urban community that has been devastated by the loss of manufacturing jobs. Analysis of interview and written documents identifies several paradoxes that highlight the ways in which the conceptions of individuals and the nature of this former manufacturing community contrasted dramatically with the realities of the emerging global economy. Findings detail these paradoxes and describe the role of the town's school district in driving the reform efforts intended to address these dilemmas.
Restless Legs Syndrome
Authors: Ryan Melody , Slevin John T.
Published: January 2008

Restless legs syndrome is a symptomatic urge to move the legs, usually accompanied or caused by uncomfortable/ unpleasant sensations deep within the legs that begin or are worsened during periods of rest or inactivity in the evening or night and are partially or totally relieved by movement. It can occur intermittently or daily. Nonpharmacologic treatments include moderate exercise; good sleep hygiene; elimination of alcohol, caffeine, and nicotine; and hot baths, massage, and stretching. Activities promoting mental alertness may improve symptoms. Moderate exercise and use of nasal continuous positive airway pressure are the only nonpharmacologic treatments with proven benefit. For intermittent restless legs syndrome, carbidopa/levodopa and nonpharmacologic therapy are recommended as primary treatments. For daily restless legs syndrome, dopamine agonists, particularly ropinirole and pramipexole, are suggested as the drugs of choice. Carbidopa/levodopa could be considered for daily restless legs syndrome, but augmentation is a significant drawback to its use. Carbamazepine and gabapentin have limited data to support their use.
The Safety and Effectiveness of Dexmedetomidine When Used for More Than 24 Hours in an Adult Intensive Care Setting
Authors: Klimek Matthew , Lacroix Matthew M.
Published: January 2008

Dexmedetomidine is a new analgesic and anxiolytic used in the intensive care setting. It has been indicated for use for less than 24 hours to aid in intubation or extubation of a patient. The advantages for dexmedetomidine compared with propofol or benzodiazepines are that it has fewer sedating effects and a short half-life. Several retrospective studies and case reports have reported its use longer than the indicated 24 hours. They reported that dexmedetomidine is safe to use past the 24-hour indicated time of use, with the same or fewer adverse side effects reported.
The Ten Commandments for Translating Simulation Results Into Real-life Performance
Authors: Wenzler Ivo
Published: January 2008

Simulation designers are continuously facing the challenge of determining how much of the expected value the simulation has delivered to the client. Addressing this challenge is not easy, and it requires simulation designers to stretch their comfort zones. This article presents a ten-step approach for meeting simulation objectives and translating simulation results into actual performance improvement. Each of these ten commandments is explained and illustrated by using real-life simulation projects.
Communities, the Private Sector, and the State
Authors: Bénit-Gbaffou Claire , Didier Sophie , Morange Marianne
Published: January 2008

In postapartheid South African cities, civil society's loss of confidence in the ability of public authorities to protect citizens reflects the international trend toward the State's delegation of a number of public functions. It has led to the proliferation of private and community initiatives which quickly spread across urban space, taking different forms according to the level of segregation, the shape of the urban fabric, the local culture of urban development and planning, the political context, and the pace of urban growth. This article, informed by the examples of Johannesburg and Cape Town, discusses the specific South African way of handling these delegation processes: a complex mix of neoliberal policies and practices and of the ANC's agenda toward equality and redistribution for democratic South Africa. Indeed, after a transitional period where these initiatives were tolerated, public authorities are currently reasserting their power over some of these forms (community-led initiatives) while still encouraging public-private partnerships (CIDs).
A Cultural Home Visit Training Experience in Medical School
Authors: Silk Hugh J. , Weber Catherine M.
Published: January 2008

Home visits are an important aspect of the art and science of medicine. The home visit experience during the third year family medicine clerkship at the University of Connecticut School of Medicine is designed to help students gain a richer understanding of where patients “are calling from” to quote the American writer Raymond Carver. It challenges them to enhance their appreciation of the cultural diversity of patients and how a broadly defined culture affects their health. Students conduct a home visit, post reflections of the visit online for their colleagues and mentors to read, and participate in an end of rotation wrap-up discussion. The results show an improvement in student knowledge, confirmation that the experience is useful, and that students appreciate the provided resources. Furthermore, students discover that information gained in a home visit is vastly more relevant and succinct than that gained in an office setting.