bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical thickness in de novo patients with Parkinson disease and mild cognitive impairment with consideration of clinical phenotype and motor laterality
Authors: Danti S. , Toschi N. , Diciotti S. , Tessa C. , Poletti M. , Del Dotto P. , Lucetti C.
Published: July 2015

Background and purpose

Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non‐motor symptoms, including cognitive deficits. Several magnetic resonance imaging approaches have been applied to investigate brain atrophy in PD. The aim of this study was to detect early structural cortical and subcortical changes in de novo PD whilst distinguishing cognitive status, clinical phenotype and motor laterality.

Methods

Eighteen de novo PD with mild cognitive impairment (PD‐MCI), 18 de novo PD without MCI (PD‐NC) and 18 healthy control subjects were evaluated. In the PD‐MCI group, nine were tremor dominant and nine were postural instability gait disorder (PIGD) phenotype; 11 had right‐sided symptom dominance and seven had left‐sided symptom dominance. FreeSurfer was used to measure cortical thickness/folding, subcortical structures and to study group differences as well as the association with clinical and neuropsychological data.

Results

Parkinson's disease with MCI showed regional thinning in the right frontal, right middle temporal areas and left insula compared to PD‐NC. A reduction of the volume of the left and right thalamus and left hippocampus was found in PD‐MCI compared to PD‐NC. PD‐MCI PIGD showed regional thinning in the right inferior parietal area compared to healthy controls. A decreased volume of the left thalamus was reported in PD‐MCI with right‐sided symptom dominance compared to PD‐NC and PD‐MCI with left‐sided symptom dominance.

Conclusions

When MCI was present, PD patients showed a fronto‐temporo‐parietal pattern of cortical thinning. This cortical pattern does not appear to be influenced by motor laterality, although one‐sided symptom dominance may contribute to volumetric reduction of specific subcortical structures.
Recurrent secondary generalization in frontal lobe epilepsy: Predictors and a potential link to surgical outcome?
Authors: Baud Maxime O. , Vulliemoz Serge , Seeck Margitta
Published: July 2015

Objective

Frontal lobe epilepsy (FLE) frequently leads to secondary generalized tonic–clonic seizures (SGTCS). However, little is known about the clinical, electrophysiologic, and radiologic correlates of SGTCS and whether these could influence diagnosis and treatment.

Methods

A cohort of 48 patients with confirmed FLE was retrospectively identified and dichotomized into a group with and a group without SGTCS defined by history (≥1/year) or video–electroencephalography (vEEG). Demographics, seizure semiology, vEEG, neuroimaging data, and estimated seizure‐onset zone were tabulated, and their association with the occurrence of SGTCS was evaluated with use of a chi‐square test. Independent predictors of SGTCS were confirmed using a stepwise multivariate analysis. Similarly, these predictors as well as a history of SGTCS were tested as multivariate predictors of the postoperative International League Against Epilepsy (ILAE) score in the surgical subgroup (n = 25).

Results

We identified three independent predictors of a history of SGTCS in FLE, including loss of responsiveness at seizure onset (corrected p = 0.04), a semiology involving early elementary motor signs (corrected p = 0.01), and multifocal spikes on EEG (corrected p = 0.02). A seizure‐free outcome occurred in 57% of surgical cases and was more likely in the group without SGTCS (100%, p = 0.001). When considering only SGTCS occurring during video‐EEG monitoring, the association with semiology and surgical outcome vanished, but the association with preserved awareness and a multifocal EEG persisted.

Significance

A history of SGTCS is related to a specific ictal semiology and interictal EEG, and may have a role in surgical risk stratification.
The signature of fine scale local adaptation in Atlantic salmon revealed from common garden experiments in nature
Authors: O'Toole Ciar L. , Reed Thomas E. , Bailie Deborah , Bradley Caroline , Cotter Deirdre , Coughlan Jamie , Cross Tom , Dillane Eileen , McEvoy Sarah , Ó Maoiléidigh Niall , Prodöhl Paulo , Rogan Ger , McGinnity Philip
Published: July 2015

Understanding the extent, scale and genetic basis of local adaptation (LA) is important for conservation and management. Its relevance in salmonids at microgeographic scales, where dispersal (and hence potential gene flow) can be substantial, has however been questioned. Here, we compare the fitness of communally reared offspring of local and foreign Atlantic salmon Salmo salar from adjacent Irish rivers and reciprocal F1 hybrid crosses between them, in the wild ‘home’ environment of the local population. Experimental groups did not differ in wild smolt output but a catastrophic flood event may have limited our ability to detect freshwater performance differences, which were evident in a previous study. Foreign parr exhibited higher, and hybrids intermediate, emigration rates from the natal stream relative to local parr, consistent with genetically based behavioural differences. Adult return rates were lower for the foreign compared to the local group. Overall lifetime success of foreigners and hybrids relative to locals was estimated at 31% and 40% (mean of both hybrid groups), respectively. The results imply a genetic basis to fitness differences among populations separated by only 50 km, driven largely by variation in smolt to adult return rates. Hence even if supplementary stocking programs obtain broodstock from neighbouring rivers, the risk of extrinsic outbreeding depression may be high.
Detrimental arterial inflammatory effect of microparticles circulating in preeclamptic women: ex vivo evaluation in human arteries
Authors: Boisramé‐Helms Julie , Meziani Ferhat , Sananès Nicolas , Boisramé Thomas , Langer Bruno , Schneider Francis , Ragot Thierry , Andriantsitohaina Ramaroson , Tesse Angela
Published: July 2015

Elevated plasmatic levels of lympho‐monocyte and platelet microparticles (MPs) have been reported in preeclampsia. Previous studies suggest that MPs could participate in preeclampsia vascular impairment. In this study, we investigated the ex vivo vascular effects of MPs from preeclamptic women on arteries from normotensive pregnant women. Omental arteries were collected from normal pregnant women undergoing cesarean section and incubated during 24 h with MPs from normal pregnant or preeclamptic women. Vascular contraction to serotonin and phenylephrine was studied on a wire myograph with or without pharmacological selective inhibitors of inducible nitric oxide synthase (iNOS) and/or cyclo‐oxygenase‐2 (COX‐2). Expression of iNOS, COX‐2, and NF‐κB and production of superoxide anion and 8‐isoprostane were also assessed by immunohistological or biochemical staining and/or Western blot or ELISA assay, respectively. Microparticles from preeclamptic women, but not those from normal pregnant women, induced hyporeactivity to vasocontracturant agonists in omental arteries. Selective inhibitor of iNOS partially restored this arterial contraction, suggesting that nitric oxide (NO) is involved in vascular contractility alteration. Conversely, COX‐2 induced 8‐isoprostane release, a vasoconstricting metabolite modulating the agonist‐induced contraction. COX‐2 selective inhibitor almost abolished the arterial contraction in the same vessels. Interestingly, the association of iNOS and COX‐2 selective inhibitors restored the contraction to control levels. Moreover, iNOS, COX‐2, and NF‐κB expressions are upregulated and superoxide anion levels increased in vessels incubated with MPs from preeclamptic women. In conclusion, circulating MPs from preeclamptic women induce vascular inflammation and enhance oxidative stress. These results suggest a possible role of MPs during preeclampsia‐induced arterial dysfunction.
Distribution of intestinal stem cell markers in colorectal precancerous lesions
Authors: Jang Bo Gun , Kim Hye Sung , Kim Kyung Ju , Rhee Ye‐Young , Kim Woo Ho , Kang Gyeong Hoon
Published: July 2015

Aims

Intestinal stem cell (ISC) markers such as LGR5, ASCL2, EPHB2 and OLFM4, and their clinical implications have been studied extensively in colorectal cancers (CRCs). However, little is known about their expression in precancerous lesions of CRCs. Here, we investigated the expression and distribution of ISC markers in serrated polyps and conventional adenomas.

Methods and results

Reverse transcription–polymerase chain reaction (RT–PCR) analysis revealed that all ISC markers were up‐regulated significantly in conventional adenomas with low‐grade dysplasia (CALGs) compared with other lesions. RNA in‐situ hybridization confirmed that CALGs exhibited strong and diffuse expression of all ISC markers, which indicate a stem cell‐like phenotype. However, normal colonic mucosa, hyperplastic polyps and sessile serrated adenomas harboured LGR5+ cells that were confined to the crypt base and demonstrated an organized expression of ISC markers. Notably, in traditional serrated adenomas, expression of LGR5 and ASCL2 was localized to the ectopic crypts as in the normal crypts, but expression of EPHB2 and OLFM4 was distributed in a diffuse manner, which is suggestive of a progenitor‐like features.

Conclusions

The expression and distribution profile of ISC markers possibly provides insights into the organization of stem and progenitor‐like cells in each type of precancerous lesion of CRC.
Serrated tubulovillous adenoma of the large intestine
Authors: Bettington Mark , Walker Neal , Rosty Christophe , Brown Ian , Clouston Andrew , McKeone Diane , Pearson Sally‐Ann , Klein Kerenaftali , Leggett Barbara , Whitehall Vicki
Published: July 2015

Aims

Most colorectal polyps are classified readily, but a subset of tubulovillous adenomas (TVA) with prominent serrated architecture causes diagnostic confusion. We aimed to (i) identify histological features that separate serrated TVAs from both conventional TVAs and traditional serrated adenomas (TSA) and (ii) perform a clinicopathological and molecular analysis to determine if the serrated TVA has unique features.

Methods and results

We collected 48 serrated TVAs, 50 conventional TVAs and 66 BRAF wild‐type TSAs for analysis. For each polyp we performed a clinicopathological assessment, BRAF and KRAS mutation profiling, cytosine–phosphate–guanosine (CpG) island methylator phenotype status, MGMT methylation and immunohistochemical assessment of seven markers [MutL homologue 1 (MLH1), p16, p53, β‐catenin, Ki67, CK7 and CK20]. We found that serrated TVAs can be diagnosed reliably, and have features distinct from both conventional TVAs and TSAs. Compared to conventional TVAs, serrated TVAs are larger, more often proximal, more histologically advanced, show more CpG island methylation and more frequent KRAS mutation. Compared to TSAs they are more often proximal, show less CpG island methylation, more frequent MGMT methylation and more frequent nuclear staining for β‐catenin.

Conclusions

The serrated TVA can be diagnosed reliably and has unique features. It represents a precursor of KRAS mutated, microsatellite stable colorectal carcinoma.
Carbonic anhydrase VI: a novel marker for salivary serous acinar differentiation and its application to discriminate acinic cell carcinoma from mammary analogue secretory carcinoma of the salivary gland
Authors: Hsieh Min‐Shu , Jeng Yung‐Ming , Jhuang Yu‐Lin , Chou Yueh‐Hung , Lin Chiao‐Ying
Published: July 2015

Aims

Carbonic anhydrase VI (CA6) is present in serous acinar cells of human salivary glands. The aim of this study was to investigate the diagnostic utility of CA6 in differentiating acinic cell carcinoma (AciCC) from its morphological mimic mammary analogue secretory carcinoma (MASC) of the salivary gland.

Methods and results

CA6 immunostaining was performed in 28 cases of AciCC and 14 cases of MASC. All cases of AciCC showed positive CA6 staining. The staining pattern correlated with the number of serous acinar cells in tumours. All MASCs stained negatively for CA6. The results were compared with those obtained with currently used markers, including DOG1, mammaglobin, S100, and vimentin. CA6 showed sensitivity and specificity as high as those of DOG1 in diagnosing AciCC. CA6 expression was focally observed in basal cell adenoma and in one case of cystadenocarcinoma (1/3), but not in other salivary gland tumours, including mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, lymphoepithelial carcinoma, epithelial–myoepithelial carcinoma, and pleomorphic adenoma.

Conclusions

CA6 is a specific marker for serous acinar cells of salivary glands and AciCC. CA6 has sensitivity and specificity equal to those of DOG1 in the differential diagnosis between AciCC and MASC. A combination of CA6 and DOG1 could be an ideal immunohistochemical panel for AciCC.
Correlation of histomorphological pattern of cardiac amyloid deposition with amyloid type: a histological and proteomic analysis of 108 cases
Authors: Larsen Brandon T , Mereuta Oana M , Dasari Surendra , Fayyaz Ahmed U , Theis Jason D , Vrana Julie A , Grogan Martha , Dogan Ahmet , Dispenzieri Angela , Edwards William D , Kurtin Paul J , Maleszewski Joseph J
Published: July 2015

Aims

Prognostication and treatment selection for cardiac amyloidosis requires accurate amyloid typing. The aim of this study was to investigate the utility of histomorphology for predicting type.

Methods and results

Autopsy cases with cardiac amyloidosis (1998–2010) were typed by the use of mass spectrometry‐based proteomics. Deposition patterns were correlated with amyloid type. Among 108 decedents (mean age 75 years; 69% men), 107 had a single type, including transthyretin (ATTR) (60 cases), amyloid light chain (AL) (32 λ; 12 κ), amyloid A (AA) (two), and apolipoprotein AIV (AApoAIV) (one). Interstitial deposition was more extensive in AL amyloidosis cases than in ATTR cases [odds ratio (OR) 6.8, P = 0.0004]. Histomorphological patterns of interstitial deposition were mixed in 61% of AL amyloidosis cases and in 61% of ATTR cases, but diffuse pericellular deposits favoured AL amyloidosis (OR 10.7, P = 0.0001), nodular deposits favoured ATTR (OR 3.1, P = 0.0229), and discrete pericellular deposits tended to partially favour ATTR (OR 1.7, P = 0.1970). Arterial and venous deposits each favoured AL amyloidosis (OR ranging from 9.3 to 192.0, P‐value ranging from 0.0022 to <0.0001), and were severe in AL amyloidosis. Endocardial deposits favoured AL amyloidosis (OR 46.3, P < 0.0001) and were also more severe in AL amyloidosis.

Conclusions

The extent and distribution of cardiac amyloidosis strongly correlate with amyloid type, suggesting fundamental differences in the pathobiology of deposition. The tendency for mixed patterns to occur limits the practicality and accuracy of using histopathology for amyloid typing.
Interrelatedness between dysbiosis in the gut microbiota due to immunodeficiency and disease penetrance of colitis
Authors: Ray Avijit , Dittel Bonnie N.
Published: July 2015

The composition of the microbiome in health and disease has only recently become a major research focus. Although it is clear that an imbalance or dysbiosis in the microbiota is associated with disease, its interrelatedness to disease penetrance is largely unknown. Inflammatory bowel disease (IBD) is an excellent disease in which to explore these questions because of the extensive genetic studies identifying disease susceptibility loci and the ability to easily sample the intestinal microbiota in IBD patients due to the accessibility of stool samples. In addition, mouse models of IBD have contributed to our understanding of the interrelatedness of the gut microbiota and genes associated with IBD. The power of the mouse studies is that multiple colitis models exist that can be used in combination with genetically modified mice that harbour deficiencies in IBD susceptibility genes. Collectively, these studies revealed that bacterial dysbiosis does occur in human IBD and in mouse colitis models. In addition, with an emphasis on immune genes, the mouse studies provided evidence that specific immune regulatory proteins associated with IBD influence the gut microbiota in a manner consistent with disease penetrance. In this review, we will discuss studies in both humans and mice that demonstrate the impact of immunodeficiences in interleukin‐10, interleukin‐17, nucleotide‐binding oligomerization domain (NOD) 2, NOD‐like receptor proteins 3 and 6, Toll‐like receptor or IgA have on the interrelatedness between the composition of the gut microbiota and disease penetrance of IBD and its mouse models.
Interleukin‐17A deficiency ameliorates streptozotocin‐induced diabetes
Authors: Tong Zan , Liu Weihuang , Yan Huichao , Dong Chen
Published: July 2015

Interleukin‐17 (IL‐17) is a cytokine with critical functions in multiple autoimmune diseases. However, its roles in type I diabetes and the underlying mechanisms remain to be fully elucidated. In the current study, we investigated the impact of IL‐17 deficiency on streptozotocin (STZ) ‐induced diabetes. Il‐17−/− mice exhibited attenuated hyperglycaemia and insulitis after STZ treatment compared with control mice. The Il‐17−/− mice had fewer CD8+ cells infiltrating the pancreas than wild‐type controls after STZ injection. Wild‐type mice showed increased percentage and number of splenic CD8+ cells and decreased Gr1+ CD11b+ myeloid‐derived suppressor cells (MDSC) after STZ treatment, but Il‐17−/− mice maintained the percentages and numbers of splenic CD8+ cells and MDSC, suggesting that IL‐17 is implicated in STZ‐induced cellular immune responses in the spleen. We further purified the MDSC from spleens of STZ‐treated mice. Il‐17−/− MDSC showed increased ability to suppress CD8+ cell proliferation in vitro compared with wild‐type MDSC. Transfer of MDSC to diabetic mice showed that MDSC from Il‐17−/− mice could ameliorate hyperglycaemia. Moreover, recipients with MDSC from Il‐17−/− mice had a decreased percentage of CD8+ cell in the spleen compared with recipients with MDSC from wild‐type mice. These data suggest that IL‐17 is required in splenic MDSC function after STZ delivery. In summary, our study has revealed a pathogenic role of IL‐17 in an STZ‐induced diabetes model with important implications for our understanding of IL‐17 function in autoimmune diseases.
Children's perception of caries and gingivitis as determinants of oral health behaviours: a cross‐sectional study
Authors: Eisalhy Mohamed , Alsumait Aishah , Behzadi Sahar , Al‐Mutawa Sabiha , Amin Maryam
Published: July 2015

Aim

To evaluate the relationship between children's perception of caries and gingivitis and their oral health behaviours.

Design

Participants in this cross‐sectional study were children aged 11–14 years. A questionnaire for measuring children's perceptions and behaviours was developed, validated and applied. Perceptions were analysed as predictors for behaviours using multiple logistic regression analysis.

Results

A total of 434 children (57% males) participated in the study. Half of them perceived caries as a disease and believed in visiting the dentist regularly regardless of dental need. More than 60% were unaware that gum bleeding is a sign of disease and only 60.7% believed that it requires a management. Being aware that gum bleeding is a sign of disease and that it requires treatment increased the odds of brushing 2.83 (OR = 2.83, 95% CI:1.33–6.12) and 2.1 (OR = 2.1, 95% CI:1.05–5.55) times, respectively. Children aware of importance of dental visits even without dental decay were 2.9 times more likely to visit the dentist regularly (OR = 2.86, 95% CI:1.25–5.75) and were 77% more likely to never miss a dental appointment (OR = 1.77, 95% CI:1.03–3.37).

Conclusion

Being aware that bleeding gum requires treatment was a determinant of toothbrushing habit. Improved perceived need for dental check‐up regardless of dental problem may promote children's preventive dental attendance.
Association Between Serum Uric Acid Levels/Hyperuricemia and Hypertension Among 85,286 Japanese Workers
Authors: Yokokawa Hirohide , Fukuda Hiroshi , Suzuki Akihito , Fujibayashi Kazutoshi , Naito Toshio , Uehara Yuki , Nakayama Akiyoshi , Matsuo Hirotaka , Sanada Hironobu , Jose Pedro A. , Miwa Yuichi , Hisaoka Teruhiko , Isonuma Hiroshi
Published: July 2015

This cross‐sectional study from January 2012 to December 2012 aimed to examine the sex‐specific association between serum uric acid (SUA) levels/hyperuricemia and hypertension among Japanese patients. SUA level, medical histories, and lifestyle‐related items were collected from 85,286 of 136,770 participants. Among those with hyperuricemia, the median age was 46 years and 97% were men, which was significantly different than those without hyperurecemia (44 years and 56%, respectively; P<.01). Hyperuricemia was 1.79 times more likely in hypertensive men than normotensive men and almost six times more likely in hypertensive women (odds ratio=5.92 and adjusted odds ratio=1.33 for men and adjusted odds ratio=1.81 for women) after multivariate analysis. SUA quartiles positively correlated with systolic and diastolic blood pressures in both sexes. Hyperuricemia and SUA levels were significantly associated with hypertension in both sexes. These findings underscore the importance of maintaining normal SUA levels to manage and prevent hypertension. Better management of SUA as well as blood pressure may have potential in preventing future cardiovascular disorders.
Correlations between two different methods to score bleeding and the relationship with plaque in systemically healthy young adults
Authors: Oliveira Sara Cioccari , Slot Dagmar E. , Celeste Roger Keller , Abegg Claides , Keijser Bart J. F. , Van der Weijden Fridus A.
Published: July 2015

Aim

To evaluate the correlation between bleeding on marginal probing (BOMP) and bleeding on pocket probing (BOPP), and the correlation of both bleeding indices with plaque.

Materials and Methods

This cross‐sectional study screened 336 participants, from which 268 were eligible for examination and analysis. Bleeding and plaque indices were assessed by single examiners, at six sites per tooth.

Results

The mean percentage of sites per individual with bleeding on marginal probing, bleeding on pocket probing and dental plaque were 19.9%, 51.2% and 32.2% respectively. In the quadrants where the margin was probed before the pocket, a 4.6 percentage points higher bleeding tendency with BOPP was observed (p < 0.05). At a site level, the correlation coefficients of plaque and bleeding on marginal probing and bleeding on pocket probing were 0.19 and 0.20 respectively. Both bleeding indices were also shown to be correlated (r = 0.89, fixed effect model).

Conclusion

The prevalence of bleeding upon probing is influenced by the scoring method that is used for the diagnosis. Probing the bottom of the pocket results in significantly more bleeding than running a probe along the margin.
Serum parathyroid hormone and active vitamin D in chronic periodontitis
Authors: Antonoglou Georgios N. , Knuuttila Matti , Niemelä Onni , Ylöstalo Pekka , Raunio Taina , Hiltunen Liisa , Karttunen Riitta , Tervonen Tellervo
Published: July 2015

Objectives

To study the association between periodontitis and serum parathyroid hormone (PTH) and the response of PTH to periodontal therapy in type 1 diabetic patients (T1DM). We also investigated the PTH‐1,25(OH)2D axis in the T1DM group.

Methods

Periodontal health status was recorded in 54 periodontitis patients and 30 periodontally healthy controls (case–control data). Data were also collected from patients with type 1 diabetes mellitus at the baseline (n = 76) and after periodontal therapy (intervention data) (n = 53).

Results

Periodontitis was not associated with serum PTH in the case–control data or at the baseline of the intervention data. A post‐therapy increase in serum PTH was found in 61% of the T1DM patients; in patients with moderate or severe periodontitis (n = 26) the average increase was 0.6 pmol/l (p = 0.016) and in patients with no or mild periodontitis (n = 27) 0.2 pmol/l (p = 0.250). In 47% of the T1DM patients, an increase in PTH was associated with an increase in serum 1,25(OH)2D.

Conclusion

An association between serum PTH and periodontal infection was found only after periodontal therapy in T1DM patients. This post‐treatment response in serum PTH may partly explain the previously reported increase in serum 1,25(OH)2D.
Genomewide association study on chronic periodontitis in Korean population: results from the Yangpyeong health cohort
Authors: Hong Kyung‐Won , Shin Myung‐Seop , Ahn Yoo‐Been , Lee Hyun‐Jin , Kim Hyun‐Duck
Published: July 2015

Aim

This study aims to locate the genes related to periodontitis through genome‐wide association study (GWAS) in Korean population.

Methods

Total of 677 adults aged 44–88 years were recruited from the Yangpyeong cohort in Korea. The participants did not have self‐reported metabolic diseases, cardiovascular diseases or cancer. Periodontitis was assessed using alveolar bone loss from a digital panoramic radiograph and classified into three groups: normal to mild, moderate and severe periodontitis. DNA from blood samples were genotyped using the Illumina Human 1M‐duo Beadchip. Multivariable logistic regression analysis in PLINK was applied to examine the single‐nucleotide polymorphisms (SNPs) related to periodontitis after controlling for various confounders.

Results

Associations of three SNPs suggested TENM2 (rs4242220) and LDLRAD4 (rs12969041, rs2027756) as putative risk genes of chronic periodontitis (p‐values <1 × 10−5). The odds ratio [95% confidence interval (CI)] of TENM2 was 0.53 (0.40–0.70) for moderate periodontitis and that of LDLRAD4 was 2.86 (1.92–4.27) for severe periodontitis. Two nonsynonymous SNPs of protein coding region and seven SNPs selected from previous reports showed nominal association.

Conclusion

Our GWAS supports a previously reported gene of TENM2 and newly suggests LDLRAD4. These two genes’ role on lipid metabolism may play a part in the molecular aetiology of periodontitis.
Comparison of scoring systems for nonvariceal upper gastrointestinal bleeding: a multicenter prospective cohort study
Authors: Yang Hae Min , Jeon Seong Woo , Jung Jin Tae , Lee Dong Wook , Ha Chang Yoon , Park Kyung Sik , Lee Si Hyung , Yang Chang Heon , Park Jun Hyung , Park Youn Sun ,   Daegu‐Gyeongbuk Gastrointestinal Study Group (DGSG)
Published: July 2015

Background and Aim:

The Glasgow–Blatchford score (GBS) and Rockall score (RS) are widely used to assess risk in patients with upper gastrointestinal bleeding (UGIB). We compared both scoring systems and evaluated their clinical usefulness.

Methods:

Between February 2011 and December 2013, 1584 patients with nonvariceal UGIB were included in the study. A prospective study was conducted to compare the performance of the GBS, pre‐RS, and full RS. We compared the performance of these scores using receiver operating characteristic curves.

Results:

For prediction of the need for hospital‐based intervention, the GBS was similar to the full RS (area under the receiver operating characteristic curves [AUROC] 0.705 vs 0.727; P = 0.282) and superior to the pre‐RS (AUROC 0.705 vs 0.601; P < 0.0001). In predicting death, the full RS was superior to the GBS (AUROC 0.758 vs 0.644; P = 0.0006) and similar to the pre‐RS (AUROC 0.758 vs 0.754; P = 0.869). In predicting rebleeding, the full RS was superior to both GBS (AUROC 0.642 vs 0.585; P = 0.031) and pre‐RS (AUROC 0.642 vs 0.593; P = 0.0003). Of 1584 patients, 13 (0.8%) scored 0 on the GBS. Therapeutic intervention was not performed in any of these patients.

Conclusions:

The GBS is more useful than the pre‐RS for predicting the need for hospital‐based intervention. A cutoff value of 0 for low‐risk patients who might be suitable for outpatient management is useful. The full RS is helpful in predicting death. None of the systems accurately predict rebleeding with a low AUROC. (Clinical trial: cris.nih.go.kr/KCT0000514).
Small intestinal bacterial overgrowth and toll‐like receptor signaling in patients with non‐alcoholic fatty liver disease
Authors: Kapil Shweta , Duseja Ajay , Sharma Bal Krishan , Singla Bhupesh , Chakraborti Anuradha , Das Ashim , Ray Pallab , Dhiman Radha K , Chawla Yogesh
Published: July 2015

Background and Aim:

The pathogenesis of non‐alcoholic fatty liver disease (NAFLD) is multifactorial. There is sparse literature on the role of small intestinal bacterial overgrowth (SIBO) and toll‐like receptor (TLR) signaling in NAFLD. The present study evaluated the relationship of SIBO with expression of TLR signaling genes in patients with NAFLD.

Methods:

A total of 142 subjects composed of NAFLD (n = 60, mean age 38.7 ± 10.4 years), chronic viral hepatitis (CVH) (n = 32, mean age 39.5 ± 10.6 years), and healthy volunteers (n = 50, mean age 36.56 ± 4.2 years) were enrolled in the study. Duodenal fluid was taken endoscopically in 32 prospective patients with NAFLD for evaluation of SIBO. Hepatic mRNA expression of TLR4, CD14, TLR2, NF‐κβ, and MD2 and protein expression of TLR4 and TLR2 were studied in 64 patients (NAFLD = 32, CVH = 32) by RT‐PCR and immunohistochemistry, respectively. Serum levels of TNF‐α, adiponectin, insulin, and endotoxins were also evaluated.

Results:

Small intestinal bacterial overgrowth was present in 12 (37.5%) out of 32 patients with NAFLD with Escherichia coli as the predominant bacterium. In comparison with those without SIBO, patients with SIBO had significantly higher endotoxin levels and higher CD14 mRNA, nuclear factor kappa beta mRNA, and TLR4 protein expression. Patients with NASH had significantly higher endotoxin levels and higher intensity of TLR4 protein expression in comparison with patients without NASH. Serum levels of TNF‐α, endotoxins, and insulin were significantly higher and of adiponectin lower in NAFLD in comparison with CVH and healthy volunteers.

Conclusions:

Our study provides the first direct evidence of role of SIBO and endotoxemia and its relation with TLR signaling genes and liver histology in patients with NAFLD.
Fecal calprotectin is a clinically relevant biomarker of mucosal healing in patients with quiescent ulcerative colitis
Authors: Yamaguchi Sayaka , Takeuchi Yoshiaki , Arai Katsuhito , Fukuda Katsuyuki , Kuroki Yuichiro , Asonuma Kunio , Takahashi Hiroshi , Saruta Masayuki , Yoshida Hitoshi
Published: July 2015

Background and Aim:

Calprotectin is an abundant protein in neutrophils, which infiltrate the mucosa during inflammation. Fecal calprotectin (FC) level has shown correlation with disease activity in ulcerative colitis (UC) patients. Additionally, FC level is expected to indicate mucosal healing (MH). This study was to see the significance of FC for predicting MH in patients with quiescent UC.

Methods:

A total of 112 patients with quiescent UC were included. After taking blood and stool samples, patients underwent total colonoscopy, and the Mayo endoscopic subscore was recorded. FC was measured by fluorescence enzyme immunoassay. C‐reactive protein, hemoglobin, erythrocyte sedimentation rate, and serum albumin were measured as conventional biomarkers. MH was defined as Mayo 0 or 0 and 1, and receiver–operator characteristic analyses were undertaken to determine the significance levels of measurements.

Results:

Data from 105 patients were available. Eleven patients showed Mayo ≥ 2. The median (interquartile range) of FC level of all patients was 115 µg/g (45.4–420). The area under the curve (AUC) in receiver operator characteristic analysis of FC to predict Mayo 0 and 1 was 0.869 with a cut‐off value of 200 µg/g yielding 67% sensitivity and 91% specificity, which were the best among all biomarkers. However, the power of FC to predict Mayo 0 was modest; the AUC was 0.639 and cut‐off value 194 µg/g with 71% sensitivity and 58% specificity.

Conclusions:

Based on the findings of this study, we believe that FC is a clinically relevant biomarker of MH in patients with quiescent UC. Other favorable features of FC test include feasibility and non‐invasiveness.
Handgrip strength as a predictor of bone mineral density in outpatients with cirrhosis
Authors: Santos Lívia Alves Amaral , Lima Talles Bazeia , Augusti Laís , Franzoni Letícia de Campos , Yamashiro Fabio da Silva , Bolfi Fernanda , Nunes Vânia dos Santos , Dorna Mariana de Souza , de Oliveira Cássio Vieira , Caramori Carlos Antonio , Silva Giovanni Faria , Romeiro Fernando Gomes
Published: July 2015

Background and Aim:

Osteoporosis is well recognized as a cirrhosis complication; however, most studies assessing this condition included only patients on liver transplantation lists with an elevated rate of bone diseases. While general population studies show that handgrip strength is clearly associated with bone mineral density, until now this tool has not been applied to patients with cirrhosis in relation to their bone condition. This study aimed to evaluate whether handgrip strength, bone, and liver tests may be useful as predictors of bone disease in outpatients with cirrhosis.

Methods:

One hundred twenty‐nine subjects were included (77 men and 52 women). Dual‐energy X‐ray absorptiometry was applied to evaluate lumbar‐spine and femoral‐neck T scores. Osteoporosis/osteopenia rates were 26.3%/35.6% in the lumbar spine and 6.9%/41.8% in the femoral neck, respectively. Model selections were based on backward procedures to find the best predictors of low T scores.

Results:

For lumbar spine, only low handgrip strength and high parathyroid hormone levels were clearly related to low T scores. For femoral neck, only age was associated with low T scores.

Conclusions:

Handgrip strength may serve as an effective predictor of low lumbar spine T score among outpatients with cirrhosis. As cirrhosis affects the lumbar spine more than the femoral neck, these results suggest that handgrip strength should be tested in all patients with cirrhosis as a first indicator of bone health. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
The meaning of gross tumor type in the aspects of cytokeratin 19 expression and resection margin in patients with hepatocellular carcinoma
Authors: Gong Sung Chan , Cho Mee‐Yon , Lee Sang Woo , Kim Sung Hoon , Kim Moon Young , Baik Soon Koo
Published: July 2015

Background:

There is no consensus on the safe resection margin in patients with hepatocellular carcinoma. Surgeons decide the extent of resection according to residual liver function and tumor location. We investigated the influence of resection margin on early recurrence with respect to gross tumor type and expression of cytokeratin 19 (CK19).

Methods:

We divided the patients into two groups based on the classification of The Korean Liver Cancer Study group as follows: group 1 included expanding and vaguely nodular types whereas group 2 included nodular with perinodular extension, multinodular confluent, and infiltrative types. We classified the resection margin as narrow (0.1–0.9 cm) or wide (greater than 1 cm). We compared clinicopathological features and CK19 positivity between the groups.

Results:

Group 2 had a higher prevalence of gross portal vein invasion, microscopic portal vein invasion, microvessel invasion, satellite nodules, intrahepatic metastasis, multicentric occurrence, and positivity for CK19. Group 1 showed no difference in recurrence according to the resection margin; however, group 2 showed a higher recurrence rate in patients with a narrow resection margin compared with those with a wide resection margin (P = 0.047). Patients in group 2 with CK19 positivity showed a higher prevalence of microvessel invasion than those without CK19 (P = 0.026).

Conclusions:

Although our study has the limitation of a small number of cases, the data suggest that patients with hepatocellular carcinoma of expanding and vaguely nodular gross types may safely undergo surgical resection with a narrow resection margin and a low risk of early recurrence.
Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of α‐synuclein in oligodendroglial cells
Authors: Pukaß Katharina , Goldbaum Olaf , Richter‐Landsberg Christiane
Published: July 2015

α‐Synuclein (α‐syn)‐containing glial cytoplasmic inclusions originating in oligodendrocytes are characteristically observed in multiple system atrophy. The mechanisms of glial cytoplasmic inclusion formation remain rather elusive. α‐Syn over‐expression, uptake from the environment, oxidative stress or impairment of the proteolytic degradation systems have been discussed. Here, we investigated whether in oligodendrocytes autophagy plays a major role in the degradation and aggregation of endogenously expressed α‐syn and of α‐syn taken up from the extracellular environment. Furthermore, we studied whether in cells with impaired mitochondria the accumulation and aggregation of exogenously added α‐syn is promoted. Using primary cultures of rat brain oligodendrocytes and an oligodendroglial cell line, genetically engineered to express green fluorescent protein–microtubule‐associated light chain 3 with or without α‐syn to monitor the autophagic flux, we demonstrate that both exogenously applied α‐syn and α‐syn stably expressed endogenously are effectively degraded by autophagy and do not affect the autophagic flux per se. Mitochondrial impairment with the protonophore carbonyl cyanide 3‐chlorophenylhydrazone or 3‐nitropropionic acid disturbs the autophagic pathway and leads to the accumulation of exogenously applied α‐syn and enhances its propensity to form aggregates intracellularly. Thus, mitochondrial dysfunction and oxidative stress, which occur over time and are significant pathological features in synucleinopathies, have an impact on the autophagic pathway and participate in pathogenesis.

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Glial cytoplasmic inclusions are characteristically observed in multiple system atrophy, their occurrence might be related to failure in protein degradation systems. Here, we show that in oligodendrocytes autophagy is the major route of α‐synuclein degradation which is either endogenously expressed or added exogenously (1, 2). Mitochondrial impairment (3) disturbs the autophagic flux and leads to the accumulation of exogenously applied α‐synuclein, and enhances its propensity to form aggregates intracellulary (4).
DISC1 regulates expression of the neurotrophin VGF through the PI3K/AKT/CREB pathway
Authors: Rodríguez‐Seoane Carmen , Ramos Adriana , Korth Carsten , Requena Jesús R.
Published: July 2015

Disrupted in schizophrenia (DISC1) is a risk factor for chronic mental disease. In a previous proteomic study, we reported that knocking down DISC1 results in a sharp decrease in the levels of the neuropeptide precursor VGF (non‐acronymic) and leads to reduced activation of cAMP response element‐binding protein (CREB) and protein kinase B (AKT) in neurons. The main objective of this study is to complete the characterization of the route, or routes, involving AKT and CREB through which DISC1 modulates the expression of VGF. For that we explored known players upstream of AKT and the DISC1 binding partners glycogen synthase kinase‐3 beta and Phosphodiesterase‐4, which might in turn reach out to CREB in murine neuron primary culture. We found that DISC1 modulates the activation of Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K). Furthermore, pharmacological inhibition of PI3K resulted in decreased expression of VGF. All this suggests that the PI3K/AKT pathway plays a role in mediating the effects of DISC1 silencing on VGF expression. Given the important roles of VGF in mental disease, and its drugability, the DISC1‐VGF connection might prove to be important for efforts to develop new therapies for these diseases.

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Our data show that DISC1 regulates the activation state of the PI3K/AKT/CREB signaling route and in turn, contributes to regulate the expression of the neuropeptide precursor VGF in neurons. DISC1 might modulate this molecular pathway by regulating the localization of Grb2 in the cell that promotes the activation of PI3K. Given the important roles of VGF in mental disease, the DISC1‐VGF connection might prove to be important for efforts to develop new therapies for these devastating diseases.
GABAB receptors couple to Gαq to mediate increases in voltage‐dependent calcium current during development
Authors: Karls Andrew , Mynlieff Michelle
Published: July 2015

Metabotropic GABAB receptors are known to modulate the activity of voltage‐dependent calcium channels. Previously, we have shown that GABAB receptors couple to a non‐Gi/o G‐protein to enhance calcium influx through L‐type calcium channels by activating protein kinase C in neonatal rat hippocampal neurons. In this study, the components of this signaling pathway were investigated further. Gαq was knocked down using morpholino oligonucleotides prior to examining GABAB‐mediated enhancement of calcium influx. When Gαq G‐proteins were eliminated using morpholino‐mediated knockdown, the enhancing effects of the GABAB receptor agonist baclofen (10 μM) on calcium current or entry were eliminated. These data suggest that GABAB receptors couple to Gαq to regulate calcium influx. Confocal imaging analysis illustrating colocalization of GABAB receptors with Gαq supports this hypothesis. Furthermore, baclofen treatment caused translocation of PKCα (protein kinase C α) but not PKCβ or PKCε, suggesting that it is the α isoform of PKC that mediates calcium current enhancement. Inhibition of calcium/calmodulin‐dependent kinase II did not affect the baclofen‐mediated enhancement of calcium levels. In summary, activation of GABAB receptors during development leads to increased calcium in a subset of neurons through Gαq signaling and PKCα activation without the involvement of calcium/calmodulin‐dependent kinase II.

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Activation of GABAB receptors in the neonatal rat hippocampus enhances voltage‐dependent calcium currents independently of Gi/o. In this study, knockdown of Gαq with morpholino oligonucleotides abolished enhancement of calcium influx and protein kinase Cα was activated by GABAB receptors. Therefore, we hypothesize that GABAB receptors couple to Gq to activate PKCα leading to enhancement of L‐type calcium current.
Live imaging of endogenous Ca2+/calmodulin‐dependent protein kinase II in neurons reveals that ischemia‐related aggregation does not require kinase activity
Authors: Barcomb Kelsey , Goodell Dayton J. , Arnold Don B. , Bayer K. Ulrich
Published: July 2015

The Ca2+/calmodulin‐dependent protein kinase II (CaMKII) forms 12meric holoenzymes. These holoenzymes cluster into larger aggregates within neurons under ischemic conditions and in vitro when ischemic conditions are mimicked. This aggregation is thought to be mediated by interaction between the regulatory domain of one kinase subunit with the T‐site of another kinase subunit in a different holoenzyme, an interaction that requires stimulation by Ca2+/CaM and nucleotide for its induction. This model makes several predictions that were verified here: Aggregation in vitro was reduced by the CaMKII inhibitors tatCN21 and tatCN19o (which block the T‐site) as well as by KN93 (which is CaM‐competitive). Notably, these and previously tested manipulations that block CaMKII activation all reduced aggregation, suggesting an alternative mechanism that instead requires kinase activity. However, experiments with the nucleotide‐competitive broad‐spectrum kinase inhibitors staurosporin and H7 showed that this is not the case. In vitro, staurosporine and H7 enabled CaMKII aggregation even in the absence of nucleotide. Within rat hippocampal neurons, an intra‐body enabled live monitoring of endogenous CaMKII aggregation. This aggregation was blocked by tatCN21, but not by staurosporine, even though both effectively inhibit CaMKII activity. These results support the mechanistic model for CaMKII aggregation and show that kinase activity is not required.

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CaMKII aggregation is prevented by inhibiting kinase activity with mutations (red italics; shown previously) or inhibitors (red bold; shown here), indicating requirement of kinase activity. However, we show here that nucleotide‐competitive inhibitors (green) allow CaMKII aggregation (including endogenous CaMKII within neurons), demonstrating that kinase activity is not required and supporting the current mechanistic model for CaMKII aggregation.
Elevated dopamine concentration in light‐adapted zebrafish retinas is correlated with increased dopamine synthesis and metabolism
Authors: Connaughton Victoria P. , Wetzell Bradley , Arneson Lynne S. , DeLucia Vittoria , L. Riley Anthony
Published: July 2015

Probing zebrafish (Danio rerio) retinal cryostat sections, collected either 8 h into the light or dark cycle, with an antibody against tyrosine hydroxylase (TH) identified a single population of immunopositive cells in the inner retina. However, the observed labeling patterns were not identical in both sets of tissues – label intensity was brighter in light‐adapted tissue. This difference was quantified by probing western blots of retinal homogenates with the same TH antibody, which showed that TH expression increased by 42% in light‐adapted tissue. High‐performance liquid chromatography with electrochemical detection revealed that the concentrations of both dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) are also elevated in light‐adapted zebrafish retinal tissue. Dopamine levels increased by 14% and DOPAC levels increased by 25% when measured in retinal homogenates harvested during the light cycle. These results indicate that dopamine levels in zebrafish retina are significantly increased in light‐adapted tissue. The increase in dopamine content is correlated with an increase in both TH and DOPAC, suggesting that changes in dopamine concentration are due to light‐adaptive changes in the synthesis, release and metabolism of dopamine.

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Dopamine concentration is elevated in lighted‐adapted zebrafish retinas. This increase is correlated with an increase in both tyrosine hydroxylase (TH) and DOPAC (3,4‐dihydroxyphenylacetic acid), suggesting that changes in dopamine concentration are due to light‐adaptive changes in the synthesis, release and metabolism of dopamine. This is applicable to studies examining retinal mutants, the role of dopamine in disease or visual system development.