PURPOSE. To determine plasma metabolite and metabolic pathway differences between patients with type 2 diabetes with diabetic retinopathy (DR) and without retinopathy (diabetic controls), and between patients with proliferative DR (PDR) and nonproliferative DR (NPDR). METHODS. Using high-resolution mass spectrometry with liquid chromatography, untargeted metabolomics was performed on plasma samples from 83 DR patients and 90 diabetic controls. Discriminatory metabolic features were identified through partial least squares discriminant analysis, and linear regression was used to adjust for age, sex, diabetes duration, and hemoglobin A1c. Pathway analysis was performed using Mummichog 2.0. RESULTS. In the adjusted analysis, 126 metabolic features differed significantly between DR patients and diabetic controls. Pathway analysis revealed alterations in the metabolism of amino acids, leukotrienes, niacin, pyrimidine, and purine. Arginine, citrulline, glutamic csemialdehyde, and dehydroxycarnitine were key contributors to these pathway differences. A total of 151 features distinguished PDR patients from NPDR patients, and pathway analysis revealed alterations in the b-oxidation of saturated fatty acids, fatty acid metabolism, and vitamin D 3 metabolism. Carnitine was a major contributor to the pathway differences. CONCLUSIONS. This study demonstrates that arginine and citrulline-related pathways are dysregulated in DR, and fatty acid metabolism is altered in PDR patients compared with NPDR patients.

Bisphosphonates have become a commonly used class of medications to treat osteoporosis and other bone diseases. Zoledronate (zoledronic acid) can be dosed annually via intravenous infusion, making it an appealing option for patients and physicians. We report the case of a 68-year-old woman who developed severe, unilateral, ocular inflammation, including corneal endotheliitis, anterior uveitis with hyphema, scleritis, and orbital inflammation beginning 12 hours after receiving her first zoledronate infusion. Symptoms escalated but ultimately resolved with topical steroids and high-dose systemic corticosteroids. To our knowledge, this is the first report of unilateral diffuse inflammation of the eye and orbit, including corneal inflammation developing within 12 hours of a first zoledronate infusion.

Protein tyrosine phosphatase 1b (Ptp1b), which represses leptin signaling, is a promising therapeutic target for obesity. Genome wide deletion of Ptp1b, increases leptin sensitivity, protects mice from obesity and diabetes, but alters cardiovascular function by increasing blood pressure (BP). Leptin-control of metabolism is centrally mediated and involves proopiomelanocortin (POMC) neurons. Whether these neurons contribute to leptin-mediated increases in BP remain unclear. We hypothesized that increasing leptin signaling in POMC neurons with Ptp1b deletion will sensitize the cardiovascular system to leptin and enhance neurogenic control of BP. We analyzed the cardiovascular phenotype of Ptp1b+/+ and POMC-Ptp1b-/- mice, at baseline and after 7 days of leptin infusion or sympatho-activation with phenylephrine. POMCPtp1b deletion did not alter baseline cardiovascular hemodynamics (BP, heart rate) but reduced BP response to ganglionic blockade and plasma catecholamine levels that suggests a decreased neurogenic control of BP. In contrast, POMC-Ptp1b deletion increased vascular adrenergic reactivity and aortic α-adrenergic receptors expression. Chronic leptin treatment reduced vascular adrenergic reactivity and blunted diastolic and mean BP increases in POMC-Ptp1b-/- mice only. Similarly POMC-Ptp1b-/- mice exhibited a blunted increased in diastolic and mean BP accompanied by a gradual reduction in adrenergic reactivity in response to chronic vascular sympatho-activation with phenylephrine. Together these data rule out our hypothesis but suggest that deletion of Ptp1b in POMC neurons protects from leptin- and sympatho-mediated increases in BP. Vascular adrenergic desensitization appears as a protective mechanism against hypertension, and POMC-Ptp1b as a key therapeutic target for the treatment of metabolic and cardiovascular dysfunctions associated with obesity.

BackgroundMonitoring antimicrobial use and resistance in hospitals are important tools of antimicrobial stewardship programs. We aimed to determine the association between the use of frequently prescribed antibiotics and the corresponding resistance rates in Escherichia coli and Klebsiella pneumoniae among the clinical departments of a tertiary care hospital.MethodsWe performed a retrospective observational study to analyse the use of nine frequently prescribed antibiotics and the corresponding antimicrobial resistance rates in hospital acquired E. coli and K. pneumoniae isolates from 18 departments of our institution over 9 years (2008–2016). The main cross-sectional analysis assessed the hypothetical influence of antibiotic consumption on resistance by mixed logistic regression models.ResultsWe found an association between antibiotic use and resistance rates in E. coli for amoxicillin-clavulanic acid (OR per each step of 5 defined daily dose/100 bed-days 1.07, 95% CI 1.02–1.12; p = 0.004), piperacillin-tazobactam (OR 2.11, 95% CI 1.45–3.07; p < 0.001), quinolones (OR 1.52, 95% CI 1.25–1.86; p < 0.001) and trimethoprim-sulfamethoxazole (OR 1.59, 95% CI 1.19–2.13; p = 0.002). Additionally, we found a significant association when all nine antibiotics were combined in one analysis. The association between consumption and resistance rates was stronger for nosocomial than for community strains. In K. pneumoniae, we found an association for amoxicillin-clavulanic acid (OR 1.07, 95% CI 1.01–1.14; p = 0.025) and for trimethoprim-sulfamethoxazole (OR 2.02, 95% CI 1.44–2.84; p < 0.001). The combined analysis did not show an association between consumption and resistance (OR 1.06, 95% CI 0.99–1.14; p = 0.07).ConclusionsWe documented an association between antibiotic use and resistance rate for amoxicillin-clavulanic acid, piperacillin-tazobactam, quinolones and trimethoprim-sulfamethoxazole in E. coli and for amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole in K. pneumoniae across different hospital departments. Our data will support stewardship interventions to optimize antibiotic prescribing at a department level.Electronic supplementary materialThe online version of this article (10.1186/s13756-018-0387-0) contains supplementary material, which is available to authorized users.