Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

Vitamin E supplementation inhibits muscle damage and inflammation after moderate exercise in hypoxia.

BACKGROUND: Exercise under hypoxic conditions represents an additional stress in relation to exercise in normoxia. Hypoxia induces oxidative stress and inflammation as mediated through tumour necrosis factor (TNF)-α release that might be exacerbated through exercise. In addition, vitamin E supplementation might attenuate oxidative stress and inflammation resulting from hypoxia during exercise. The present study aimed to evaluate the effects of vitamin E supplementation (250 mg) on inflammatory parameters and cellular damage after exercise under hypoxia simulating an altitude of 4200 m. METHODS: Nine volunteers performed three sessions of 60 min of exercise (70% maximal oxygen uptake) interspersed for 1 week under normoxia, hypoxia and hypoxia after vitamin E supplementation 1 h before exercise. Blood was collected before, immediately after and at 1 h after exercise to measure inflammatory parameters and cell damage. RESULTS: Percentage oxygen saturation of haemoglobin decreased after exercise and recovered 1 h later in the hypoxia + vitamin condition (P < 0.05). Supplementation decreased creatine kinase (CK)-TOTAL, CK-MB and lactate dehydrogenase 1 h after exercise (P < 0.05). The exercise in hypoxia increased interleukin (IL)-6, TNF-α, IL-1ra and IL-10 immediately after exercise (P < 0.05). Supplementation reversed the changes observed after exercise in hypoxia without supplementation (P < 0.05). CONCLUSIONS: We conclude that 250 mg of vitamin E supplementation at 1 h before exercise reduces cell damage markers after exercise in hypoxia and changes the concentration of cytokines, suggesting a possible protective effect against inflammation induced by hypoxia during exercise.

Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach.

BACKGROUND: There appears little consensus concerning protein requirements in phenylketonuria (PKU). METHODS: A questionnaire completed by 63 European and Turkish IMD centres from 18 countries collected data on prescribed total protein intake (natural/intact protein and phenylalanine-free protein substitute [PS]) by age, administration frequency and method, monitoring, and type of protein substitute. Data were analysed by European region using descriptive statistics. RESULTS: The amount of total protein (from PS and natural/intact protein) varied according to the European region. Higher median amounts of total protein were prescribed in infants and children in Northern Europe (n=24 centres) (infants <1 year, >2-3g/kg/day; 1-3 years of age, >2-3 g/kg/day; 4-10 years of age, >1.5-2.5 g/kg/day) and Southern Europe (n=10 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, 2 g/kg/day; 4-10 years of age, 1.5-2 g/kg/day), than by Eastern Europe (n=4 centres) (infants <1 year, 2.5 g/kg/day, 1-3 years of age, >2-2.5 g/kg/day; 4-10 years of age, >1.5-2 g/kg/day) and with Western Europe (n=25 centres) giving the least (infants <1 year, >2-2.5 g/kg/day, 1-3 years of age, 1.5-2 g/kg/day; 4-10 years of age, 1-1.5 g/kg/day). Total protein prescription was similar in patients aged >10 years (1-1.5 g/kg/day) and maternal patients (1-1.5 g/kg/day). CONCLUSIONS: The amounts of total protein prescribed varied between European countries and appeared to be influenced by geographical region. In PKU, all gave higher than the recommended 2007 WHO/FAO/UNU safe levels of protein intake for the general population.

Attenuation of Atherosclerosis with PAR4 Deficiency: Differential Platelet Outcomes in apoE -/- vs. Ldlr -/- Mice.

Objective: Cardiovascular disease (CVD) is a significant burden globally and, despite current therapeutics, remains the leading cause of death. Platelet inhibitors are of interest in CVD treatment to reduce thrombus formation post-plaque rupture as well their contribution to inflammation throughout the progression of atherosclerosis. Protease activated receptor 4 (PAR4) is a receptor highly expressed by platelets, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4. Approach and Results: Mice on a low-density lipoprotein receptor-deficient ( Ldlr -/- ) background were bred with Par4 deficient ( Par4 -/- ) mice to create Ldlr -/- /Par4 +/+ and Ldlr -/- /Par4 -/- cousin lines. Mice were fed high fat (42%) and cholesterol (0.2%) 'Western' diet for 12 weeks for all studies. Bone marrow transplant (BMT) studies were conducted by irradiating Ldlr -/- /Par4 +/+ and Ldlr -/- /Par4 -/- mice with 550 rads (2x, 4 hours apart) and then repopulated with Par4 +/+ or Par4 -/- bone marrow. To determine if the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the 'Western' diet. Ldlr -/- /Par4 -/- given dabigatran did not further decrease their atherosclerotic burden. Differences between apolipoprotein E deficient ( apoE -/- ) and Ldlr -/- platelets were assessed for changes in reactivity. We observed higher PAR4 abundance in arteries with atherosclerosis in human and mice versus healthy controls. PAR4 deficiency attenuated atherosclerosis in the aortic sinus and root versus proficient controls. BMT studies demonstrated this effect was due to hematopoietic cells, most likely platelets. PAR4 appeared to be acting independent of PAR1, as there werer no changes with addition of dabigatran to PAR4 deficient mice. apoE -/- platelets are hyperreactive compared to Ldlr -/- platelets. Conclusions: Hematopoietic-derived PAR4, most likely platelets, plays a vital role in the development and progression of atherosclerosis. Specific targeting of PAR4 may be a potential therapeutic target for CVD. Highlights: Deficiency of protease-activated receptor 4 attenuates the development of diet-induced atherosclerosis in a Ldlr -/- mouse model. PAR4 deficiency in hematopoietic cells is atheroprotective. PAR4 deficiency accounts for the majority of thrombin-induced atherosclerosis in a Ldlr -/- mouse model. The examination of platelet-specific proteins and platelet activation should be carefully considered before using the apoE -/- or Ldlr -/- mouse models of atherosclerosis.

The Possible Importance of Glutamine Supplementation to Mood and Cognition in Hypoxia from High Altitude.

Hypoxia induced by low O2 pressure is responsible for several physiological and behavioral alterations. Changes in physiological systems are frequent, including inflammation and psychobiological declines such as mood and cognition worsening, resulting in increased reaction time, difficulty solving problems, reduced memory and concentration. The paper discusses the possible relationship between glutamine supplementation and worsening cognition mediated by inflammation induced by high altitude hypoxia. The paper is a narrative literature review conducted to verify the effects of glutamine supplementation on psychobiological aspects. We searched MEDLINE/PubMed and Web of Science databases and gray literature by Google Scholar for English articles. Mechanistic pathways mediated by glutamine suggest potential positive effects of its supplementation on mood and cognition, mainly its potential effect on inflammation. However, clinical studies are scarce, making any conclusions impossible. Although glutamine plays an important role and seems to mitigate inflammation, clinical studies should test this hypothesis, which will contribute to a better mood and cognition state for several people who suffer from problems mediated by hypoxia.

Carbohydrate supplementation and psychophysiological responses during moderate exercise in hypoxia.

BACKGROUND: Rating of Perceived Exertion (RPE) is a subjective scale to monitor overload and fatigue during exercise. Hypoxia may worsen the perception of fatigue, compromising the self-reported perception of effort and increasing RPE. The objective was to evaluate the effects of carbohydrate (CHO) supplementation on RPE during exercise in hypoxia simulating 4200 m. METHODS: Eight male physically active volunteers performed two exercises at 50% VO2peak and 1% slope: exercise in hypoxia + placebo or exercise in hypoxia + CHO (6% maltodextrin) with supplementation at 20, 40, and 60 min during exercise. Oxygen Saturation (SaO2%) was assessed at baseline and after exercise, while RPE and HR were measured each 10 min during the trial. RESULTS: SaO2% decreased after exercise in both conditions of hypoxia compared to rest. The RPE did not differ between groups. However, the RPE increased in hypoxia after 20 min of exercise in relation to 10 min. The Area Under the Curve (AUC) of RPE was lower in hypoxia + CHO compared to hypoxia. The AUC of the HR/RPE ratio in the hypoxia + CHO group was higher in relation to hypoxia. CONCLUSIONS: Our results indicate that CHO supplementation does not change RPE induced by 60 min of exercise at 50% VO2peak in hypoxia equivalent to 4200 m at the different times analyzed. However, in hypoxia + CHO the (AUC)-60 min of total RPE decreased during exercise, while the heart rate/RPE ratio improved, indicating lower RPE in the hypoxic environment.

Knowledge gaps among South African healthcare providers regarding the prevention of neonatal group B streptococcal disease.

OBJECTIVE: To evaluate obstetric healthcare provider knowledge regarding the prevention of group B streptococcal disease in South African infants. METHODS: Questionnaires exploring knowledge, attitudes and beliefs around group B streptococcal prevention were administered to consenting doctors and maternity nurses in a tertiary academic hospital. Qualitative assessments (focus groups) were undertaken with junior doctors and nurses. RESULTS: 238 participants completed the questionnaire: 150 (63.0%) doctors and 88 (37.0%) nurses. Overall, 22.7% of participants correctly identified the risk-based prevention protocol recommended at this hospital. Most doctors (68.0%) and nurses (94.3%) could not correctly list a single risk factor. A third of doctors did not know the correct antibiotic protocols, and most (80.0%) did not know the recommended timing of antibiotics in relation to delivery. Focus group discussions highlighted the lack of knowledge, awareness and effective implementation of protocols regarding disease prevention. CONCLUSIONS: Our study highlighted knowledge gaps on the risk-based prevention strategy in a setting which has consistently reported among the highest incidence of invasive group B streptococcal disease globally. In these settings, education and prioritization of the risk-based intrapartum antibiotic strategy is warranted, but an alternative vaccine-based strategy may prove more effective in preventing invasive group B streptococcal disease in the long-term.

Protein expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 in young patients with oral squamous cell carcinoma.

The purpose of this study was to evaluate the expression of the enzymes involved in the biotransformation of tobacco and alcohol. A study group of 41 young patients (≤40 years old) with oral squamous cell carcinoma (OSCC) was compared to 59 control subjects (≥50 years old) with tumours of similar clinical stages and topographies. The immunohistochemical expression of CYP1A1, CYP1B1, ALDH1A1, and ALDH2 was evaluated using the tissue microarray technique. There was a predominance of males, smokers, and alcohol drinkers in both groups. Most tumours were located in the tongue (43.9% vs. 50.8%), were well-differentiated (63.4% vs. 56.6%), and were in clinical stages III or IV (80.5% vs. 78.0%). No difference was observed in the expression of CYP1A1, ALDH1A1, or ALDH2 between the two groups. CYP1A1 and ALDH2 protein expression had no influence on the prognosis. The immunoexpression of CYP1B1 was significantly higher in the control group than in the young group (P<0.001). The 5-year relapse-free survival was better in patients with CYP1B1 overexpression vs. protein underexpression (64% vs. 25%; P<0.05), regardless of age. ALDH1A1 expression improved relapse-free survival in young patients. These results suggest a lower risk of recurrence with increased metabolism of carcinogens by CYP1B1. Further studies involving other genes and proteins are necessary to complement the results of this research.

Prevalence and antifungal resistance profile of Candida spp. oral isolates from patients with type 1 and 2 diabetes mellitus.

OBJECTIVE: The goal of the study was to measure the prevalence of Candida spp. in the oral cavity of patients with diabetes types 1 and 2 when compared to healthy individuals and to study antifungal resistance profile of the isolates. DESIGN: There were 162 subjects in the study: diabetes type 1 (n=39); control group 1 (n=50): healthy individuals matched in gender, age, and oral conditions to diabetes type 1 patients; diabetes type 2 (n=37); control group 2 (n=36) who were matched to each patient of the diabetes type 2 group. Stimulated saliva was collected and isolates were identified with phenotypic tests. The presence of C. dubliniensis was determined by multiplex PCR. RESULTS: There were no statistically significant differences in Candida spp. frequency between the diabetes 1 group and its control (p=0.443) nor between the diabetes 2 group and its control (p=0.429). C. albicans was the most frequently isolated yeast in all groups. In the diabetes groups, C. stellatoidea, C. parapsilosis, C. tropicalis, C. lipolytica, C. glabrata, and C. krusei were also identified. Additionally, in control groups, C. kefyr was also detected. None of the isolates were resistant to amphotericin B and flucytosine. A low percentage of the isolates were resistant to ketoconazole. CONCLUSIONS: No differences were detected in colonization of Candida spp. oral isolates from type 1 and type 2 diabetes when compared to matched controls. The antifungal resistance of Candida spp. isolates for ketoconazole from type 1 diabetes patients was significantly higher than that of its matched control.