Characterization of clinical and electrocardiographic findings in a youth population

Resting 12-lead electrocardiogram (ECG) has been employed in the evaluation of young asymptomatic subjects to detect pre-existing heart diseases. Although the incorporation of routine ECG remains controversial, there is increasing evidence that cardiomyopathies and ion channelopathies show ECG changes as the initial manifestation. The causes of sudden cardiac death in young people show a significant geographical variation. We aim to determine the prevalence and spectrum of ECG findings in a youth population. Methodology: From May 2010 to April 2013, a total of 976 young secondary school students (mean age, 14 years; range, 13-15) underwent voluntary medical screening that included a resting 12-lead ECG and structured clinical survey. Subjects with abnormal ECG findings were classified into two groups: major ECG findings group, which fulfilled a pre-specified checklist to screen for principal structural and electrical cardiopathies, and minor ECG findings group showing other ECG changes. The major ECG findings group was referred for secondary diagnostic tests at a tertiary institution. Results: Of the 976 subjects screened, 252 (25.82%; CI95%, 23.17-28.66) had ECG findings. Of note, 17 (1.74%) had major findings and 235 (24.08%) had minor findings on ECG. The prevalence of cardiovascular pathology within the major ECG findings group was 35.29%. The prevalence of ECG abnormalities was significantly higher in males than in females (29% vs 20.9%, P<0.01). Conclusions: The prevalence of ECG findings in a youth population was 25.82%. There were significant gender differences. The inclusion of universal ECG screening, in addition to medical history, may increase the sensitivity of a cardiovascular screening program. Knowledge of the spectrum and prevalence of ECG findings and disease conditions would be pivotal in designing customized screening programs

Role of Myotonic Dystrophy Protein Kinase [DMPK] in Glucose Homeostasis and Muscle Insulin Action

Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.

Role of Myotonic Dystrophy Protein Kinase [DMPK] in Glucose Homeostasis and Muscle Insulin Action

Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.

Neurophysiologic diagnosis, clinical symptoms and neuropathologic findings in polyneuropathies

Tausta: Polyneuropatia (PNP) on ääreishermoston sairaus, joka aiheuttaa laaja-alaisia, yleensä symmetrisiä vaurioita ääreishermostossa. PNP:aan johtavia syitä on satoja. Tavoitteet: Löytää parhaat neurofysiologiset menetelmät uremian, myelooman hoidossa käytettävän talidomidin sekä Fabryn taudin aiheuttaman PNP:n diagnosoimiseksi. Fabryn taudissa tutkin lisäksi ohutsäieneuropatian aiheuttamia neuropatologisia löydöksiä iholta otetusta koepalasta. Tutkimuksissa kartoitettiin lisäksi PNP:n aiheuttamien subjektiivisten oireiden korrelaatio neurofysiologisten ja neuropatologisten löydösten kanssa. Munuaisten vajaatoimintaa sairastavilla potilailla tavoitteena oli tutkia dialyysihoidon tehon vaikutusta autonomisen hermoston toimintaan sekä yhden dialyysikerran vaikutusta neurofysiologisiin löydöksiin. Aineisto ja menetelmät: I: Tutkittiin 21 uremiapotilaan sensoristen ja motoristen hermojen vasteet, värinä- sekä lämpötuntokynnykset ennen ja jälkeen hemodialyysin. Subjektiiviset PNP oireet kartoitettiin PNP oireita kysyvillä kaavakkeella. II:12 talidomidi hoitoa saavaa myeloomapotilasta, tutkimuksen menetelmät olivat samat kuin tutkimuksessa I. III: 12 Fabryn tautia sairastavaa potilasta, edellä mainittujen neurofysiologisten tutkimusten lisäksi potilailta otettiin ihobiopsia säären alueelta. Ihobiopsiasta laskettiin ohuiden hermosyiden määrä koepalan värjäyksen jälkeen. Subjektiiviset PNP oireet kartoitettiin kyselykaavakkeella. Sydämen sykevaihtelu tutkittiin levossa taajuustason analyysillä. IV: 32 uremiapotilaan autonomisen hermoston toimintaa tutkittiin sydämen sykevaihtelun aikatason analysillä, paksujen myelinoituneiden säikeiden toimintaa tutkittiin perifeeristen sensoristen hermojen mittauksilla toistetusti noin 2.9 vuoden aikana. Tulokset: Ureemisen PNP:n diagnostiikassa herkimmät tutkimukset ovat F-aaltojen parametrit alaraajojen motorisista hermoista, värinätuntokynnys alaraajoista sekä suralishermon amplitudi. Positiiviset PNP oireet uremiassa korreloivat värinätunto-kynnyksen sekä sensoristen hermojen neurografialöydösten kanssa. Neurofysiologisten tutkimusten ajankohdalla dialyysiajankohtaan nähden ei ole merkitystä. Talidomidi-PNP on pääasiassa sensorinen, mutta motoriset syyt ovat lievästi vaurioituneet. Talidomidi PNP:ssa subjektiiviset oireet korreloivat huonosti neurofysiologisten löydösten kanssa. Fabryn taudissa naisilla on oletettua enemmän ohutsäieneuropatian aiheuttamia oireita ja löydöksiä. Paksujen säikeiden löydöksiä ei tullut esiin. Ohutsäieneuropatian diagnostiikassa ihobiopsia ja kvantitatiiviset tuntokynnysmittaustestit täydentävät toisiaan. Tehokas dialyysi parantaa autonomisen hermoston toimintaa uremiapotilailla. Päätelmät: Erityyppisten polyneuropatioiden diagnostiikassa pitää etukäteen valita PNP tyypille oikeat tutkimusmenetelmät raskaiden tutkimuspatterien vähentämiseksi sekä diagnostiikan parantamiseksi. PNP:n aiheuttamat oireet ja kliiniset löydökset pitää aina tutkia, mutta yksin ne eivät ole herkkiä PNP:n diagnostiikassa.

Brain-Derived Neurotrophic Factor as a potential biomarker of cognitive recovery in schizophrenia

Brain-derived neurotrophic factor (BDNF) has been proposed as a biomarker of schizophrenia and, more specifically, as a biomarker of cognitive recovery. Evidence collected in this review indicates that BDNF is relevant in the pathophysiology of schizophrenia and could play a role as a marker of clinical response. BDNF has been shown to play a positive role as a marker in antipsychotic treatment, and it has been demonstrated that typical antipsychotics decrease BDNF levels while atypical antipsychotics maintain or increase serum BDNF levels. Furthermore, BDNF levels have been associated with severe cognitive impairments in patients with schizophrenia. Consequently, BDNF has been proposed as a candidate target of strategies to aid the cognitive recovery process. There is some evidence suggesting that BDNF could be mediating neurobiological processes underlying cognitive recovery. Thus, serum BDNF levels seem to be involved in some synaptic plasticity and neurotransmission processes. Additionally, serum BDNF levels significantly increased in schizophrenia subjects after neuroplasticity-based cognitive training. If positive replications of those findings are published in the future then serum BDNF levels could be definitely postulated as a peripheral biomarker for the effects of intensive cognitive training or any sort of cognitive recovery in schizophrenia. All in all, the current consideration of BDNF as a biomarker of cognitive recovery in schizophrenia is promising but still premature.

Ewing sarcoma of the rib: respiratory tract infection as initial symptoms in a 14-year-old boy. Functional medical imaging findings

Ewing sarcoma or primitive neuroectodermal tumor (PNET) of bone is the second most common pediatric malignant bone tumor. The median age at diagnosis is 15 years and there is a male predilection of 1.5/1. The authors present the case of a 14-year-old boy with Ewing sarcoma situated on the left ninth rib which was being investigated for respiratory tract infection. Pleurisy is the most common misdiagnosis. Our case illustrates the importance of recognizing exceptional features when interpreting FDG PET or scintigraphy to prevent the misinterpretation of metastases as other etiologies, such as infection.

The Vulnerable Brain and Very Preterm Infants - Findings from the PIPARI-Study

Preterm birth is a risk for normal brain development. Brain maturation that normally happens in the uterus is in very preterm infants a developmental challenge during their stay in a neonatal intensive care unit (NICU). Typical brain injuries of preterm infants include ischemic injuries, brain haemorrhages, ventricular dilatation (VD), and reduced brain volumes. Brain injury is a serious complication of prematurity leading to possible long term consequences for the neurodevelopment of the very low birth weight (VLBW) infant, such as cerebral palsy (CP), hearing impairments, vision problems, and delay in cognitive development.There is a need for further studies to ascertain the potential risk factors and their causal relationships to brain vulnerability, growth and development in the increasing number of surviving VLBW infants. This thesis consists of four studies evaluating the definitions, causes and consequences of brain lesions in VLBW(<1500g) or very low gestationalage (VLGA) (gestational age <32 gestational weeks) infants. We showed that the redistribution of fetal blood flow is a risk factor for smaller brain volumes at term. In addition,we showed that brain lesions related to prematurity are not associated with increased spontaneous crying behaviour or circadian rhythm development in infancy. However, the preterm infants began to fuss more often and were held more than term infants at five months of age. Furthermore, we showed that VD is associated with brain lesions and smaller brain volumes. Therefore, brain magneticresonance imaging can be recommended for infants with VD. VD together with other brain pathology is a risk factor for the onset of developmental impairments in VLBW/VLGA infants at two years of age.

Anchor or Accelerate – A Study on Cancer Cell Adhesion and Motility

Cell migration and adhesion to the extracellular matrix (ECM) are crucial in many biological and pathological processes such as morphogenesis, tissue repair, inflammatory responses, survival, and cancer. Cell-matrix adhesion is mediated by the integrin family of transmembrane receptors, which not only anchor cells to their surroundings, but also transmit bidirectional signalling at the cell surface and couple the ECM to the cytoskeleton. Another group of adhesion receptors are the syndecan proteoglycans, which engage the ECM and possess signalling activity in response to a variety of ligands. Cell migration is a complex process that requires spatial and temporal coordination of adhesion, cell contractility, intracellular traffic of integrins, and matrix turnover by matrix metalloproteinases (MMPs). Thus, integrins and syndecans, as well as MMPs, play essential roles in cancer cell migration and invasion. The understanding of the cooperation of syndecans and integrins was broadened in this thesis study. The results reveal that syndecan-1 functions in concert with 21 integrin in cell adhesion to collagen, whereas syndecan-4 is essential in 21 integrin-mediated matrix contraction. Finally, oncogenic K-Ras was shown to regulate 21 integrin, membrane-type 1 MMP, and syndecan-1 and -4 expression and their cooperation in cell invasion. Epithelial-mesenchymal transition (EMT) is fundamental during embryogenesis and organ development. Activation of EMT processes, including the upregulation of mesenchymal intermediate filament protein vimentin, has also been implicated in the acquisition of a malignant phenotype by epithelial cancer cells. Members of the protein kinase C (PKC) superfamily are involved in cell migration and various integrindependent cellular functions. One aim of this work was to shed light on the role of vimentin in the regulation of integrin traffic and cell motility. In addition, the mechanism by which vimentin participates in EMT was investigated. The results show that integrin recycling and motility are dependent on the PKC–mediated phosphorylation of vimentin. In addition, vimentin was found to be a positive regulator of EMT and regulate the expression of several migratory genes. Specifically, vimentin governs the expression of receptor tyrosine kinase Axl, which is implicated in tumour growth and metastasis. Taken together, the findings described in this thesis reveal novel aspects of the complex interplay between distinct cellular components: integrins, syndecans, and the vimentin cytoskeleton, which all contribute to the regulation of human cancer cell adhesion, migration, and invasion.

Submandibular gland excision

OBJECTIVE: to analyze the value of fine needle aspiration and the rates of postoperative complications in patients undergoing resection of the submandibular gland. METHODS: we analyzed the records of patients treated with resection of the gland from January 1995 to December 2008. The data collected included age, gender, findings on clinical history, surgical procedure, results of fine needle aspiration (FNA), pathological diagnosis and complications. RESULTS: 117 patients were studied, aged 12-89 years (mean 48), 70 women and 47 men. Thirty-nine patients (33.3%) were affected by inflammatory diseases (28 patients with lithiasis), 70 had benign tumors, and malignant tumors, eight. Regarding FNA, the sensitivity and specificity were 85.7% and 100%, respectively. Nine patients (7.7%) had temporary paralysis of the marginal mandibular nerve and one had permanent paralysis. CONCLUSION: resection of the submandibular gland is a safe procedure, with low complication rates.

Correlation between the oropharyngo-laryngoscopic findings and the severity of obstructive sleep apnea

Objective: To correlate anatomical and functional changes of the oral cavity, pharynx and larynx to the severity of obstructive sleep apnea syndrome (OSAS). Methods : We conducted a cross-sectional study of 66 patients of both genders, aged between 21 and 59 years old with complaints of snoring and / or apnea. All underwent full clinical evaluation, including physical examination, nasolarybgoscopy and polisonography. We classified individuals into groups by the value of the apnea-hypopnea index (AHI), calculated measures of association and analyzed differences by the Kruskal-Wallis and chi-square tests. Results : all patients with obesity type 2 had OSAS. We found a relationship between the uvula projection during nasoendoscopy and OSAS (OR: 4.9; p-value: 0.008; CI: 1.25-22.9). In addition, there was a major strength of association between the circular shape of the pharynx and the presence of moderate or severe OSAS (OR: 9.4, p-value: 0.002), although the CI was wide (1.80-53.13). The septal deviation and lower turbinate hypertrophy were the most frequent nasal alterations, however unrelated to gravity. Nasal obstruction was four times more common in patients without daytime sleepiness. The other craniofacial anatomical changes were not predictors for the occurrence of OSAS. Conclusion : oral, pharyngeal and laryngeal disorders participate in the pathophysiology of OSAS. The completion of the endoscopic examination is of great value to the evaluation of these patients.

Hofbauer cells morphology and density in placentas from normal and pathological gestations

PURPOSE: In placentas from uncomplicated pregnancies, Hofbauer cells either disappear or become scanty after the fourth to fifth month of gestation. Immunohistochemistry though, reveals that a high percentage of stromal cells belong to Hofbauer cells. The aim of this study was to investigate the changes in morphology and density of Hofbauer cells in placentas from normal and pathological pregnancies. METHODS: Seventy placentas were examined: 16 specimens from normal term pregnancies, 10 from first trimester's miscarriages, 26 from cases diagnosed with chromosomal abnormality of the fetus, and placental tissue specimens complicated with intrauterine growth restriction (eight) or gestational diabetes mellitus (10). A histological study of hematoxylin-eosin (HE) sections was performed and immunohistochemical study was performed using the markers: CD 68, Lysozyme, A1 Antichymotrypsine, CK-7, vimentin, and Ki-67. RESULTS: In normal term pregnancies, HE study revealed Hofbauer cells in 37.5% of cases while immunohistochemistry revealed in 87.5% of cases. In first trimester's miscarriages and in cases with prenatal diagnosis of fetal chromosomal abnormalities, both basic and immunohistochemical study were positive for Hofbauer cells. In pregnancies complicated with intrauterine growth restriction or gestational diabetes mellitus, a positive immunoreaction was observed in 100 and 70% of cases, respectively. CONCLUSIONS: Hofbauer cells are present in placental villi during pregnancy, but with progressively reducing density. The most specific marker for their detection seems to be A1 Antichymotrypsine. It is remarkable that no mitotic activity of Hofbauer cells was noticed in our study, as the marker of cellular multiplication Ki-67 was negative in all examined specimens.

Novel Functions of ErbB4 and NRG-1 in Development and Cancer

Cells communicate, or signal, with each other constantly to ensure proper functioning of tissues and organs. Cell signaling is often performed by interplay of receptors and ligands that bind these receptors. ErbB receptors (epidermal growth factor receptors, EGFR, HER) bind extracellular growth factors and transduce these signals inside of cells. ErbB dysfunction promotes carcinogenesis, and also results in numerous defects during normal development. This study focused on the functions of one member of the ErbB receptor family, ErbB4, and growth factor, neuregulin-1 (NRG-1), that can bind and activate ErbB4. This study aimed to find novel functions of ErbB4 and NRG-1. Hypoxia, or deficiency of oxygen, is common in cancer and ischemic conditions. One of the key findings of the work was the identification and characterization of a cross-talk between ErbB4 and Hypoxia-inducible factor 1α (HIF-1α), the central mediator of hypoxia signaling. ErbB4 activation by NRG-1 was found to increase HIF-1α activity. Interestingly, this regulation occurred in reciprocal manner as HIF-1α was also able to increase protein levels of NRG-1 and ErbB4. Moreover, expression of NRG-1 and ErbB4 was associated with HIF activity in vivo in human clinical samples and in mice. Reduction of functional ErbB4 in developing zebrafish embryos resulted in defects in development of the skeletal muscles. To study ErbB4 functions in pathological situation in humans, clinical samples of serous ovarian carcinoma were analyzed using tissue microarrays and real-time RT-PCR. A specific isoform of ErbB4, CYT-1, was associated with poor survival in serous ovarian cancer and increased anchorage independent growth of ovarian cancer cells in vitro. These observations demonstrate that ErbB4 and NRG-1 are essential regulators of cellular response to hypoxia, of development, and of ovarian carcinogenesis.

Paratuberculosis in a dairy Gyr herd in the State of Paraíba, Brazil

This paper describes the clinical, pathological, and microbiologic aspects of paratuberculosis (Johne's disease) in a dairy Gyr herd in the State of Paraíba, northeastern Brazil. An eight years old cow with chronic unresponsive diarrhea was clinically examined and euthanized for pathological evaluation. Fecal samples from all 160 animals over 12 months of age from the herd were collected for isolation of Mycobacterium avium subsp. paratuberculosis. Clinically, the index case cow was severely dehydrated, cachectic, with profuse mucous diarrhea. The main post-mortem findings were emaciation and thickened intestinal wall. Microscopically, the intestinal lamina propria and submucosa were infiltrated by macrophages, epithelioid cells, and Langhans giant cells with numerous alcohol-acid resistant bacilli in the cytoplasm. Two fecal samples displayed growth in slants of Herrold's egg-yolk agar supplemented with mycobactin J, 150 days after incubation. No growth was noticed in slants without mycobactin J. Microscopic examination of the isolated microorganisms stained by Ziehl-Neelsen revealed considerable amounts of alcohol-acid resistant bacilli, morphologically compatible with Mycobacterium spp. Based on the clinical signs, gross and histological lesions, growth time, bacterial morphology in Ziehl-Neelsen staining, and dependence of mycobactin J, the first diagnosis of paratuberculosis in Zebu cattle was made.

Fireweed (Senecio madagascariensis) poisoning in cattle

In a dairy cattle herd in southern Brazil, 7 out of 554 cattle were affected and died due to Senecio madagascariensis poisoning. Clinical, pathological, and epidemiological findings in the affected cattle were indistinguishable from those usually seen in poisoning caused by other Senecio species. The plant invaded extensive areas in heavily stocked paddocks. Senecio madagascariensis had been spreading in this farm for the last three years, with no control strategy, because neither the farmers nor the local veterinarian knew about the potential risks of this Sernecio species.

Experimental poisoning of goats by Ipomoea carnea subsp. fistulosa in Argentina: a clinic and pathological correlation with special consideration on the central nervous system

Ipomoea carnea subsp. fistulosa, aguapei or mandiyura, is responsible for lysosomal storage in goats. The shrub contains several alkaloids, mainly swansonine which inhibits lysosomal α-mannosidase and Golgi mannosidase II. Poisoning occurs by inhibition of these hydrolases. There is neuronal vacuolation, endocrine dysfunction, cardiovascular and gastrointestinal injury, and immune disorders. Clinical signs and pathology of the experimental poisoning of goats by Ipomoea carnea in Argentina are here described. Five goats received fresh leaves and stems of Ipomoea. At the beginning, the goats did not consume the plant, but later, it was preferred over any other forage. High dose induced rapid intoxication, whereas with low doses, the course of the toxicosis was more protracted. The goats were euthanized when they were recumbent. Cerebrum, cerebellum, medulla oblongata, pons and colliculi, were routinely processed for histology. In nine days, the following clinical signs developed: abnormal fascies, dilated nostrils and abnormal postures of the head, cephalic tremors and nystagmus, difficulty in standing. Subsequently, the goats had a tendency to fall, always to the left, with spastic convulsions. There was lack in coordination of voluntary movements due to Purkinje and deep nuclei neurons damage. The cochlear reflex originated hyperreflexia, abnormal posture, head movements and tremors. The withdrawal reflex produced flexor muscles hypersensitivity at the four legs, later depression and stupor. Abnormal responses to sounds were related to collicular lesions. Thalamic damage altered the withdrawal reflex, showing incomplete reaction. The observed cervical hair bristling was attributed to a thalamic regulated nociceptive response. Depression may be associated with agonists of lysergic acid contained in Ipomoea. These clinical signs were correlated with lesions in different parts of the CNS.