Simple sugar intake and hepatocellular carcinoma: epidemiological and mechanistic insight

Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non-alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved.

Sociodemographic Factors and Clinical Conditions Associated to Hospitalization in Influenza A (H1N1) 2009 Virus Infected Patients in Spain, 2009-2010

The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population

Genotypic comparison of Pantoea agglomerans plant and clinical strains

Pantoea agglomerans strains are among the most promising biocontrol agents for avariety of bacterial and fungal plant diseases, particularly fire blight of apple and pear. However, commercial registration of P. agglomerans biocontrol products is hampered because this species is currently listed as a biosafety level 2 (BL2) organism due to clinical reports as an opportunistichuman pathogen. This study compares plant-origin and clinical strains in a search for discriminating genotypic/phenotypic markers using multi-locus phylogenetic analysis and fluorescent amplified fragment length polymorphisms (fAFLP) fingerprinting.Results: Majority of the clinical isolates from culture collections were found to be improperly designated as P. agglomerans after sequence analysis. The frequent taxonomic rearrangements underwent by the Enterobacter agglomerans/Erwinia herbicola complex may be a major problem in assessing clinical associations within P. agglomerans. In the P. agglomerans sensu stricto (in the stricter sense) group, there was no discrete clustering of clinical/biocontrol strains and no marker was identified that was uniquely associated to clinical strains. A putative biocontrol-specific fAFLP marker was identified only in biocontrol strains. The partial ORF located in this band corresponded to an ABC transporter that was found in all P. agglomerans strains. Conclusion: Taxonomic mischaracterization was identified as a major problem with P.agglomerans, and current techniques removed a majority of clinical strains from this species. Although clear discrimination between P. agglomerans plant and clinical strains was not obtained with phylogenetic analysis, a single marker characteristic of biocontrol strains was identified whichmay be of use in strain biosafety determinations. In addition, the lack of Koch's postulate fulfilment, rare retention of clinical strains for subsequent confirmation, and the polymicrobial nature of P. agglomerans clinical reports should be considered in biosafety assessment of beneficial strains in this species

Machine Learning and Clinical Text. Supporting Health Information Flow

Fluent health information flow is critical for clinical decision-making. However, a considerable part of this information is free-form text and inabilities to utilize it create risks to patient safety and cost-­effective hospital administration. Methods for automated processing of clinical text are emerging. The aim in this doctoral dissertation is to study machine learning and clinical text in order to support health information flow.First, by analyzing the content of authentic patient records, the aim is to specify clinical needs in order to guide the development of machine learning applications.The contributions are a model of the ideal information flow,a model of the problems and challenges in reality, and a road map for the technology development. Second, by developing applications for practical cases,the aim is to concretize ways to support health information flow. Altogether five machine learning applications for three practical cases are described: The first two applications are binary classification and regression related to the practical case of topic labeling and relevance ranking.The third and fourth application are supervised and unsupervised multi-class classification for the practical case of topic segmentation and labeling.These four applications are tested with Finnish intensive care patient records.The fifth application is multi-label classification for the practical task of diagnosis coding. It is tested with English radiology reports.The performance of all these applications is promising. Third, the aim is to study how the quality of machine learning applications can be reliably evaluated.The associations between performance evaluation measures and methods are addressed,and a new hold-out method is introduced.This method contributes not only to processing time but also to the evaluation diversity and quality. The main conclusion is that developing machine learning applications for text requires interdisciplinary, international collaboration. Practical cases are very different, and hence the development must begin from genuine user needs and domain expertise. The technological expertise must cover linguistics,machine learning, and information systems. Finally, the methods must be evaluated both statistically and through authentic user-feedback.

Targeting striatal metabotropic glutamate receptor type 5 in Parkinson's disease: bridging molecular studies and clinical trials

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced diskynesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

Mild developmental dyslexia in university students: diagnosis and performance features in L1, L2, and L3

Avhandling visar att lindrig dyslexi påverkar läs- och skrivprestationer hos högpresterare. Särdrag träder tydligast fram i främmande språk och vid hantering av språkljud i krävande testuppgifter. Även om dyslexirelaterade problem vanligtvis är lindriga hos universitetsstudenter, är det centralt att dessa identifieras, eftersom de ses påverka akademiska prestationer. Avhandlingen lägger fram det första finlandssvenska dyslexitestet normerat för universitetsnivå (FS-DUVAN) och ger verktyg för utredning av läs- och skrivsvårigheter hos unga vuxna i Svenskfinland. Avhandlingen utforskar också språkspecifika särdrag av dyslexi hos högpresterande finlandssvenska universitetsstudenter i läs- och skrivuppgifter i svenska, finska och engelska. Detaljerade felanalyser visar att studenter med dyslexi speciellt har problem med kopplingar mellan språkljud och bokstav i det främmande språket engelska, som också i detta avseende är komplext. Resultat i komplexa kognitiva testuppgifter som förutsätter hantering av språkljud pekar på svikt i fonologisk processering, som betecknas som den huvudsakliga underliggande kognitiva nedsättningen vid utvecklingsbetingad dyslexi.

Bioactive Glass in Lumbar Spondylodesis. A Pre-Clinical and Clinical Study

Bioactive glasses (BGs) form a group of synthetic, surface-active, composition-dependent, silica-based biomaterials with osteoconductive, osteopromotive, and even angiogenic, as well as antibacterial, properties. A national interdisciplinary research group, within the Combio Technology Program (2003–2007), developed a porous load-bearing composite for surgical applications made of BG 1–98 and polymer fibers. The pre-clinical part of this thesis focused on the in vitro and in vivo testing of the composite materials in a rabbit femur and spinal posterolateral fusion model. The femur model failed to demonstrate the previously seen positive effect of BG 1–98 on osteogenesis, probably due to the changed resorption properties of BG in the form of fibers. The spine study was terminated early due to adverse events. In vitro cultures showed the growth inhibition of human mesenchymal stems next to BG 1–98 fibers and radical pH changes. A prospective, long-term, follow-up study was conducted on BG–S53P4 and autogenous bone used as bone graft substitutes for instrumented posterolateral spondylodesis in the treatment of degenerative spondylolisthesis (n=17) and unstable burst fractures (n=10) during 1996–1998. The operative outcome was evaluated from X-rays and CT scans, and a clinical examination was also performed. On the BG side, a solid fusion was observed in the CT scans of 12 patients, and a partial fusion was found in 5 patients, the result being a total fusion rate in all fusion sites (n=41) 88% for levels L4/5 and L5/S1 in the spondylolisthesis group. In the spine fracture group, solid fusion was observed in five patients, and partial fusion was found in five resulting in a total fusion rate of 71% of all fusion sites (n=21). The pre-clinical results suggest that under certain conditions the physical form of BG can be more critical than its chemical composition when a clinical application is designed. The first long-term clinical results concerning the use of BG S53P4 as bone graft material in instrumented posterolateral spondylodesis seems to be a safe procedure, associated with a very low complication rate. BG S53P4 used as a stand-alone bone substitute cannot be regarded as being as efficient as AB in promoting solid fusion.

Resection of liver metastasis from neuroendocrine tumors: evaluation of results and prognostic factors

OBJECTIVES: to determine the prognostic factors that may impact on morbidity and mortality and survival of patients undergoing surgical treatment of liver metastases from neuroendocrine tumors. METHODS: We studied 22 patients undergoing liver resection for metastases from neuroendocrine tumors between 1997 and 2007. Epidemiological and clinical data were correlated with morbidity and mortality and overall and disease-free survivals. RESULTS: twelve patients were male and ten female, with a mean age of 48.5 years. Bilobar disease was present in 17 patients (77.3%). In ten patients (45.5%) the primary tumor originated in the pancreas, terminal ileum in eight, duodenum in two, rectum in one and jejunum in one. Complete surgical resection (R0) was achieved in 59.1% of patients. Eight patients (36.3%) developed complications in the immediate postoperative period, one of them dying from septicemia. All patients undergoing re-hepatectomy and/or two-stage hepatectomy had complications in the postoperative period. The overall survival at one and five years was 77.3% and 44.2%. The disease-free survival at five years was 13.6%. The primary pancreatic neuroendocrine tumor (p = 0.006) was associated with reduced overall survival. Patients with number of metastatic nodules < 10 (p = 0.03) and asymptomatic at diagnosis (p = 0.015) had higher disease-free survival. CONCLUSION: liver metastases originating from pancreatic neuroendocrine tumors proved to be a negative prognostic factor. Symptomatic patients with multiple metastatic nodules showed a significant reduction in disease-free survival.

Comparison of nuclear grade and immunohistochemical features in situ and invasive components of ductal carcinoma of breast

PURPOSE:To compare the prognostic and predictive features between in situ and invasive components of ductal breast carcinomas. METHODS:We selected 146 consecutive breast samples with ductal carcinoma in situ (DCIS) associated with adjacent invasive breast carcinoma (IBC). We evaluated nuclear grade and immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR) in both components, in situ and invasive, and the Ki-67 percentage of cells in the invasive part. The DCIS and IBC were classified in molecular surrogate types determined by the immunohistochemical profile as luminal (RE/PR-positive/ HER2-negative), triple-positive (RE/RP/HER2-positive), HER2-enriched (ER/PR-negative/HER2-positive), and triple-negative (RE/RP/HER2-negative). Discrimination between luminal A and luminal B was not performed due to statistical purposes. Correlations between the categories in the two groups were made using the Spearman correlation method. RESULTS:There was a significant correlation between nuclear grade (p<0.0001), expression of RE/RP (p<0.0001), overexpression of HER2 (p<0.0001), expression of EGFR (p<0.0001), and molecular profile (p<0.0001) between components in situ and IBC. CK 5/6 showed different distribution in DCIS and IBC, presenting a significant association with the triple-negative phenotype in IBC, but a negative association among DCIS. CONCLUSIONS: Our results suggest that classical prognostic and predictive features of IBC are already determined in the preinvasive stage of the disease. However the role of CK5/6 in invasive carcinoma may be different from the precursor lesions.

Immunohistochemical evaluation of e-cadherin, Ki-67 and PCNA in canine mammary neoplasias: correlation of prognostic factors and clinical outcome

E-cadherin is a cell-cell adhesion molecule and low e-cadherin expression is related to invasiveness and may indicate a bad prognosis in mammary neoplasms. The expression of cell proliferation markers PCNA and especially Ki-67, has also proved to have a strong prognostic value in this tumor class. The expression of these markers was related to the clinical-pathological characteristics of 73 surgically removed mammary tumors in female dogs by immunohistochemistry. There was no statistical correlation between these markers and death by neoplasm, survival time and disease-free interval. However, the loss of e-cadherin expression and marked Ki-67 expression (p=0.016) were considered statistically significant for the diagnosis (p=0.032). When evaluated as independent factors, there was evidence of the relationship between the loss of e-cadherin expression and high PCNA expression with changes in the body status (divided into obese, normal and cachectic) of female dogs (p=0.030); there was also evidence of the relationship between pseudopregnancy and e-cadherin alone (p=0.021) and for ulceration and PCNA alone (p=0.035). The significant correlation between the markers expression and these well known prognostic factors used individually or in combination suggests their prognostic value in canine mammary tumors.

Effects of Socioeconomic Status and Sociodemographic Features on Cardiovascular Disease. Mortality and Morbidity in Finland

Despite declining trends in morbidity and mortality, cardiovascular diseases have a considerable impact on Finnish public health. A goal in Finnish health policy is to reduce inequalities in health and mortality among population groups. The aim of this study was to assess inequalities in cardiovascular diseases according to socioeconomic status (SES), language groups and other sociodemographic characteristics. The main data source was generated from events in 35-99 year-old men and women registered in the population-based FINMONICA and FINAMI myocardial infarction registers during the years ranging from 1988-2002. Information on population group characteristics was obtained from Statistics Finland. Additional data were derived from the FINMONICA and FINSTROKE stroke registers and the FINRISK Study. SES, measured by income level, was a major determinant of acute coronary syndrome (ACS) mortality. Among middle-aged men, the 28-day mortality rate of the lowest group of six income groups was 5.2 times and incidence 2.7 times as high when compared to the highest income group. Among women, the differences were even larger. Among the unmarried, the incidence of ACS was approximately 1.6 times as high and their prognosis was significantly worse than among married persons - both in men and women and independent of age. Higher age-standardized attack rates of ACS and stroke were found among Finnish-speaking compared to Swedish-speaking men in Turku and these differences could not be completely explained by SES. In these language groups, modest differences were found in traditional risk factor levels possibly explaining part of the found morbidity and mortality inequality. In conclusion, there are considerable differences in the morbidity and mortality of ACS and stroke between socioeconomic and sociodemographic groups, in Finland. Focusing measures to reduce the excess morbidity and mortality, in groups at high risk, could decrease the economic burden of cardiovascular diseases and thus be an important public health goal in Finland.

Nested-PCR for the detection of Mycoplasma hyopneumoniae in bronchial alveolar swabs, frozen tissues and formalin-fixed paraffin-embedded swine lung samples: comparative evaluation with immunohistochemical findings and histological features

The diagnosis of Mycoplasma hyopneumoniae infection is often performed through histopathology, immunohistochemistry (IHC) and polymerase chain reaction (PCR) or a combination of these techniques. PCR can be performed on samples using several conservation methods, including swabs, frozen tissue or formalin-fixed and paraffin-embedded (FFPE) tissue. However, the formalin fixation process often inhibits DNA amplification. To evaluate whether M. hyopneumoniae DNA could be recovered from FFPE tissues, 15 lungs with cranioventral consolidation lesions were collected in a slaughterhouse from swine bred in herds with respiratory disease. Bronchial swabs and fresh lung tissue were collected, and a fragment of the corresponding lung section was placed in neutral buffered formalin for 48 hours. A PCR assay was performed to compare FFPE tissue samples with samples that were only refrigerated (bronchial swabs) or frozen (tissue pieces). M. hyopneumoniae was detected by PCR in all 15 samples of the swab and frozen tissue, while it was detected in only 11 of the 15 FFPE samples. Histological features of M. hyopneumoniae infection were presented in 11 cases and 7 of these samples stained positive in IHC. Concordance between the histological features and detection results was observed in 13 of the FFPE tissue samples. PCR was the most sensitive technique. Comparison of different sample conservation methods indicated that it is possible to detect M. hyopneumoniae from FFPE tissue. It is important to conduct further research using archived material because the efficiency of PCR could be compromised under these conditions.

Quantification and Clinical Relevance of Cystatin C

An aging population and increasing rates of diabetes mellitus contribute to a high prevalence of kidney dysfunction – approximately 10 percent of adults in developed countries have chronic kidney disease (CKD). CKD is a progressive loss of kidney function and this remains permanent. Early recognition of this condition is important for prevention or impeding severe adverse cardiac and renal outcomes. Cystatin C is a low molecular weight cysteine protease inhibitor that has emerged as a biomarker of kidney function. The special potential of plasma cystatin C in this setting is related to its independency of muscle mass, which is a remarkable limitation of the traditional marker creatinine. Cystatin C is a sensitive marker in diagnosing mild and moderate CKD, especially in small children, in the elderly and in conditions where muscle mass is affected. Cystatin C is quantified with immunoassays, mainly based on particle-enhanced nephelometry (PENIA) or turbidimetry (PETIA). The aim of this study was to develop a rapid and reliable assay for quantification of human cystatin C in plasma or serum by utilizing time-resolved fluorescence-based immunoassay methods. This was accomplished by utilizing different antibodies, including polyclonal and 7 monoclonal antibodies against cystatin C. Different assay designs were tested and the best assay was further modified to a dry-reagent double monoclonal assay run on an automated immunonalyzer. This assay was evaluated for clinical performance in estimating reduced kidney function and in predicting risk of adverse outcomes in patients with non-ST elevation acute coronary syndrome. Of the tested assay designs, heterogeneous non-competitive assay had the best performace and was chosen to be developed further. As an automated double monoclonal assay, this assay enabled a reliable measurement of clinically relevant cystatin C concentrations. It also showed a stronger concordance with the reference clearance method than the conventional PETIA method in patients with reduced kidney function. Risk of all-cause mortality and combined events, defined by death and myocardial infarction, increased with higher cystatin C and cystatin C remained an independent predictor of death and combined events after adjustment to nonbiochemical baseline factors. In conclusion, the developed dry-reagent double monoclonal assay allows rapid and reliable quantitative measurement of cystatin C. As measured with the developed assay, cystatin C is a potential predictor of adverse outcomes in cardiac patients.