Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.

PURPOSE. To assess the diagnostic validity of a fully automated image analysis algorithm of in vivo confocal microscopy images in quantifying corneal subbasal nerves to diagnose diabetic neuropathy.METHODS. One hundred eighty-six patients with type 1 and type 2 diabetes mellitus (T1/ T2DM) and 55 age-matched controls underwent assessment of neuropathy and bilateral in vivo corneal confocal microscopy (IVCCM). Corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL) were quantified with expert, manual, and fully-automated analysis. The areas under the curve (AUC), odds ratios (OR), and optimal thresholds to rule out neuropathy were estimated for both analysis methods.RESULTS. Neuropathy was detected in 53% of patients with diabetes. A significant reduction in manual and automated CNBD (P < 0.001) and CNFD (P < 0.0001), and CNFL (P < 0.0001) occurred with increasing neuropathic severity. Manual and automated analysis methods were highly correlated for CNFD (r ¼ 0.9, P < 0.0001), CNFL (r ¼ 0.89, P < 0.0001), and CNBD (r ¼ 0.75, P < 0.0001). Manual CNFD and automated CNFL were associated with the highest AUC, sensitivity/specificity and OR to rule out neuropathy.CONCLUSIONS. Diabetic peripheral neuropathy is associated with significant corneal nerve loss detected with IVCCM. Fully automated corneal nerve quantification provides an objective and reproducible means to detect human diabetic neuropathy.

OBJECTIVEQuantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard.RESEARCH DESIGN AND METHODSEighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy.RESULTSManual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14).CONCLUSIONSThis study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN.

BackgroundTo determine, in a meta-analysis, the diagnostic performance of quantitative diffusion-weighted (DW) MR imaging in patients with breast lesions.MethodsEnglish and Chinese studies published prior to June 2009 to assess the diagnostic performance of quantitative DWI in patients with breast lesions were reviewed and summarized with reference to the inclusion and exclusion criteria. Methodological quality was assessed by using the quality assessment of diagnostic studies (QUADAS) instrument. Publication bias analysis was performed by using Comprehensive Meta-analysis version 2. Meta-Disc version 1.4 was used to describe primary results and explore homogeneity by Chi-square test and inconsistency index; to explore threshold effect by receiver operator characteristic (ROC) space and Spearman correlation coefficient; and to pool weighted sensitivity and specificity by fixed or random effect model. A summary ROC (sROC) curve was constructed to calculate the area under the curve (AUC).ResultsOf 65 eligible studies, 13 with 615 malignant and 349 benign lesions were included in the original meta-analysis, among which heterogeneity arising from factors other than threshold effect and publication bias was explored. Methodological quality was moderate. The pooled weighted sensitivity and specificity with corresponding 95% confidence interval (CI) in one homogenous subgroup of studies using maximum b = 1000 s/mm2 were 0.84 (0.80, 0.87) and 0.84 (0.79, 0.88) respectively. AUC of sROC was 0.9085. Sensitivity analysis demonstrated that the pooled estimates were stable and reliable.ConclusionsQuantitative DWI has a higher specificity to differentiate between benign and malignant breast lesions compared to that of contrast-enhanced MRI. However, large scale randomized control trials (RCTs) are necessary to assess its clinical value because of disunified diffusion gradient factor b and diagnosis threshold.

This study demonstrates good repeatability for the manual assessment of all major corneal NF parameters with the exception of NBD, which highlights the difficulty in defining nerve branches and suggests the need for experienced observers or automated image analysis to ensure optimal repeatability.