Long-Term Lamivudine Treatment of Children with Chronic Hepatitis B: Durability of Therapeutic Responses and Safety

Lamivudine has been demonstrated safe and efficacious in the short term in a large cohort of children with chronic hepatitis B (CHB), but optimal duration of treatment has not been elucidated and limited data on the safety of long-term lamivudine administration have been reported. In addition, the durability of favourable therapeutic outcomes after lamivudine therapy in children has not been well characterized. The aim of this study was to examine the safety of lamivudine and the durability of clinical responses in a group of children who received up to 3 years of treatment for CHB. One hundred and fifty-one children from centres in nine countries who had previously received lamivudine in a large prospective trial were enrolled. During the first year, children had been randomized to either lamivudine or placebo treatment. Subsequently, in a separate extension study, those who remained hepatitis B e antigen (HBeAg) positive were given lamivudine for up to 2 years and those who were HBeAg negative were observed for additional 2 years. Results of these studies have been previously reported. In this study, these children were followed for 2 additional years. Data gathered from medical record review included weight, height, signs and symptoms of hepatitis, alanine aminotransferase (ALT) levels, serologic markers, hepatitis B virus (HBV) DNA levels and serious adverse events (SAEs). Other pharmacological treatments for CHB were allowed according to the practices of individual investigators and were documented. Subjects were divided into two groups for analysis, those who had achieved virological response (VR), defined as HBeAg negative and undetectable HBV DNA by the bDNA assay by the end of the extension study at 3 years, and those who had not. In those who had achieved VR by the end of the extension study, long-term durability of HBeAg seroconversion was 82% and >90% in those who had received lamivudine for 52 weeks and at least 2 years respectively. This compares to 75% for those who had achieved seroconversion after placebo. In those who had not achieved VR by the end of the extension study, an additional 11% did so by the end of the study; they had all received lamivudine in the previous trial, and none had received further treatment during the study. Eight children lost hepatitis B surface antigen during the study and all had received lamivudine at some point during the previous trials. Evaluation of safety data revealed no SAEs related to lamivudine. There was no effect of treatment on weight or height z scores. Clinically benign ALT flares (>10 times normal) were seen in 2% of children. Favourable outcomes from lamivudine treatment of CHB in children are maintained for at least several years after completion of treatment. Up to 3 years of lamivudine treatment is safe in children.

Dominant and Recessive RYR1 Mutations in Adults with Core Lesions and Mild Muscle Symptoms

INTRODUCTION: Ryanodine receptor gene (RYR1) mutations have been associated with central core disease (CCD), multiminicore/minicore/multicore disease (MmD), and susceptibility to malignant hyperthermia (MH). METHODS: Patients with muscle symptoms in adulthood, who had features compatible with CCD/MmD, underwent clinical, histological, and genetic (RYR1 and SEPN1 genes) evaluations. Published cases of CCD and MmD with adult onset were also reviewed. RESULTS: Eight patients fulfilled the criteria for further analysis. Five RYR1 mutations, 4 of them unreported, were detected in 3 patients. Compound heterozygosity was proven in 1 case. CONCLUSIONS: To our knowledge, this is the only report of adult onset associated with recessive RYR1 mutations and central core/multiminicores on muscle biopsy. Although adult patients with CCD, MmD, and minimally symptomatic MH with abnormal muscle biopsy findings usually have a mild clinical course, differential diagnosis and carrier screening is crucial for prevention of potentially life-threatening reactions to general anesthesia.

Lisboa e a Invasão de Junot: população, periódicos e panfletos (1807-1808)

No termo das comemorações dos duzentos anos da Guerra Peninsular (1808-1814), este trabalho propõe-se trazer uma reflexão sobre a ocupação de Lisboa pelo exército francês, comandado pelo general Jean-Andoche Junot, e a luta do povo da cidade contra as forças napoleónicas, durante um período de nove meses, entre 30 de Novembro de 1807 e 30 de Agosto de 1808. A cidade de Lisboa foi personagem principal e testemunha dos acontecimentos que marcaram a ocupação militar francesa, cujos participantes foram, em primeiro lugar a população de Lisboa, com maior relevo para o povo simples, mas também outros estratos da população que, em menor ou maior grau, sofreram igualmente as difíceis condições criadas pela presença militar estrangeira. A importância do papel que Lisboa viria a desempenhar nestas difíceis circunstâncias, justifica o relevo que foi dado ao período da sua ocupação pelo exército francês, através das diversas formas de que se revestia a vida na cidade, nos seus aspectos sociais e culturais, incluindo, além da sua morfologia urbana, a vida social e cultural, os hábitos e tradições, as condições de vida, os entretenimentos e as instituições que identificavam a cidade. Em seguida, estabelecemos as circunstâncias em que a cidade se encontrava nesse último mês de Dezembro de 1807, com a retirada para o Brasil do Príncipe Regente D. João, acompanhado pela família real, a corte e a maioria da primeira nobreza do país, coincidindo com a entrada das tropas francesas em Lisboa. Finalmente, abordámos as consequências destes acontecimentos para a população, cuja manifestação se evidenciou no sentimento de perda e na fraqueza de ânimo por ela sentidos. Por último, sublinha-se o papel desempenhado pela imprensa portuguesa da época que, embora pouco representativa em número, conseguiu um efeito mobilizador junto de largas camadas da população, transformando-se num dos principais veículos da sustentação da luta contra o ocupante francês, através não apenas da imprensa periódica mas, igualmente, dos panfletos anti-napoleónicos que se imprimiram e distribuíram às centenas.

Endocrine response and perceived stress test during an experimental challenge task in adult survivors of a childhood cancer.

BACKGROUND: Although long-term implications of cancer in childhood or adolescence with regard to medical conditions are well documented, the impact on mental health and on response to stress, which may be an indicator of psychological vulnerability, is not yet well understood. In this study, psychological and physiological responses to stress were examined.¦PROCEDURE: Fifty-three participants aged 18-39 years (n = 25 survivors of childhood or adolescence cancer, n = 28 controls) underwent an experimental stress test, the Trier Social Stress Test (TSST). Participants were asked to provide repeated evaluations of perceived stress on visual-analogical scales and blood samples were collected before and after the TSST to measure plasma cortisol.¦RESULTS: The psychological perception of stress was not different between the two groups. However, the cancer survivors group showed a higher global plasma cortisol level as well as higher amplitude in the response to the TSST. The global cortisol level in cancer survivors was increased when depression symptoms were present. The subjective perception of stress and the plasma cortisol levels were only marginally correlated in both groups.¦CONCLUSIONS: It is suggested that the exposure to a life-threatening experience in childhood/adolescence increases the endocrine response to stress, and that the presence of depressive symptoms is associated with an elevation of plasma cortisol levels. A better knowledge of these mechanisms is important given that the dysregulations of the stress responses may cause psychological vulnerability. Pediatr Blood Cancer 2012; 59: 138-143. © 2011 Wiley Periodicals, Inc.

Protein interaction data curation: the International Molecular Exchange (IMEx) consortium.

The International Molecular Exchange (IMEx) consortium is an international collaboration between major public interaction data providers to share literature-curation efforts and make a nonredundant set of protein interactions available in a single search interface on a common website (http://www.imexconsortium.org/). Common curation rules have been developed, and a central registry is used to manage the selection of articles to enter into the dataset. We discuss the advantages of such a service to the user, our quality-control measures and our data-distribution practices.

Effects of MRI scan acceleration on brain volume measurement consistency.

PURPOSE: To evaluate the effects of recent advances in magnetic resonance imaging (MRI) radiofrequency (RF) coil and parallel imaging technology on brain volume measurement consistency. MATERIALS AND METHODS: In all, 103 whole-brain MRI volumes were acquired at a clinical 3T MRI, equipped with a 12- and 32-channel head coil, using the T1-weighted protocol as employed in the Alzheimer's Disease Neuroimaging Initiative study with parallel imaging accelerations ranging from 1 to 5. An experienced reader performed qualitative ratings of the images. For quantitative analysis, differences in composite width (CW, a measure of image similarity) and boundary shift integral (BSI, a measure of whole-brain atrophy) were calculated. RESULTS: Intra- and intersession comparisons of CW and BSI measures from scans with equal acceleration demonstrated excellent scan-rescan accuracy, even at the highest acceleration applied. Pairs-of-scans acquired with different accelerations exhibited poor scan-rescan consistency only when differences in the acceleration factor were maximized. A change in the coil hardware between compared scans was found to bias the BSI measure. CONCLUSION: The most important findings are that the accelerated acquisitions appear to be compatible with the assessment of high-quality quantitative information and that for highest scan-rescan accuracy in serial scans the acquisition protocol should be kept as consistent as possible over time. J. Magn. Reson. Imaging 2012;36:1234-1240. ©2012 Wiley Periodicals, Inc.

VAX1 mutation associated with microphthalmia, corpus callosum agenesis and orofacial clefting-the first description of a VAX1 phenotype in humans.

Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia. In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for anophthalmia/microphthalmia. ©2011 Wiley Periodicals, Inc.

Spatially selective implementation of the adiabatic T2 prep sequence for magnetic resonance angiography of the coronary arteries.

In coronary magnetic resonance angiography, a magnetization-preparation scheme for T2 -weighting (T2 Prep) is widely used to enhance contrast between the coronary blood-pool and the myocardium. This prepulse is commonly applied without spatial selection to minimize flow sensitivity, but the nonselective implementation results in a reduced magnetization of the in-flowing blood and a related penalty in signal-to-noise ratio. It is hypothesized that a spatially selective T2 Prep would leave the magnetization of blood outside the T2 Prep volume unaffected and thereby lower the signal-to-noise ratio penalty. To test this hypothesis, a spatially selective T2 Prep was implemented where the user could freely adjust angulation and position of the T2 Prep slab to avoid covering the ventricular blood-pool and saturating the in-flowing spins. A time gap of 150 ms was further added between the T2 Prep and other prepulses to allow for in-flow of a larger volume of unsaturated spins. Consistent with numerical simulation, the spatially selective T2 Prep increased in vivo human coronary artery signal-to-noise ratio (42.3 ± 2.9 vs. 31.4 ± 2.2, n = 22, P < 0.0001) and contrast-to-noise-ratio (18.6 ± 1.5 vs. 13.9 ± 1.2, P = 0.009) as compared to those of the nonselective T2 Prep. Additionally, a segmental analysis demonstrated that the spatially selective T2 Prep was most beneficial in proximal and mid segments where the in-flowing blood volume was largest compared to the distal segments. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage. Hum Brain Mapp 36:1609-1619, 2015. © 2014 Wiley Periodicals, Inc.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

City of St. Catharines fonds, 1951-1964, 1970-1973, 1978-1982, n.d.

The fonds contains materials relating to the City of St. Catharines from the 1950s to 1980s. The materials included are correspondence, clippings, media releases, and some photographs. Folders are arranged alphabetically and then chronologically within each series. The series are arranged alphabetically.

The Gentleman's Magazine and Historical Chronicle - 1812 July

Specific pages with War of 1812 content in this volume: Page 77: The American senate declares war on Great Britain. Click on the pdf links to the right to view the monthly issue. The Gentleman's Magazine and Historical Chronicle was a monthly periodical published in England during the years of 1736-1833. The volumes of interest from 1812-1815 were written and compiled by Sylvanus Urban, Gentleman. These volumes were printed in London by Nichols, Son and Bentley at Cicero's Head, Red Lion Passage and Fleet Street. The magazine contains accounts of important historical events, abstracts of foreign occurrences, letters from noted figures, articles on geography, biographical entries for prominent people, poems, statistics, obituaries, reviews of books and more.

The Gentleman's Magazine and Historical Chronicle - 1812 August

Specific pages with War of 1812 content in this volume: August: Page 179: The official American declaration of war. Click on the pdf links to the right to view the monthly issue. The Gentleman's Magazine and Historical Chronicle was a monthly periodical published in England during the years of 1736-1833. The volumes of interest from 1812-1815 were written and compiled by Sylvanus Urban, Gentleman. These volumes were printed in London by Nichols, Son and Bentley at Cicero's Head, Red Lion Passage and Fleet Street. The magazine contains accounts of important historical events, abstracts of foreign occurrences, letters from noted figures, articles on geography, biographical entries for prominent people, poems, statistics, obituaries, reviews of books and more.

The Weekly Register September 1811 to March 1812

The Weekly Register, also known as Niles Weekly Register was a weekly periodical edited by Hezekiah Niles (1777-1839), and published in Baltimore Maryland. Volumes of Interest were published between 1811 (Vol. 1, No. 1, September 7, 1811) to 1814 (Vol. 5, No. 26, February 26, 1814). These volumes focus primarily on 19th century Politics and Government in the United States of America. Niles edited and published the Weekly Register until 1836, making it one of the most widely-circulated magazines in the United States. The popularity also made Niles into one of the most influential journalists of his day. Devoted primarily to politics, Niles' Weekly Register is considered an important source for the history of the period. The Register also recorded current economics, technology, science, medicine, geography, archaeology, the weather, and stories of human interest. PLEASE CLICK ON THE WEEKLY PERIODICALS ON THE RIGHT OF THE SCREEN (PDF FILES)TO DOWNLOAD FILES. Pages are divided as follows: 1811 September 7th pages 1-16 14th pages 17-32 21st pages 33-48 28th pages 49-72 1811 October 5th pages 73-88 12th pages 89-104 19th pages 105-120 26th pages 121-136 1811 November 2nd pages 137-152 9th pages 153-184 15th pages 185-208 23rd pages 209-224 30th pages 225-240 1811 December 7th pages 241-256 14th pages 257-280 21st pages 281-296 28th pages 299-320 1812 January 4th pages 321-336 11th pages 337-360 18th pages 361-376 25th pages 377-392 1812 February 1st pages 393-408 8th pages 409-432 15th pages 433-448 22nd pages 449-464 29th pages 465-480 PLEASE CLICK ON THE WEEKLY PERIODICALS ON THE RIGHT OF THE SCREEN (PDF FILES)TO DOWNLOAD FILES. Call Number: SPCL PER JK 1 N52