The effects of oral methionine and homocysteine on endothelial function

BACKGROUND—Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established.
AIM—To study the effect of oral methionine and then oral homocysteine on endothelial function.
METHODS—22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline.
RESULTS—Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p < 0.04; endothelium independent responses were unchanged. Study 2: homocysteine concentration increased significantly while methionine remained unchanged. Endothelium dependent responses were reduced from 34.6 (95% CI 20.6 to 48.6) to 22.8 (95% CI 12.0 to 33.6), p < 0.03.
CONCLUSIONS—Homocysteine and not methionine is responsible for the changes in endothelial function. This supports the hypothesis that homocysteine promotes atherosclerosis by inducing endothelial dysfunction.


Keywords: homocysteine; methionine; endothelial function; plethysmography     

Treatment of the chronic total occlusion: A call to action for the interventional community

There is substantial evidence that recanalization of a chronic total occlusion is beneficial; nonetheless, it is generally underutilized in clinical practice. We consider the Aesop's fable of the “Fox and the Grapes” as analogous to the current situation in interventional cardiology. The technical challenges in achieving CTO recanalization has led interventionalists, clinical cardiologists, and sometimes even patients to believe that CTO recanalization is not effective, and, therefore, not needed. This perspective reviews available data regarding efficacy and safety of CTO percutaneous coronary intervention (PCI) in the current drug‐eluting stent era, discusses areas where more studies are required, and encourages the interventional community to utilize CTO PCI where appropriate based on current evidence. © 2014 Wiley Periodicals, Inc.     

Clinics in diagnostic imaging (159). Jejunal intussusception due to Peutz-Jeghers syndrome.

A 21-year-old woman presented with acute onset of upper abdominal pain. A diagnosis of Peutz-Jeghers syndrome (PJS) was made based on the clinical picture of perioral pigmentation with imaging findings of transient jejunojejunal intussusceptions and small bowel polyps, and confirmed by characteristic histopathological appearances of Peutz-Jeghers polyps. PJS is a rare hereditary condition characterised by unique hamartomatous polyps, perioral mucocutaneous pigmentations, and increased susceptibility to gastrointestinal and extraintestinal neoplasms. Patients usually present with recurrent abdominal pain due to intussusception caused by polyps. Other modes of presentations include rectal bleeding and melaena. We describe the imaging findings of PJS and provide a brief review of bowel polyposis syndromes. The latter are relatively rare disorders characterised by multiple polyps in the large or small intestine, with associated risk of malignancies and other extraintestinal manifestations. Awareness of the manifestations and early diagnosis of these syndromes is crucial to prevent further complications.     

Elevated adenosine deaminase and purine nucleoside phosphorylase activity in peripheral blood null lymphocytes from patients with acquired immune deficiency syndrome

The purine metabolic enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are important in lymphocyte differentiation, and genetic deficiencies of either enzyme have been associated with hereditary immunodeficiency states. Both ADA and PNP activity were measured in null cell-enriched and T cell-enriched peripheral blood lymphocytes from 16 patients with the acquired immune deficiency syndrome (AIDS), seven patients with the AIDS-related symptom complex (ARC), and seven asymptomatic homosexuals. ADA activity in nmol/10(6) lymphocytes/h was significantly elevated in null lymphocytes from AIDS (161 +/- 12) as compared with 23 healthy heterosexual controls (127 +/- 8;P less than .025). PNP activity was also significantly increased in null lymphocytes from AIDS patients (96 +/- 10;P less than .005) as well as those from ARC patients (84 +/- 11:P less than .025) relative to controls (61 +/- 5). No significant differences in enzyme activity were noted in T cell-enriched cells in any group. Along with elevated enzyme activity, AIDS patients had small yet significant increases in the percentages of HLA-DR (P less than .025), terminal deoxynucleotidyl transferase (TdT) (P less than .0001), and peanut agglutinin receptor (P less than .0001) positive lymphocytes in the null fraction compared with controls. TdT-positive cells appeared morphologically as large lymphoblasts with irregular nuclei. The data imply that the cellular immune deficiency in AIDS is not a result of deficiencies in lymphocyte ADA or PNP activity, but is more likely associated with an increase in an immature and/or activated lymphocyte subset.     

Purification and properties of bacterially synthesized human granulocyte-macrophage colony stimulating factor

Human granulocyte-macrophage colony stimulating factor (GM-CSF) has been synthesized in high yield using a temperature inducible plasmid in Escherichia coli. The human GM-CSF is readily isolated from the bacterial proteins because of its differential solubility and chromatographic properties. The bacterially synthesized form of the human GM-CSF contains an extra methionine residue at position 1, but otherwise it is identical to the polypeptide predicted from the cDNA sequence. The specific activity of 2.9 X 10(7) units/mg of protein for purified bacterially synthesized human GM-CSF indicates that despite the lack of glycosylation, the molecule is substantially in its native conformation. This molecule stimulated the same number and type of both seven- and 14-day human bone marrow colonies as the CSF alpha preparation from human placental conditioned medium. Human GM-CSF had no activity on murine bone marrow or murine leukemic cells. There was no detectable, direct stimulation of adult human erythroid burst forming units (BFU-E) by the bacterially synthesized human GM-CSF. Although impure preparations containing native human GM-CSF (eg, human placental conditioned medium) stimulated the formation of mixed colonies, even in the presence of erythropoietin, the bacterially synthesized human GM-CSF failed to stimulate the formation of mixed colonies from adult human bone marrow cells. The bacterially synthesized human GM-CSF increased N-formyl-methionyl-leucyl- phenylalanine (FMLP)-induced superoxide production and lysozyme secretion. Antibody-dependent cytotoxicity and phagocytosis by human neutrophils was stimulated by the bacterially synthesized human GM-CSF and eosinophils were also activated in the antibody-dependent cytotoxicity assay.     

Socioeconomic differences in service use, payment and receipt of illness-related benefits in the last year of life: findings from the British Household Panel Survey

BACKGROUND: Terminal illness presents a financial challenge to many households, but in Britain the situation should be eased by state benefits, such as attendance allowance, which is available to everyone in the last six months of life without means testing. AIM: To investigate the use of health and social services, payments and benefit receipt by individuals in differing financial circumstances in the year before death. Methods: Analysis of individual level panel data for 1652 community-dwelling decedents from 12 waves of the British Household Panel Study (1991-2003). RESULTS: In the year before death, over 90% of decedents saw their GP, and around one-third spent some time in hospital. More than 80% paid no fees for any services. Over a third of decedents aged over 65 reported financial strain, but only 13.9% of these were receiving attendance allowance. People who felt that they were having financial difficulties were more likely to be frequent attenders in primary care, taking age, health status and other factors into account (adjusted OR=1.9, 95% CI=1.3-2.6, P<0.001). Older age was associated with less use of primary, but not secondary care. CONCLUSIONS: Financial strain was common, but benefit uptake low. Primary health care professionals saw nearly all decedents in their last year, and could play an important role in ensuring that the elderly and the less well off are aware of the services and benefits available to them.     

Making the most of routine data in palliative care research--a case study analysis of linked hospital and mortality data on cancer and heart failure patients in Scotland and Oxford

The research base of palliative care is growing rapidly, but despite methodological advances, some of the practical challenges of working with people at the end of life will persist. This means that analysis of routine data is arguably more important in studying palliative care than it is in other aspects of health services research. End-of-life researchers have been using the high-quality linked data from cancer registries for many years. This paper explores the value of a less well-known resource for palliative care research: linked mortality and hospital activity data. Two case studies are presented using information from Scotland (population 5.1 million) and the former Oxford region of England (population 2.5 million). The advantages and limitations of linked hospital and mortality data for research and service planning in palliative care are drawn out through analyses investigating hospital bed utilisation by people with cancer and heart failure and the influence of social deprivation on the use of hospital services in the last year of life. The use of such data deserves a higher profile.     

Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice

Background and purpose:

Reactive oxygen species (ROS) derived from Nox2-containing reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is reportedly detrimental in cerebrovascular disease. However, ROS generation by other Nox isoforms may have a physiological role. No Nox2-selective inhibitors have yet been identified, and thus it is unclear whether isoform non-selective Nox inhibitors would necessarily improve outcome after stroke. We assessed the effect of apocynin on cerebrovascular ROS production and also on outcome following cerebral ischaemia when administered either before ischaemia or after cerebral reperfusion. The involvement of Nox2-containing NADPH oxidase in the effects of apocynin was assessed using Nox2^−/− mice.

Experimental approach:

Transient cerebral ischaemia was induced by 0.5 h middle cerebral artery occlusion followed by 23.5 h reperfusion. Mice received apocynin (2.5 mg·kg⁻¹, i.p.) either 0.5 h before ischaemia or 1 h after reperfusion. In situ superoxide production after cerebral ischaemia-reperfusion was measured in brain sections of wild-type mice at 24 h using dihydroethidium fluorescence.

Key results:

Treatment with apocynin 0.5 h before ischaemia reduced total infarct volume, neurological impairment and mortality in wild-type but not Nox2^−/− mice. Conversely, treatment with apocynin 1 h after initiation of reperfusion had no protective effect. Cerebral ischaemia and reperfusion increased superoxide production in the brain at 24 h, and pretreatment but not posttreatment with apocynin reduced superoxide levels.

Conclusions and implications:

Apocynin improves outcome following stroke when administered before ischaemia in wild-type but not Nox2^−/− mice.     

The nature of lexico-semantic processing deficits in mild cognitive impairment

Lexico-semantic impairments in Alzheimer disease (AD) have been attributed to abnormalities in both intentional and automatic access to semantic memory. However, the order in which these impairments appear during the course of the disease is unclear. We sought to answer this question by documenting lexico-semantic impairments in 61 subjects with mild cognitive impairment (MCI), a pre-AD stage, and by comparing them to those of 39 AD and 60 normal elderly (NE) subjects. All subjects were tested with intentional access tasks (picture naming and semantic probes), automatic access tasks (lexical decision and priming), and executive function tasks (Stroop and Stroop-Picture naming). Results indicated that the MCI group was only impaired on tasks of intentional access relative to the AD group who was impaired on both types of tasks. Because most MCI subjects eventually develop AD, these results suggest that intentional access to semantic memory is impaired before automatic access. Further, impairments on the Stroop-Picture naming task but not on the Stroop task, suggest that lexico-semantic impairments in the MCI group may be related to inhibition deficits during semantic search. Findings are discussed in light of executive dysfunctions within the framework of semantic memory theories.