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.

Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial.

BACKGROUND AND OBJECTIVES: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design. PROTOCOL DESIGN: The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly. OUTCOMES: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety. SAMPLE SIZE CALCULATION: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

Demonstration of the effectiveness of zinc in diarrhoea of children living in Switzerland.

We designed a double-blinded randomized clinical trial of zinc (10 or 20 mg of zinc sulphate for 2-5 month-old or 6-59 month-old children, respectively, during 10 days) vs. placebo in otherwise healthy children aged 2 months to 5 years who presented with acute diarrhoea (i.e. ≥3 stools/day for less than 72 h). Eighty-seven patients (median age 14 months; range 3.1-58.3) were analysed in an intention-to-treat approach. Forty-two patients took zinc and 45 placebo. There was no difference in the duration nor in the frequency of diarrhoea, but only 5% of the zinc group still had diarrhoea at 120 h of treatment compared to 20% in the placebo group (P = 0.05). Thirty-one patients (13 zinc and 18 placebo) were available for per-protocol analyses. The median (IQR) duration of diarrhoea in zinc-treated patients was 47.5 h (18.3-72) and differed significantly from the placebo group (median 76.3; IQR 52.8-137) (P = 0.03). The frequency of diarrhoea was also lower in the zinc group (P = 0.02). CONCLUSION: zinc treatment decreases the frequency and severity of diarrhoea in children aged 2 months to 5 years living in Switzerland. However, the intention-to-treat analysis reveals compliance issues that question the proper duration of treatment and the choice of optimal pharmaceutical formulation.

Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial.

BACKGROUND: Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers. METHODS: We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 × 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 × 10(4) CFU MTBVAC, and those in the third cohort received 5 × 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 × 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0·1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon γ release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. FINDINGS: Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5×10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells. INTERPRETATION: To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries. FUNDING: Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI).

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 Gentleman's Magazine and Historical Chronicle - 1812 July to December Index and Supplement

Specific pages related to the War of 1812 include: Pages 655, 656, 657: Battles on the Niagara Frontier, with the death of Major General Sir Isaac Brock at the Battle of Queenston Heights on October 13, 1812. Page 670: Oct 13 - Obituary for Major General Sir Isaac Brock. 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 September

Specific pages related to the War of 1812 include: Pages 282 to 283: Mention of border hostilities, the occupation of the town of Sandwich (in Canada, near Detroit (present day Windsor, Ontario) and a riot in Baltimore. 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, 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 October

Specific pages related to the War of 1812 include: Page 385: The capture of Fort Detroit; battles at Plattsburgh and Sackett's Harbour. Page 389: On 10 October 1812, Major General Sir Isaac Brock was knighted. 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 November

Specific pages related to the War of 1812 include: Pages 490: Fall of Major General Isaac Brock at the Battle of Queenston Heights and victory by Major General Roger Shaeffe. 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 December

*Pages 497-504 are duplicated. Please check both November and December for these pages listed in the Index. Specific pages related to the War of 1812 include: Page 574: Battles at Fort Michilimackinac and the Invasion of Upper Canada by the Americans on October 12, 1812. Pages 576, 577, 578: Intelligence from Major General Sir Isaac Brock with mentions of the battles of Fort Detroit, Amherstburg, etc. 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, letters from noted figures, articles on geography, biographical entries for prominent people, poems, reviews of books and more.

The Gentleman's Magazine and Historical Chronicle - 1813 January to June - Index and Supplements

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. Click on the pdf links to the right to view the monthly issue. This bound volume has been divided by months. The page divisions are as listed. Index pages 673-700 January pages 1-96 February pages 97-192 March pages 193-296 April pages 297-400 Prefix to May pages 401-408 * May pages 401-504 June pages 505-600 Supplement pages 601-672 *Pages 401-408 are duplicated. Please check both the Prefix to May and May for these pages listed in the Index.

The Gentleman's Magazine and Historical Chronicle - 1813 January

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. Click on the pdf links to the right to view the monthly issue. This bound volume has been divided by months. The page divisions are as listed. Index pages 673-700 January pages 1-96 February pages 97-192 March pages 193-296 April pages 297-400 Prefix to May pages 401-408 * May pages 401-504 June pages 505-600 Supplement pages 601-672 *Pages 401-408 are duplicated. Please check both the Prefix to May and May for these pages listed in the Index.

The Gentleman's Magazine and Historical Chronicle - 1813 February

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. Click on the pdf links to the right to view the monthly issue. This bound volume has been divided by months. The page divisions are as listed. Index pages 673-700 January pages 1-96 February pages 97-192 March pages 193-296 April pages 297-400 Prefix to May pages 401-408 * May pages 401-504 June pages 505-600 Supplement pages 601-672 *Pages 401-408 are duplicated. Please check both the Prefix to May and May for these pages listed in the Index.