Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress.

Excessive reactive oxygen species production by mitochondria (mtROS) is a key contributor to age-related vascular endothelial dysfunction. We recently showed in a crossover design, placebo-controlled clinical trial in older adults that 6 wk of treatment with the mitochondria-targeted antioxidant (MitoQ) improved endothelial function, as measured by nitric oxide (NO)-mediated endothelium-dependent dilation (EDD), by lowering mtROS and was associated with reduced circulating levels of oxidized low-density lipoprotein (oxLDL). Here, we conducted an ancillary analysis using plasma samples from our clinical trial to determine if MitoQ treatment-mediated changes in the "circulating milieu" (plasma) contribute to improvements in endothelial function and the mechanisms involved. With the use of an ex vivo model of endothelial function, acetylcholine-stimulated NO production was quantified in human aortic endothelial cells (HAECs) exposed to plasma collected after chronic MitoQ and placebo supplementation in 19 older adults (67 ± 1 yr; 11 females). We also assessed the influence of plasma on endothelial cell (EC) mtROS bioactivity and the role of lower circulating oxLDL in plasma-mediated changes. NO production was ∼25% higher (P = 0.0002) and mtROS bioactivity was ∼25% lower (P = 0.003) in HAECs exposed to plasma collected from subjects after MitoQ treatment versus placebo. Improvements in NO production ex vivo and NO-mediated EDD in vivo with MitoQ were correlated (r = 0.4683; P = 0.0431). Increasing oxLDL in plasma collected after MitoQ to placebo levels abolished MitoQ treatment effects on NO production and mtROS bioactivity, whereas inhibition of endogenous oxLDL binding to its lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) prevented these effects. These findings provide novel insight into the mechanisms by which MitoQ treatment improves endothelial function in older adults.NEW & NOTEWORTHY Chronic supplementation with a mitochondria-targeted antioxidant (MitoQ) improves vascular endothelial function in older adults, but the mechanisms of action are incompletely understood. Here, we show that MitoQ supplementation leads to changes in the circulating milieu (plasma), including reductions in oxidized low-density lipoprotein that enhance nitric oxide production and reduce mitochondrial oxidative stress in endothelial cells. These findings provide new information regarding the mechanisms by which MitoQ improves age-related endothelial dysfunction.

Cerebrovascular pulsatility index is higher in chronic kidney disease.

Patients with chronic kidney disease (CKD) are more likely to die of cardiovascular diseases, including cerebrovascular disease, than to progress to end-stage kidney disease. Cerebrovascular dysfunction, characterized by reduced cerebrovascular reactivity, cerebral hypoperfusion, and increased pulsatile flow within the brain, precedes the onset of dementia and is linked to cognitive dysfunction. However, whether impaired cerebrovascular function is present in non-dialysis dependent CKD is largely unknown. Using transcranial Doppler, we compared middle cerebral artery (MCA) blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO2 ; a measure of cerebrovascular reactivity) and MCA pulsatility index (PI; a measure of cerebrovascular stiffness) in patients with stage 3-4 CKD vs. age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function), measured carotid-femoral pulse-wave velocity (PWV; aortic stiffness), and assessed ex vivo nitric oxide (NO) and reactive oxygen species (ROS) production from human brain endothelial cells incubated with serum obtained from study participants. MCA PI was higher in patients with CKD vs. controls; however, normalized MCA blood velocity response to hypercapnia did not differ between groups. Similar results were observed in a validation cohort of midlife and older adults divided by the median estimated glomerular filtration rate (eGFR). MCA PI was associated with greater large-elastic artery stiffness (carotid-femoral PWV), worse executive function (trails B time), lower eGFR, and higher ex vivo ROS production. These data suggest that impaired kidney function is associated with greater cerebrovascular stiffness, which may contribute to the known increased risk for cognitive impairment in patients with CKD.

The evolution of ocean literacy: A new framework for the United Nations Ocean Decade and beyond.

First introduced in the early 2000s, the concept of ocean literacy has evolved in recent years, not least since its inclusion as a mechanism for change within the United Nations Ocean Decade's goals. Building on early definitions of ocean literacy, there has been increasing recognition of a range of additional dimensions which contribute to an individual or collective sense of 'ocean literacy'. Drawing on existing research, and parallel and supporting concepts, e.g., marine citizenship, ocean connectedness, and public perceptions research, this paper proposes ten dimensions of ocean literacy: knowledge, communication, behaviour, awareness, attitudes, activism, emotional connection, access and experience, adaptive capacity and trust and transparency, and recommends expanding previously recognised dimensions, in a bid to ensure that ocean literacy encompasses diverse knowledges, values and experiences. The paper provides a useful framework for ongoing ocean literacy research, and highlights aspects of ocean literacy which have received limited focus to date.

Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol.

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide and aging is the primary risk factor for the development of CVD. The increased risk of CVD with aging is largely mediated by the development of vascular dysfunction. Excessive production of mitochondrial reactive oxygen species (mtROS) is a key mechanism of age-related vascular dysfunction. Therefore, establishing the efficacy of therapies to reduce mtROS to improve vascular function with aging is of high biomedical importance. Previously, in a small, randomized, crossover-design pilot clinical trial, our laboratory obtained initial evidence that chronic oral supplementation with the mitochondrial-targeted antioxidant MitoQ improves vascular function in healthy older adults. Here, we describe the protocol for an ongoing R01-funded phase IIa clinical trial to establish the efficacy of MitoQ as a therapy to improve vascular function in older adults (ClinicalTrials.gov Identifier: NCT04851288). Outcomes: The primary outcome of the study is nitric oxide (NO)-mediated endothelium-dependent dilation (EDD) as assessed by brachial artery flow-mediated dilation (FMDBA). Secondary outcomes include mtROS-mediated suppression of EDD, aortic stiffness as measured by carotid-femoral pulse wave velocity, carotid compliance and ß-stiffness index, and intima media thickness. Other outcomes include the assessment of endothelial mitochondrial health and oxidative stress in endothelial cells obtained by endovascular biopsy; the effect of altered circulating factors following MitoQ treatment on endothelial cell NO bioavailability and whole cell and mitochondrial reactive oxygen species production ex vivo; and circulating markers of oxidative stress, antioxidant status, and inflammation. Methods: We are conducting a randomized, placebo-controlled, double-blind, parallel group, phase IIa clinical trial in 90 (45/group) healthy older men and women 60 years of age or older. Participants complete baseline testing and are then randomized to either 3 months of oral MitoQ (20 mg; once daily) or placebo supplementation. Outcome measures are assessed at the midpoint of treatment, i.e., 6 weeks, and again at the conclusion of treatment. Discussion: This study is designed to establish the efficacy of chronic supplementation with the mitochondrial-targeted antioxidant MitoQ for improving vascular endothelial function and reducing large elastic artery stiffness in older adults, and to investigate the mechanisms by which MitoQ supplementation improves endothelial function.

We, um, have, like, a problem: excessive use of fillers in scientific speech.

A filler is any word or sound that interpolates (i.e., is inserted into) the main message of a speaker. Common fillers include "um", "ah," "like," "so," and "you know?" among others. Excessive use of fillers in scientific presentations can reduce the credibility of the speaker as well as impair the comprehension of the speaker's message by the audience. Primary causes of fillers include nervousness/speaking too quickly, inadequate preparation time, and infrequently used words that are difficult for the speaker to remember while presenting. Recommendations for reducing the use of fillers include self-awareness of the problem, reinforcing feedback, and active intervention to render pauses silent (instead of verbal) by "chunking" content, increasing preparation time, and slowing presentation pace. Excessive use of fillers is an obstacle to becoming an effective public speaker, and therefore, efforts to reduce filler use should be a goal of professional development.NEW & NOTEWORTHY Although many articles exist on the use of filler words during public speaking, to our knowledge this is the first comprehensive discussion of the issue in the context of scientific presentations and speech in biomedical research. This Personal View discusses the problem of excessive filler use, the underlying causes, and tips for reducing fillers based on a combination of available literature and personal advice from a laboratory with nearly 40 years of experience in mentoring.

Factors associated with time to initiation of a PCSK9 inhibitor after hospital discharge for acute myocardial infarction.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower atherosclerotic cardiovascular disease (ASCVD) event risk. OBJECTIVE: Analyze patient characteristics associated with time to PCSK9i initiation following an acute myocardial infarction (AMI). METHODS: We analyzed characteristics of patients ≥21 years of age in the Marketscan or Medicare databases who initiated a PCSK9i 0-89 days, 90-179 days, or 180-365 days after an AMI between July 2015 and December 2018 (n=1,705). We estimated the cumulative incidence of recurrent ASCVD events before PCSK9i initiation. RESULTS: Overall, 42%, 25%, and 33% of patients who initiated a PCSK9i did so 0-89 days, 90-179 days, and 180-365 days following AMI hospital discharge, respectively. Taking ezetimibe prior to AMI hospitalization and initiating ezetimibe within 30 days after AMI hospital discharge were each associated with a higher likelihood of PCSK9i initiation in the 0-89 days versus 180-365 days post-discharge (adjusted odds ratio [OR] 1.83, 95% confidence interval [95%CI] 1.35-2.49 and 1.76, 95%CI 1.11-2.80, respectively). Statin use before and statin initiation within 30 days after AMI hospitalization were associated with a lower likelihood of PCSK9i initiation 0-89 days versus 180-365 days post-discharge (adjusted OR 0.64, 95%CI 0.49-0.84 and 0.39, 95%CI 0.28-0.54, respectively). Overall, 8.0%, 10.5%, and 12.5% of patients had an ASCVD event at 90, 180, and 365 days following AMI hospital discharge and before initiating a PCSK9i, respectively. CONCLUSION: Among patients initiating a PCSK9i after AMI, a low proportion did so within 89 days of hospital discharge. Many patients had a recurrent ASCVD event before treatment initiation.

Changes in nonstructural protein 3 are associated with attenuation in avian coronavirus infectious bronchitis virus.

Full-length genome sequencing of pathogenic and attenuated (for chickens) avian coronavirus infectious bronchitis virus (IBV) strains of the same serotype was conducted to identify genetic differences between the pathotypes. Analysis of the consensus full-length genome for three different IBV serotypes (Ark, GA98, and Mass41) showed that passage in embryonated eggs, to attenuate the viruses for chickens, resulted in 34.75-43.66% of all the amino acid changes occurring in nsp 3 within a virus type, whereas changes in the spike glycoprotein, thought to be the most variable protein in IBV, ranged from 5.8 to 13.4% of all changes. The attenuated viruses did not cause any clinical signs of disease and had lower replication rates than the pathogenic viruses of the same serotype in chickens. However, both attenuated and pathogenic viruses of the same serotype replicated similarly in embryonated eggs, suggesting that mutations in nsp 3, which is involved in replication of the virus, might play an important role in the reduced replication observed in chickens leading to the attenuated phenotype.

Digital constriction bands in pseudoainhum: morphological radiographic, and histological analysis.

Pseudoainhum is a rare condition of unknown etiology that produces digital constricting rings, most commonly on the small fingers. A thorough discussion of pseudoainhum in the plastic surgical literature is apparently lacking at this time. The authors describe the gross morphology, radiographic and laboratory features, and surgical pathology of the disease, and provide well-defined guidelines for its treatment.

Signet-ring squamous cell carcinoma: a case report.

A-50-year-old Hispanic man presented to the dermatology clinic with a 0.6-cm eroded, erythematous, scaly plaque on the left side of his neck. On shave biopsy, the lesion was composed of intra-epidermal and invasive dermal cells characterized by a signet-ring appearance. One area suggestive of typical squamous cell carcinoma prompted the inclusion of that entity in the differential diagnosis. Mucicarmine stains were negative, while the extra-vacuolar cytoplasm focally reacted with periodic acid-Schiff staining, the positive reaction for which was abolished by diastase, consistent with glycogen. Malignant cells expressed keratins by reacting to antibodies, Mak6, AE1/AE3, Ker 903, and CAM5.2. Additionally, weak reactivity occurred with antibodies to CEA and EMA. Tumor cells did not express S-100, HM-B45, Leu M1, or actin. By ultrastructural examination, the large vacuoles corresponded to markedly dilated endoplasmic reticulum. A diagnosis of signet-ring squamous cell carcinoma, a rare form of cutaneous squamous cell carcinoma which has been described in only one case report in the last 10 years, was made. Immunohistochemical staining provided information useful in differentiating this lesion from other clear cell and signet-ring cell tumors which involve the skin.

Differences in end-of-life decision making among black and white ambulatory cancer patients.

OBJECTIVE: African-American (black) and white individuals have been shown to differ in their desire for life-sustaining treatments and their use of living wills for end-of-life care, but the reasons for these differences are unclear. This study was designed to test the hypothesis that these ethnic differences exist because black patients trust the health care system less, fear inadequate medical treatment more, and feel less confident that living wills can give them more control over their terminal care. DESIGN: Cross-sectional, in-person survey conducted from November 1993 to June 1994. SETTING: Two medical oncology clinics with 40% to 50% black patient representation. PARTICIPANTS: Ambulatory cancer patients, 92 black and 114 white, who were awaiting their physician visits and agreed to participate (76% of those eligible). Patients were excluded if they were under age 40 or if they had nonmelanoma skin cancer only. MEASUREMENTS AND MAIN RESULTS: Black ambulatory cancer patients wanted more life-sustaining treatments (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.4-5.3), and were less likely to want to complete a living will at some time in the future (OR 0.36; 95% CI 0.17-0.75) than were white patients after controlling for socioeconomic variables. However, these differences were not related to lack of trust or fear of inadequate medical treatment in this study population. Both groups of patients trusted the health care system and felt that physicians treated patients equally well. Neither group feared inadequate or excessive medical care, and the majority of both groups agreed that living wills would help them keep control over their terminal care. CONCLUSIONS: Black and white cancer patients make different end-of-life choices, even after adjusting for likely explanatory variables. The other factors that influence decision making remain unclear and need to be further explored if physicians are to understand and help their patients make choices for end-of-life care.

Isolation of Yersinia pseudotuberculosis and Listeria monocytogenes serotype 4 from a gray fox (Urocyon cinereoargenteus) with canine distemper.

In February 1993, clinical, pathological, and microbiological investigations were performed on an adult female gray fox (Urocyon cinereoargenteus) from northern Mississippi (USA). The fox had clinical signs consistent with canine distemper virus encephalitis. Eosinophilic inclusions characteristic of canine distemper virus were in the nuclei and cytoplasm of cerebral neurons and glial cells and in the cytoplasm of urinary, gastric, pancreatic and biliary epithelial cells. The liver contained multifocal microscopic nodular foci of granulomatous to pyogranulomatous inflammation and necrosis with large colonies of small Gram-negative coccobacilli. A low number of small Gram-positive bacilli were within viable-appearing Kupffer cells and hepatocytes. Yersinia pseudotuberculosis and Listeria monocytogenes serotype 4 were isolated from the liver and a mesenteric lymph node.

Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.

BACKGROUND: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS: To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS: The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

PIP: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15-50% despite antimalarial therapy. In order to determine whether combining iron chelation with quinine therapy speeds recovery of consciousness, the authors conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be under age 6, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they cannot be aroused. Deferoxamine (100 mg/kg of body weight/day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pryimethamine. The time to recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 time that among the 41 who received the placebo (95% confidence interval [CI], 0.7-2.3; the median time to recovery was 20.2 hours in the deferoxamine group, and 43.1 hours in the placebo group (p=0.38). Among 50 patients in deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95% CI, 1.1-4-7), decreasing the median recovery time from 68.2 to 24.1 hours (p=0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95% CI, 1.2-3.6). Among all 83 patients, mortality was 17% in the deferoxamine group and 22% in the placebo group (p=0.52). It is concluded that iron chelation therapy may speed the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant.

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.

Patulin mycotoxicosis in the rat: toxicology, pathology and clinical pathology.

Patulin, a secondary metabolite produced by species of the genera Penicillium and Aspergillus, was administered to male Sprague-Dawley rats, weighing 50-60 g, by the oral, sc and ip routes. The 72-hr LD50 values (in mg/kg weight) were: oral, 55.0; sc, 11.0; ip, 10.0. Mortality was greatest 0-24 hr after administration by the oral and sc routes and 49-72 hr after ip dosing. Gross alterations consisted of gastric and intestinal hyperaemia and distention. Histopathological alterations consisted principally of ulceration and inflammation of the stomach. Patulin was administered orally to rats daily or every other day for 2 wk at doses of 50 or 75% of the oral LD50. Mortality in the treated groups was greater than in controls but was similar for all treated groups. No evidence of cumulative toxicity was found and the gross and histopathological alterations were similar to those found in the LD50 studies. Clinicopathological alterations included metabolic alkalosis with respiratory compensation, oliguria, decreased serum sodium, elevated blood glucose, reduced plasma protein and an elevated total leucocyte count which differential leucocyte counts indicated to be due to neutrophilia. The inflammatory alterations observed in the gastro-intestinal tract may be due to the irritant properties of patulin or to an alteration in the gastro-intestinal flora by the antibiotic activity of patulin.