Hemoglobin levels are associated with retinal vascular caliber in a middle-aged birth cohort.

Vascular and neural structures of the retina can be visualized non-invasively and used to predict ocular and systemic pathologies. We set out to evaluate the association of hemoglobin (Hb) levels within the national reference interval with retinal vascular caliber, optical coherence tomography (OCT) and visual field (VF) parameters in the Northern Finland 1966 Birth Cohort (n = 2319, 42.1% male, average age 47 years). The studied parameters were evaluated in Hb quintiles and multivariable linear regression models. The lowest Hb quintile of both sexes presented the narrowest central retinal vein equivalent (CRVE) and the healthiest cardiometabolic profile compared to the other Hb quintiles. In the regression models, CRVE associated positively with Hb levels in both sexes, (Bmales = 0.068 [0.001; 0.135], Bfemales = 0.087 [0.033; 0.140]), after being adjusted for key cardiometabolic and inflammatory parameters, smoking status, and fellow vessel caliber. No statistically significant associations of Hb levels with central retinal artery equivalent, OCT or VF parameters were detected. In conclusion, Hb levels were positively and specifically associated with CRVE, indicating that Hb levels are an independent factor affecting CRVE and the effect is in parallel with established risk factors for cardiometabolic diseases.

Metabolic characteristics of transmembrane prolyl 4-hydroxylase (P4H-TM) deficient mice.

Transmembrane prolyl 4-hydroxylase (P4H-TM) is an enigmatic enzyme whose cellular function and primary substrate remain to be identified. Its loss-of-function mutations cause a severe neurological HIDEA syndrome with hypotonia, intellectual disability, dysautonomia and hypoventilation. Previously, P4H-TM deficiency in mice was associated with reduced atherogenesis and lower serum triglyceride levels. Here, we characterized the glucose and lipid metabolism of P4h-tm-/- mice in physiological and tissue analyses. P4h-tm-/- mice showed variations in 24-h oscillations of energy expenditure, VO2 and VCO2 and locomotor activity compared to wild-type (WT) mice. Their rearing activity was reduced, and they showed significant muscle weakness and compromised coordination. Sedated P4h-tm-/- mice had better glucose tolerance, lower fasting insulin levels, higher fasting lactate levels and lower fasting free fatty acid levels compared to WT. These alterations were not present in conscious P4h-tm-/- mice. Fasted P4h-tm-/- mice presented with faster hepatic glycogenolysis. The respiratory rate of conscious P4h-tm-/- mice was significantly lower compared to the WT, the decrease being further exacerbated by sedation and associated with acidosis and a reduced ventilatory response to both hypoxia and hypercapnia. P4H-TM deficiency in mice is associated with alterations in whole-body energy metabolism, day-night rhythm of activity, glucose homeostasis and neuromuscular and respiratory functions. Although the underlying mechanism(s) are not yet fully understood, the phenotype appears to have neurological origins, controlled by brain and central nervous system circuits. The phenotype of P4h-tm-/- mice recapitulates some of the symptoms of HIDEA patients, making this mouse model a valuable tool to study and develop tailored therapies.

Activation of the hypoxia response protects mice from amyloid-ß accumulation.

Alzheimer's disease (AD) is the most common cause of dementia with limited treatment options affecting millions of people and the prevalence increasing with the aging population. The current knowledge on the role of the hypoxia/hypoxia-inducible factor (HIF) in the AD pathology is restricted and controversial. We hypothesized based on benefits of the genetic long-term inactivation of HIF prolyl 4-hydroxylase-2 (HIF-P4H-2) on metabolism, vasculature and inflammatory response that prolonged moderate activation of the hypoxia response could hinder AD pathology. We used an aging model to study potential spontaneous accumulation of amyloid-ß (Aß) in HIF-P4H-2-deficient mice and a transgenic APP/PSEN1 mouse model subjected to prolonged sustained environmental hypoxia (15% O2 for 6 weeks) at two different time points of the disease; at age of 4 and 10 months. In both settings, activation of the hypoxia response reduced brain protein aggregate levels and this associated with higher vascularity. In the senescent HIF-P4H-2-deficient mice metabolic reprogramming also contributed to less protein aggregates while in APP/PSEN1 mice lesser Aß associated additionally with hypoxia-mediated favorable responses to neuroinflammation and amyloid precursor protein processing. In conclusion, continuous, non-full-scale activation of the HIF pathway appears to mediate protection against neurodegeneration via several mechanisms and should be studied as a treatment option for AD.

Antibacterial Activity of 2-Hydroxyisocaproic Acid (HICA) Against Obligate Anaerobic Bacterial Species Associated With Periodontal Disease.

Topical antiseptics are used to assist and further increase the effect of mechanical biofilm eradication and to potentially prevent new biofilm formation in periodontal treatment. This is of importance in treatment-resistant infections with 10% prevalence of all periodontitis cases to avoid the need for antibiotic therapy. The purpose of this study was to evaluate the antimicrobial activity of DL-2-hydroxyisocaproic acid on human pathogenic obligate anaerobic bacteria related to periodontitis. In this study antimicrobial activity of 2-hydroxyisocaproic acid was observed against 14 bacterial reference strains and clinical isolates of obligate anaerobic bacterial species using a microdilution method in 1.25 to 160 mg/mL concentrations of 2-hydroxyisocaproic acid. The 11 strains of bacteria included in this study are typically associated with periodontal disease; Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Parvimonas micra. Three strains of Cutibacterium acnes, normally associated with skin diseases, were tested for comparison. 90% inhibitory concentration was determined at 48 hours and minimum bactericidal concentration was determined after 72 hours incubation. The 2-hydroxyisocaproic acid was bactericidal at ⩾160 mg/mL for all isolates tested. The reference strain of T. forsythia, and the reference strain and the clinical isolates of C. acnes were the most tolerant ones. The reference strains and clinical isolates of F. nucleatum and A. actinomycetemcomitans were killed at ⩾40 mg/mL concentration. In conclusion, topical use of 2-hydroxyisocaproic acid could eventually be a well-tolerated and useful method in the therapy of patients with difficult-to-treat periodontal disease or other superficial infections to avoid unnecessary antibiotic use and the emergence of antibiotic resistance.