Rates of common diagnoses in the Down Syndrome Cohort and as reported in the WA population by Silva et al. (1999).

<p>Rates of common diagnoses in the Down Syndrome Cohort and as reported in the WA population by Silva et al. (1999).</p

Primary diagnosis by group, ordered by median age at first admission.

1<p>PYAR: person-years-at-risk of admission;</p>2<p>includes 10 children with no record of admission on the HMDS.</p

Proportion of children with congenital cardiac defects and resulting recorded surgical procedures.

1<p>n = 405;</p>2<p>subgroups are not mutually exclusive, eg.: 20 children were diagnosed with both CSD and PDA, 4 were admitted;</p>3<p>CABG: coronary artery bypass graft;</p>4<p>CC: cardiac catheterization.</p

Cumulative probability of hospital Length of Stay, by admission type.

<p>Cumulative probability of hospital Length of Stay, by admission type.</p

Fatty acid profile in liver of Non-Maternally Separated rats fed un-supplemented diet (A), Maternally Separated rats fed un-supplemented diet (B), Non-Maternally Separated rats fed <i>B. breve</i> DPC6330 (C), Maternally Separated rats fed <i>B. breve</i> DPC6330 (D), Non-Maternally Separated rats fed <i>B. breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid (E), Maternally Separated rats fed <i>B. breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid (F) for 7 weeks.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048159#s3" target="_blank">Results</a> are expressed as percentage of total identified fatty acids. Data are Means ± SEM g/100 g FAME. ^{A, B, C, D, E, F} Different superscript letters within a column indicate significant difference (* = p<0.05, ** = p<0.01, *** = p<0.001). FAME = fatty acid methyl esters. C16:0 palmitic acid; C16:1c9 palmitoleic acid; C18:0 stearic acid; C18:1c9 oleic acid; C18:2n-6 linoleic acid; C18:3n-3 linolenic acid; C20:4n-6 arachidonic acid; C22:5n-3 docosapentaenoic acid; C22:6n-3 docosahexaenoic acid.</p

Fatty acid profile in adipose tissue of Non-Maternally Separated rats fed un-supplemented diet (A), Maternally Separated rats fed un-supplemented diet (B), Non-Maternally Separated rats fed <i>B. breve</i> DPC6330 (C), Maternally Separated rats fed <i>B. breve</i> DPC6330 (D), Non-Maternally Separated rats fed <i>B. breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid (E), Maternally Separated rats fed <i>B. breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid (F) for 7 weeks.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048159#s3" target="_blank">Results</a> are expressed as percentage of total identified fatty acids. Data are Means ± SEM g/100 g FAME.</p><p>^{A, B, C, D, E, F} Different superscript letters within a column indicate significant difference (* = p<0.05, ** = p<0.01, *** = p<0.001). FAME = fatty acid methyl esters. C16:0 palmitic acid; C16:1c9 palmitoleic acid; C18:0 stearic acid; C18:1<i>c</i>9 oleic acid; C18:1<i>t</i>9 elaidic acid<b>;</b> C18:2n-6 linoleic acid; C18:3n-3 linolenic acid; C20:1<i>c</i>11 eicosenoic acid; C20:4n-6 arachidonic acid.</p

The average threshold value (pressure at which the animal shows the first pain behaviour) of each group. (* = p<0.05).

<p>White columns- Non separated rats fed un-supplemented diet, Chequered columns- Maternally separated fed un-supplemented diet, Horizontal lines- Non separated rats fed <i>Bifidobacterium breve</i> DPC 6330, Vertical lines- Maternally separated rats fed <i>Bifidobacterium breve</i> DPC 6330, Upward diagonal lines- Non separated rats fed <i>Bifidobacterium breve</i> DPC 6330 plus 0.5% linoleic acid and 0.5% α-linolenic acid, Downward diagonal lines- Maternally separated rats fed <i>Bifidobacterium breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid.</p

Fatty acid profile in prefrontal cortex of Non-Maternally Separated rats fed un-supplemented diet (A), Maternally Separated rats fed un-supplemented diet (B), Non-Maternally Separated rats fed <i>B. breve</i> DPC6330 (C), Maternally Separated rats fed <i>B. breve</i> DPC6330 (D), Non-Maternally Separated rats fed <i>B. breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid (E), Maternally Separated rats fed <i>B. breve</i> DPC6330 plus 0.5% (w/w) linoleic acid and 0.5% (w/w) α-linolenic acid (F) for 7 weeks.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048159#s3" target="_blank">Results</a> are expressed as percentage of total identified fatty acids. Data are Means ± SEM g/100 g FAME.</p><p>^{A, B, C, D, E, F} Different superscript letters within a column indicate significant difference (* = p<0.05, ** = p<0.01, *** = p<0.001). FAME = fatty acid methyl esters. C16:0 palmitic acid; C16:1c9 palmitoleic acid; C18:0 stearic acid; C18:1<i>c</i>9 oleic acid; C18:1<i>t</i>9 elaidic acid; C18:2n-6 linoleic acid; C20:4n-6 arachidonic acid; C22:4 adrenic acid; C24:1 nervonic acid; C22:5n-3 docosapentaenoic acid; C22:6n-3 docosahexaenoic acid.</p

Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, <b>3A</b>, was identified from this SAR effort. As a potent sstr3 antagonist, <b>3A</b> was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, <b>3A</b> elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress