Etiology of diarrheal infections in children of Porto Velho (Rondonia, Western Amazon region, Brazil)

In the present study, 470 children less than 72 months of age and presenting acute diarrhea were examined to identify associated enteropathogenic agents. Viruses were the pathogens most frequently found in stools of infants with diarrhea, including 111 cases of rotavirus (23.6% of the total diarrhea cases) and 30 cases of adenovirus (6.3%). The second group was diarrheogenic Escherichia coli (86 cases, 18.2%), followed by Salmonella sp (44 cases, 9.3%) and Shigella sp (24 cases, 5.1%). Using the PCR technique to differentiate the pathogenic categories of E. coli, it was possible to identify 29 cases (6.1%) of enteropathogenic E. coli (EPEC). Of these, 10 (2.1%) were typical EPEC and 19 (4.0%) atypical EPEC. In addition, there were 26 cases (5.5%) of enteroaggregative E. coli, 21 cases (4.4%) of enterotoxigenic E. coli, 7 cases (1.4%) of enteroinvasive E. coli (EIEC), and 3 cases (0.6%) of enterohemorrhagic E. coli. When comparing the frequencies of diarrheogenic E. coli, EPEC was the only category for which significant differences were found between diarrhea and control groups. A low frequency of EIEC was found, thus EIEC cannot be considered to be a potential etiology agent of diarrhea. Simultaneous infections with two pathogens were found in 39 diarrhea cases but not in controls, suggesting associations among potential enteropathogens in the etiology of diarrhea. The frequent association of diarrheogenic E. coli strains was significantly higher than the probability of their random association, suggesting the presence of facilitating factor(s).

Sequence change in the HS2-LCR and Gg-globin gene promoter region of sickle cell anemia patients

The fetal hemoglobin (HbF) levels and ßS-globin gene haplotypes of 125 sickle cell anemia patients from Brazil were investigated. We sequenced the Gg- and Ag-globin gene promoters and the DNase I-2 hypersensitive sites in the locus control regions (HS2-LCR) of patients with HbF level disparities as compared to their ßS haplotypes. Sixty-four (51.2%) patients had CAR/Ben genotype; 36 (28.8%) Ben/Ben; 18 (14.4%) CAR/CAR; 2 (1.6%) CAR/Atypical; 2 (1.6%) Ben/Cam; 1 (0.8%) CAR/Cam; 1 (0.8%) CAR/Arab-Indian, and 1 (0.8%) Sen/Atypical. The HS2-LCR sequence analyses demonstrated a c.-10.677G>A change in patients with the Ben haplotype and high HbF levels. The Gg gene promoter sequence analyses showed a c.-157T>C substitution shared by all patients, and a c.-222_-225del related to the Cam haplotype. These results identify new polymorphisms in the HS2-LCR and Gg-globin gene promoter. Further studies are required to determine the correlation between HbF synthesis and the clinical profile of sickle cell anemia patients.

To divide or differentiate? : nestin-mediated regulation of Cdk5 in cell fate decisions

The molecular functions of the non-cell cycle-related Cyclin-dependent kinase 5 (Cdk5) have been of primary interest within the neuroscience field, but novel undertakings are constantly emerging for the kinase in tissue homeostasis, as well as in diseases such as diabetes and cancer. Although Cdk5 activation is predominantly regulated by specific non-cyclin activator protein binding, additional mechanisms have proved to orchestrate Cdk5 signaling in cells. For example, the interaction between the intermediate filament protein nestin and Cdk5 has been proposed to determine cellular fate during neuronal apoptosis through nestin-dependent adjustment of the sensitive balance and turnover of Cdk5 activators. While nestin constitutes a crucial regulatory scaffold for appropriate Cdk5 activation in apoptosis, Cdk5 itself phosphorylates nestin with the consequence of filament reorganization in both neuronal progenitors and differentiating muscle cells. Interestingly, the two proteins are often found coexpressed in various tissues and cell types, proposing that nestin-mediated scaffolding of Cdk5 and its activators may be applicable to other tissue systems as well. In the literature, the molecular functions of nestin have remained in the shade, as it is mostly exploited as a marker protein for progenitor cells. In light of these studies, the aim of this thesis was to assess the importance of the nestin scaffold in regulation of Cdk5 actions in cell fate decisions. This thesis can be subdivided into two major projects: one that studied the nature of the Cdk5-nestin interplay in muscle, and one that assessed their role in prostate cancer. During differentiation of a myoblast cell line, the filament formation properties of nestin was found to be crucial in directing Cdk5 activity, with direct consequences on the process of differentiation. Also the genetic knockout of nestin was found to influence Cdk5 activity, although differentiation per se was not affected. Instead, the genetic ablation of nestin had broad consequences on muscle homeostasis and regeneration. While the nestin-mediated regulation of Cdk5 in muscle was found to act in multiple ways, the connection remained more elusive in cancer models. Cdk5 was, however, established as a significant determinant of prostate cancer proliferation; a behavior uncharacteristic for this differentiation-associated kinase. Through complex and simultaneous regulation of two major prostate cancer pathways, Cdk5 was placed upstream of both Akt kinase and the androgen receptor. Its action on proliferation was nonetheless mainly exerted through the Akt signaling pathway in various cancer models. In summary, this thesis contributed to the knowledge of Cdk5 regulation and functions in two atypical settings; proliferation (in a cancer framework) and muscle differentiation, which is a poorly understood model system in the Cdk5 field. This balance between proliferation and differentiation implemented by Cdk5 is ultimately regulated (where present) by the dynamics of the cytoskeletal nestin scaffold.

Meningoencephalitis caused by a zygomycete fungus (Basidiobolus) associated with septic shock in an immunocompetent patient: 1-year follow-up after treatment

Zygomycosis is an infection caused by opportunistic fungi of the Zygomycetes class, specifically those from the Mucorales and Entomophthorales orders. It is an uncommon disease, mainly restricted to immunocompromised patients. We report a case of a 73-year-old male patient with a history of fever (39°C) lasting for 1 day, accompanied by shivering, trembling, and intense asthenia. The patient was admitted to the intensive care unit with complex partial seizures, and submitted to orotracheal intubation and mechanical ventilation under sedation with midazolam. The electroencephalogram showed evidence of non-convulsive status epilepticus. There is no fast specific laboratory test that permits confirmation of invasive fungal disease. Unless the physician suspects this condition, the disease may progress rapidly while the patient is treated with broad-spectrum antibiotics. Differential diagnosis between fungal and bacterial infection is often difficult. The clinical presentation is sometimes atypical, and etiological investigation is not always successful. In the present case, the histopathological examination of the biopsy obtained from the right temporal lobe indicated the presence of irregular, round, thick-walled fungi forming papillae and elongated structures of irregular diameter, with no septa, indicative of zygomycete (Basidiobolus). Treatment with liposomal amphotericin B and fluconazole was initiated after diagnosis of meningoencephalitis by zygomycete, with a successful outcome.

Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis

We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for suspected lung cancer. Finalizing this conclusion will require a wider study in a randomized and prospective trial.

Aamiaiskahvilasta ötökkätarjontaan. Suomen kirjoitetun yleiskielen morfosyntaktisten yhdyssanarakenteiden produktiivisuus

Tämän tutkimuksen kohde on suomen kirjoitetun yleiskielen morfosyntaktisten yhdyssanarakenteiden produktiivisuus. Tutkimuksen tärkein päämäärä on selvittää, kuinka ahkerasti erilaisia suomen kielen suomia mahdollisuuksia käytetään uusien yhdyssanojen muodostuksessa. Käytännöllistä produktiivisuutta kartoittava tutkimus täydentää kielioppien ja sanastonkuvausten antamaa kuvaa kielestä. Tutkimuksen kohteena oleva kielimuoto on kaikille kielenkäyttäjille yhteinen kirjoitettu yleiskieli. Tutkimusaineisto koostuu 28 091 uudesta yhdyssanasta, jotka on kerätty painetun median kielestä vuosina 2000–2009. Aineiston pohjana on Kotimaisten kielten keskuksen Nykysuomen sanastotietokanta, johon poimitaan uusia ja uudella tavalla käytettyjä sanoja ensisijaisesti sanakirjatyön ja kielenhuollon tarpeisiin. Tutkimusaihetta lähestytään useiden yhdyssanan osien muotoa, sanaluokkaa, määrää ja pituutta koskevien alakysymysten kautta. Tutkimus etenee yksittäisten muut-tujien käsittelystä muuttujien keskinäisiä suhteita tarkasteleviin malleihin. Tutkimuksessa käytetään kaksivaiheista metodia: Metodin ensimmäinen askel on uudessa sanastossa havaittujen rakenteiden tyyppifrekvenssin tilastollinen analyysi. Toinen askel on varsinkin matalafrekvenssisten tai tilastollisessa analyysissa muuten poikkeavaksi osoittautuneiden rakenteiden kvalitatiivinen tarkastelu. Metodi on kehitetty tätä tutkimusta varten, sillä aiemmin produktiivisuuden mittaamisessa käytetyt menetelmät eivät sellaisenaan sovi suomen kielen yhdyssanarakenteiden tutkimukseen. Tutkimusmetodien kehittäminen on tutkimuksen keskeinen tavoite. Tutkimus osoittaa, että suomen kielen uudet yhdyssanat ovat rakenteeltaan homogeenisempiä, kuin aiempia kielenkuvauksia lukemalla voisi olettaa. Uusi suomen kielen yhdyssana on todennäköisimmin kahdesta substantiivista yhdistämällä muodostettu substantiivi, jonka alkuosa on nominatiivissa eikä kongruoi jälkiosan kanssa. Ennakko-oletusta huomattavasti yleisempiä ovat myös prefiksinkaltaisella alkuosalla alkavat yhdyssanat. Genetiivialkuiset yhdyssanat puolestaan ovat ennakko-oletusta harvinaisempia. Kaikki kieliopillisesti mahdolliset yhdyssanarakenteet eivät ole lainkaan produktiivisia kielenkäytön tasolla. Tutkimus on luonteeltaan kielen rakennetta kartoittavaa perustutkimusta. Tutkimustulosten tärkeimmät sovellusalat ovat kieliteknologia ja sananmuodostuksen opetus. Tutkimus avaa useita näkökulmia jatkotutkimukselle.

Adhesion and production of degrading enzymes by bacteria isolated from biofilms in raw milk cooling tanks

Biofilms in milk cooling tanks compromise product quality even on farms. Due to the lack of studies of this topic, this study evaluated the microbiological conditions of raw milk cooling tanks on farms and characterized the microorganisms isolated from these tanks. Samples were wiped off with sterile swabs from seven milk cooling tanks in three different points in each tank. Mesophiles and psychrotrophic counts were performed in all samples. The isolation of Pseudomonas spp., Bacillus cereus and atypical colonies formed on selective media were also performed, totalizing 297 isolates. All isolates were tested for protease and lipase production and biofilm formation. Of the total isolates, 62.9% produced protease, 55.9% produced lipase, and 50.2% produced biofilm. The most widespread genus inside the milk cooling tank was Pseudomonas since it was not possible to associate this contamination with a single sampling point in the equipment. High counts of microorganisms were found in some cooling tanks, indicating poor cleaning of the equipment and providing strong evidences of microbial biofilm presence. Moreover, it is worth mentioning the milk potential contamination with both microbial cells and their degrading enzymes, which compromises milk quality.

Monooxygenase Diversity and Oxygen Activation within Polyketide Antibiotic Biosynthesis

Molecular oxygen (O2) is a key component in cellular respiration and aerobic life. Through the redox potential of O2, the amount of free energy available to organisms that utilize it is greatly increased. Yet, due to the nature of the O2 electron configuration, it is non-reactive to most organic molecules in the ground state. For O2 to react with most organic compounds it must be activated. By activating O2, oxygenases can catalyze reactions involving oxygen incorporation into organic compounds. The oxygen activation mechanisms employed by many oxygenases to have been studied, and they often include transition metals and selected organic compounds. Despite the diversity of mechanisms for O2 activation explored in this thesis, all of the monooxygenases studied in the experimental part activate O2 through a transient carbanion intermediate. One of these enzymes is the small cofactorless monooxygenase SnoaB. Cofactorless monooxygenases are unusual oxygenases that require neither transition metals nor cofactors to activate oxygen. Based on our biochemical characterization and the crystal structure of this enzyme, the mechanism most likely employed by SnoaB relies on a carbanion intermediate to activate oxygen, which is consistent with the proposed substrate-assisted mechanism for this family of enzymes. From the studies conducted on the two-component system AlnT and AlnH, both the functions of the NADH-dependent flavin reductase, AlnH, and the reduced flavin dependent monooxygenase, AlnT, were confirmed. The unusual regiochemistry proposed for AlnT was also confirmed on the basis of the structure of a reaction product. The mechanism of AlnT, as with other flavin-dependent monooxygenases, is likely to involve a caged radical pair consisting of a superoxide anion and a neutral flavin radical formed from an initial carbanion intermediate. In the studies concerning the engineering of the S-adenosyl-L-methionine (SAM) dependent 4-O-methylase DnrK and the homologous atypical 10-hydroxylase RdmB, our data suggest that an initial decarboxylation of the substrate is catalyzed by both of these enzymes, which results in the generation of a carbanion intermediate. This intermediate is not essential for the 4-O-methylation reaction, but it is important for the 10-hydroxylation reaction, since it enables substrate-assisted activation of molecular oxygen involving a single electron transfer to O2 from a carbanion intermediate. The only role for SAM in the hydroxylation reaction is likely to be stabilization of the carbanion through the positive charge of the cofactor. Based on the DnrK variant crystal structure and the characterizations of several DnrK variants, the insertion of a single amino acid in DnrK (S297) is sufficient for gaining a hydroxylation function, which is likely caused by carbanion stabilization through active site solvent restriction. Despite large differences in the three-dimensional structures of the oxygenases and the potential for multiple oxygen activation mechanisms, all the enzymes in my studies rely on carbanion intermediates to activate oxygen from either flavins or their substrates. This thesis provides interesting examples of divergent evolution and the prevalence of carbanion intermediates within polyketide biosynthesis. This mechanism appears to be recurrent in aromatic polyketide biosynthesis and may reflect the acidic nature of these compounds, propensity towards hydrogen bonding and their ability to delocalize π-electrons.

Central auditory processing and the acquisition of phonology in 2-year-old children with recurrent acute otitis media

Middle ear infections (acute otitis media, AOM) are among the most common infectious diseases in childhood, their incidence being greatest at the age of 6–12 months. Approximately 10–30% of children undergo repetitive periods of AOM, referred to as recurrent acute otitis media (RAOM). Middle ear fluid during an AOM episode causes, on average, 20–30 dB of hearing loss lasting from a few days to as much as a couple of months. It is well known that even a mild permanent hearing loss has an effect on language development but so far there is no consensus regarding the consequences of RAOM on childhood language acquisition. The results of studies on middle ear infections and language development have been partly discrepant and the exact effects of RAOM on the developing central auditory nervous system are as yet unknown. This thesis aims to examine central auditory processing and speech production among 2-year-old children with RAOM. Event-related potentials (ERPs) extracted from electroencephalography can be used to objectively investigate the functioning of the central auditory nervous system. For the first time this thesis has utilized auditory ERPs to study sound encoding and preattentive auditory discrimination of speech stimuli, and neural mechanisms of involuntary auditory attention in children with RAOM. Furthermore, the level of phonological development was studied by investigating the number and the quality of consonants produced by these children. Acquisition of consonant phonemes, which are harder to hear than vowels, is a good indicator of the ability to form accurate memory representations of ambient language and has not been studied previously in Finnish-speaking children with RAOM. The results showed that the cortical sound encoding was intact but the preattentive auditory discrimination of multiple speech sound features was atypical in those children with RAOM. Furthermore, their neural mechanisms of auditory attention differed from those of their peers, thus indicating that children with RAOM are atypically sensitive to novel but meaningless sounds. The children with RAOM also produced fewer consonants than their controls. Noticeably, they had a delay in the acquisition of word-medial consonants and the Finnish phoneme /s/, which is acoustically challenging to perceive compared to the other Finnish phonemes. The findings indicate the immaturity of central auditory processing in the children with RAOM, and this might also emerge in speech production. This thesis also showed that the effects of RAOM on central auditory processing are long-lasting because the children had healthy ears at the time of the study. An effective neural network for speech sound processing is a basic requisite of language acquisition, and RAOM in early childhood should be considered as a risk factor for language development.

A Business Incubator, Accelerator, or Coworking Space? Case Health Innovation Village at GE

Health Innovation Village at GE is one of the new communities targeted for startup and growth-oriented companies. It has been established at the premises of a multinational conglomerate that will promote networking and growth of startup companies. The concept combines features from traditional business incubators, accelerators, and coworking spaces. This research compares Health Innovation Village to these concepts regarding its goals, target clients, source of income, organization, facilities, management, and success factors. In addition, a new incubator classification model is introduced. On the other hand, Health Innovation Village is examined from its tenants’ perspective and improvements are suggested. The work was implemented as a qualitative case study by interviewing GE staff with connections to Health Innovation Village as well as startup entrepreneurs and employees’ working there. The most evident features of Health Innovation Village correspond to those of business incubators although it is atypical as a non-profit corporate business incubator. Strong network orientation and connections to venture capitalists are common characteristics of these new types of accelerators. The design of the premises conforms to the principles of coworking spaces, but the services provided to the startup companies are considerably more versatile than the services offered by coworking spaces. The advantages of Health Innovation Village are that there are first-class premises and exceptionally good networking possibilities that other types of incubators or accelerators are not able to offer. A conglomerate can also provide multifaceted special knowledge for young firms. In addition, both GE and the startups gained considerable publicity through their cooperation, indeed a characteristic that benefits both parties. Most of the expectations of the entrepreneurs were exceeded. However, communication and the scope of cooperation remain challenges. Micro companies spend their time developing and marketing their products and acquiring financing. Therefore, communication should be as clear as possible and accessible everywhere. The startups would prefer to cooperate significantly more, but few have the time available to assume the responsibility of leadership. The entrepreneurs also expected to have more possibilities for cooperation with GE. Wider collaboration might be accomplished by curation in the same way as it is used in the well-functioning coworking spaces where curators take care of practicalities and promote cooperation. Communication issues could be alleviated if the community had its own Intranet pages where all information could be concentrated. In particular, a common calendar and a room reservation system could be useful. In addition, it could be beneficial to have a section of the Intranet open for both the GE staff and the startups so that those willing to share their knowledge and those having project offers could use it for advertising.

Intramolecular carbenoid insertions : the reactions of [alpha]-diazoketones derived from furanyl, thienyl, benzofuranyl and benzothienyl acetic acids with rhodium (II) acetate /

A number of synthetically useful ring systems can be prepared via the intramolecular insertion of a metal-stabilized carbenoid into a heteroaromatic systems. The chemical outcome of these reactions are dependent not only on the nature of the heteroatom but also on the length of the aliphatic tether linking the carbenoid moiety with the aromatic fragment. Our work with furanyl and thienyl systems containing a single methylene tether have allowed for some rather atypical chemistry. For example, treatment of l-diazo-3-(2-thienyl)-2-propanone (6) with catalytic rhodium (II) acetate yields 5,6- dihydro-4^-cyclopenta[Z>]thiophen-5-one (3) while, the isomeric l-diazo-3-(3-thienyl)-2- propanone(15) gives a spiro-disulphide (20). Novel chemistry was also exhibited in the analogous furanyl systems. While treatment of l-diazo-3-(3-furanyl)-2-propanone (52) with Rh2(OAc)4 resulted in the expected 2-(4-Oxo-2-cyclopentenyliden)acetaldehyde (54), isomeric l-diazo-3-(2- furanyl)-2-propanone (8) undergoes vinylogous Wolff rearrangement to give a mixture of 6a-methyl-2,3,3a,6a-tetrahydrofuro[2,i-^>]furan-2-one (44) and 2-(2-methyl-3-furyl)acetic acid (43). Rhodium acetate catalyzed decomposition of l-diazo-3-(3-benzofuranyl)-2- propanone (84) and l-diazo-3-(2-benzofuranyl)-2-propanone (69)also allows for vinylogous Wolff rearrangement, a chemistry unseen in benzofuranyl systems with longer tethers. A number of interesting products were isolated from the trapping of intermediate ketenes. Decomposition of l-diazo-3-(3-benzothienyl)-2-propanone (100) resulted in the formation of 2,3-dihydro-l//-benzo[^]cyclopenta[^thiophen-2-one (102). However, in addition to (102), a dimer was also generated from the decomposition of l-diazo-3-(2- benzothienyl)-2-propanone (109). The insight into the mechanistic underpinnings of the above reactions are provided by molecular modeling at a PM3 level.

Aspects of the hemes and modulation of hydrogen donors in catalases from bovine liver, yeast, and escherichia coli

Catalase is the enzyme which decomposes hydrogen peroxide to water and oxygen. Escherichia coli contains two catalases. Hydroperoxidase I (HPI) is a bifunctional catalase-peroxidase. Hydroperoxidase II (HPII) is only catalytically active toward H202. Expression of the genes encoding these proteins is controlled by different regimes. HPJI is thought to be a hexamer, having one heme d cis group per enzymatic subunit. HPII wild type protein and heme containing mutant proteins were obtained from the laboratory of P. Loewen (Univ. of Manitoba). Mutants constructed by oligonucleotidedirected mutagenesis were targeted for replacement of either the His128 residue or the Asn201 residue in the vicinity of the HPII heme crevice. His128 is the residue thought to be analogous to the His74 distal axial ligand of the heme in the bovine liver enzyme, and Asn201 is believed to be a residue critical to the function of the enzyme because of its role in orienting and interacting with the substrate molecule. Investigation of the nature of the hemes via absorption spectroscopy of the unmodified catalase proteins and their derived pyridine hemochromes showed that while the bovine and Saccharomyces cerevisiae catalase enzymes are protoheme-containing, the HPII wild type protein contains heme d, and the mutant proteins contain either solely protoheme, or heme d-protoheme mixtures. Cyanide binding studies supported this, as ligand binding was monophasic for the bovine, Saccharomyces cerevisiae, and wild type HPII enzymes, but biphasic for several of the HPII mutant proteins. Several mammalian catalases, and at least two prokaryotic catalases, are known to be NADPH binding. The function of this cofactor appears to be the prevention of inactivation of the enzyme, which occurs via formation of the inactive secondary catalase peroxide compound (compound II). No physiologically plausible scheme has yet been proposed for the NADPH mediation of catalase activity. This study has shown, via fluorescence and affinity chromatography techniques, that NADPH binds to the T (Typical) and A (Atypical) catalases of Saccharomyces cerevisiae, and that wild type HPII apparently does not bind NADPH. This study has also shown that NADPH is unlike any other hydrogen donor to catalase, and addresses its features as a unique donor by proposing a mechanism whereby NADPH is oxidized and catalase is protected from inactivation via the formation of protein radical species. Migration of this radical to a position close to the NADPH is also proposed as an adjunct hypothesis, based on similar electron migrations that are known to occur within metmyoglobin and cytochrome c peroxidase when reacted with H202. Validation of these hypotheses may be obtained in appropriate future experiments.

Morphonotactic and phonotactic processing in German-speaking adults

Based on the theoretical framework of Dressler and Dziubalska-Kołaczyk (2006a,b), the Strong Morphonotactic Hypothesis will be tested. It assumes that phonotactics helps in decomposition of words into morphemes: if a certain sequence occurs only or only by default over a morpheme boundary and is thus a prototypical morphonotactic sequence, it should be processed faster and more accurately than a purely phonotactic sequence. Studies on typical and atypical first language acquisition in English, Lithuanian and Polish have shown significant differences between the acquisition of morphonotactic and phonotactic consonant clusters: Morphonotactic clusters are acquired earlier and faster by typically developing children, but are more problematic for children with Specific Language Impairment. However, results on acquisition are less clear for German. The focus of this contribution is whether and how German-speaking adults differentiate between morphonotactic and phonotactic consonant clusters and vowel-consonant sequences in visual word recognition. It investigates whether sub-lexical letter sequences are found faster when the target sequence is separated from the word stem by a morphological boundary than when it is a part of a morphological root. An additional factor that is addressed concerns the position of the target cluster in the word. Due to the bathtub effect, sequences in peripheral positions in a word are more salient and thus facilitate processing more than word-internal positions. Moreover, for adults the primacy effect most favors word-initial position (whereas for young children the recency effect most favors word- final position). Our study discusses effects of phonotactic vs. morphonotactic cluster status and of position within the word.

Développement des habiletés linguistiques chez les enfants porteurs d'un implant cochléaire

Cette thèse examine le développement du langage des enfants sourds qui ont reçu un implant cochléaire (IC) en bas âge. Une première étude rapporte une revue systématique qui avait pour but d’évaluer les connaissances actuelles concernant le développement du vocabulaire et de la grammaire chez les enfants qui ont reçu un IC avant l’âge de trois ans. Vingt-huit études ont été sélectionnées; une analyse descriptive de même qu’une méta-analyse ont été effectuées séparément pour chaque aspect du langage évalué (vocabulaire et grammaire, aspect réceptif et expressif). Au résultat, en dépit de la variabilité observée dans les études, il appert que l’implant cochléaire influence positivement le développement langagier; toutefois, seule une minorité de participants aux études a atteint des niveaux de langage comparables à ceux d’enfants entendants de même âge chronologique. La majorité des enfants continuent de présenter divers degrés de retard de langage, tant au plan réceptif qu’expressif, et ce, après jusqu’à cinq années de port de l’appareil. Les résultats suggèrent aussi, malgré la variabilité observée dans les études, que les bénéfices langagiers sont influencés par le fait de recevoir l’implant à deux ans plutôt qu’à trois ans. À partir des tendances retrouvées dans la littérature, les habiletés de vocabulaire et de grammaire chez 27 enfants qui ont reçu l’implant cochléaire en bas âge (entre 8 et 28 mois) ont été comparées avec celles d’un groupe d’enfants entendants, en utilisant des outils d’évaluation standardisés. Alors que les résultats de groupe montrent que les enfants qui reçoivent un IC autour de l’âge de deux ans atteignent des niveaux de langage dans les limites de la normale, les résultats individuels d’un sous-groupe formé de enfants les plus âgés font état de quatre profils de développement, soit des niveaux de langage dans les limites de la normale pour l’ensemble des composantes, un retard généralisé à l’ensemble des composantes, des habiletés lexicales dans la norme assorti d’un retard morphosyntaxique et enfin un profil atypique montrant des disparités importantes à travers les composantes du langage. Dans trois des quatre profils, la compréhension des phrases était particulièrement faible. Ces résultats suggèrent que le fait de recevoir un implant cochléaire entre l’âge d’un et deux ans ne garantit pas l’atteinte de niveaux de langage dans les limites de la normale malgré une expérience de port de l’appareil d’une durée appréciable. Une étape antérieure du développement linguistique a été examinée de plus près dans la troisième étude. La taille et la composition du vocabulaire expressif de onze enfants ayant reçu un IC à un âge moyen de 15 mois ont été comparées à celles de l’échantillon d’enfants entendants ayant servi à établir les normes en français québécois pour le questionnaire Mots et énoncés des Inventaires MacArthur-Bates du développement de la communication (IMBDC). Les scores d’âge équivalent selon la taille totale du vocabulaire des enfants avec IC étaient supérieurs à l’âge auditif (correspondant à la durée de port de l’appareil) mais inférieurs à l’âge chronologique. La représentation grammaticale en fonction de la taille du vocabulaire des enfants avec IC suit la tendance observée dans la norme. Ces résultats suggèrent que le profil lexical des enfants avec implant est très similaire à celui des enfants entendants lorsque le nombre total de mots acquis est le même. Les résultats de cette thèse suggèrent que l’implant peut, de manière générale, avoir un effet « normalisant » sur le langage ; toutefois, il semble que l’amélioration de l’accès auditif ne suffise pas pour rattraper à coup sûr le niveau de langage des pairs entendants dans l’ensemble des composantes du langage. Alors que les habiletés lexicales se rapprochent du profil typique, les habiletés de compréhension morphosyntaxique sont fortement atteintes chez une majorité d’enfants, suggérant un profil apparenté à un trouble de langage.

Syndrome inflammatoire chez les schizophrènes toxicomanes

La schizophrénie est une maladie mentale grave qui présente une comorbidité fréquente avec la toxicomanie et avec divers troubles immunitaires. Une méta-analyse réalisée récemment dans notre laboratoire a montré une augmentation d’IL-6 (une cytokine pro-inflammatoire), du récepteur soluble d’IL-2 (un marqueur d’activation du système immunitaire), et d’IL-1RA (une cytokine anti-inflammatoire) dans la schizophrénie, suggérant l’existence d’un syndrome inflammatoire dans cette maladie. La toxicomanie aussi est associée au dérèglement du réseau des cytokines inflammatoires, mais les effets dépendent du type de drogues et ils sont parfois diamétralement opposés. On dispose encore de peu d’informations sur le statut immunitaire et inflammatoire des patients qui ont un double diagnostic de schizophrénie et de toxicomanie. Le but de ce travail était d’explorer l’existence d’un état inflammatoire systémique chez les patients schizophrènes et toxicomanes, et l’influence du traitement avec un médicament antipsychotique atypique, la quétiapine. Les objectifs spécifiques étaient : 1) Mesurer les concentrations plasmatiques des cytokines inflammatoires chez les schizophrènes et toxicomanes avant, pendant et après traitement avec la quétiapine ; et 2) Faire des études de corrélations entre les taux de cytokines, les symptômes cliniques, et la consommation de drogues. Les résultats montrent que comparativement aux contrôles normaux, les patients avec un double diagnostic présentent une augmentation d’IL-6, d’IL-1RA, du sIL-2R et d’IL-8 avant traitement à la quétiapine. Les augmentations des concentrations plasmatiques d’IL-1RA sont particulièrement importantes chez les patients avec double diagnostic, si on les compare à celles publiées chez les schizophrènes sans toxicomanie. Le traitement à la quétiapine n’influence pas les concentrations plasmatiques de ces cytokines, sauf sIL-2R qui augmente davantage au cours du traitement. Des corrélations positives de puissance modérée sont retrouvées entre IL-6 et dépression, IL-6 et alcool, IL-1RA et cognition, IL-8 et dépression, IL-8 et alcool, sIL-2R et cannabis. Notre étude révèle que la réponse inflammatoire est activée chez les schizophrènes et toxicomanes. De plus, la toxicomanie semble jouer un rôle facilitant ou potentialisateur dans les augmentations des taux circulants d’IL-1RA. Les études en cours sur différentes populations de schizophrènes avec ou sans toxicomanie, et chez des toxicomanes non schizophrènes permettront de préciser le rôle des différentes drogues d’abus dans le syndrome inflammatoire chez les schizophrènes, ainsi que les implications de ce syndrome sur le plan clinique et thérapeutique.