Study selection process (PRISMA flowchart).

<p>Study selection process (PRISMA flowchart).</p

Summary of the studies that are included in this analysis.

<p>Summary of the studies that are included in this analysis.</p

Summary of the reported IGF-1 levels of serun and CSF/brain from AD or wildtype mice.

<p>Summary of the reported IGF-1 levels of serun and CSF/brain from AD or wildtype mice.</p

Forest plot of serum IGF-1 in AD and control subjects in included studies.

<p>The analysis did not include the outlier study by Salehi et al. The analysis showed that the difference is not significant within the groups in whole. CI: confidence intervals.</p

Summary of the studies which investigated IGF-1 and AD but are not included in this analysis because these studies did not provide actual values of serum IGF-1 levels.

<p>Summary of the studies which investigated IGF-1 and AD but are not included in this analysis because these studies did not provide actual values of serum IGF-1 levels.</p

Funnel plot of serum IGF-1 in AD and controls in included studies.

<p>Funnel plot for all 9 studies included trials to visualize potential publication bias. The shape of funnel plots did not reveal obvious evidence of asymmetry, suggesting no publication bias.</p

Short Report: TRPV1-polymorphism 1911 A>G alters capsaicin-induced sensory changes in healthy subjects

<div><p>Background</p><p>C-fibers express transient receptor potential (TRP) channels. These high-voltage gated channels function as integrators of different physical stresses (e.g. heat, protons, ATP). Additionally channel activation can be induced by capsaicin. Topically applied, capsaicin elicits burning pain, heat and mechanical hyperalgesia and serves as a human surrogate model for pain. It was suggested that the TRPV1-variant rs8065080 (1911A>G) plays a pivotal role in patients with neuropathic pain syndromes. We investigated the effect of this TRPV1-SNP on thermal sensitivity and superficial skin perfusion in 25 healthy subjects.</p><p>Methods and findings</p><p>Nine subjects being homozygous TRPV1 wild type (AA), 8 heterozygous (AG) and 8 homozygous variant (GG) carriers were selected out of a pool of genotyped healthy individuals. Under physiological conditions (no capsaicin application), there was no statistical significant difference in thermal thresholds or skin perfusion between carriers of different TRPV1 1199A>G genotypes. However, intra-individual calculations (Δ% pre vs. post capsaicin) revealed (1) less warm-detection in AA/AG (-82.1%) compared to GG (-13.1%) and (2) a gain of heat pain sensitivity in AA/AG (+22.2%) compared to GG carriers (+15.6%) after adjustment for perfusion measurements ((1)p = 0.009, (2)p = 0.021).</p><p>Conclusion</p><p>Presence of homozygous variant TRPV1 genotype (GG) demonstrated less capsaicin-induced warm hypoesthesia in warm-detection and less capsaicin-induced heat pain sensitivity suggesting an altered channel function. This demonstrates not only the functional influence of TRPV1 rs8065080 polymorphism itself; it further more underpins the relevance of genotyping-based approaches in both patients and surrogate models of neuropathic pain in healthy volunteers.</p></div

Laser Doppler measurement.

<p><b>a)</b> Sample image of Laser Doppler measurement setup. Regions of interest (ROI) were created around the capsaicin patch stimulation area for further calculations. The intensity image depicts the color-coded perfusion magnitude. <b>b)</b> Area of elevated skin perfusion (flare) was measured in mm². There was no significant difference between the genotypes, however a trend towards smaller flare areas in 1911 GG carriers can be observed. <b>c-d</b>) Perfusion changes during capsaicin application were measured via Laser Doppler flowmetry. There was no significant difference between the genotypes, but a trend towards a decreased perfusion gain in 1911 GG carriers.</p

Thermal quantitative sensory testing of TRPV1 variants.

<p>Comparison of intra-individual data (Δ%change prior vs. after capsaicin) of homozygous G (1911GG) against homozygous and heterozygous A carriers (1911AA+1911AG) reveals lower changes (1) towards loss of warm detection in GG (13.1%) compared to AA/AG (82.1%) and (2) towards gain of heat pain sensitivity in GG (15.6%) compared to AA/AG (22.2%) ((1) p = 0.009; (2) p = 0.021). Note: Data are displayed as means (±SEM) for all analyzed patients. P<0.05 considered significance. ((1)Mann-Whitney U test, (2)ANCOVA). *p<0.05; **p<0.01.</p