Marta Amaral

Stress-related mucosal disease: incidence of bleeding and the role of omeprazole in its prophylaxis.

BACKGROUND Upper gastrointestinal bleeding is the severe complication of stress-related mucosal disease in hospitalized patients. In intensive care units (ICU), risk factors are well defined and only mechanical ventilation and coagulopathy proved to be relevant for significant bleeding. On the contrary, in non-ICU settings there is no consensus about this issue. Nevertheless, omeprazole is still widely used in prophylaxis of bleeding. The objective of our study was to evaluate the relevance of stress-related mucosal disease bleeding in patients admitted to an internal medicine ward, and the role of omeprazole in its prophylaxis. METHODS We conducted a retrospective study in which we analysed consecutive patients who were admitted to our ward over a year. We recorded demographic characteristics of the patients, potential risk factors for stress-related mucosal disease (clinical data, laboratory, and medication), administration of prophylactic omeprazole, and total cost of this prophylaxis. Patients with active gastrointestinal bleeding on the admission were excluded. We recorded every upper gastrointestinal bleeding event with clinical relevance. RESULTS Five hundred and thirty-five patients, mean age 70 years, mean length of stay 9.6+/-7.7 days; 140 (26.2%) patients were treated with 40 mg of omeprazole intravenously, 193 (36.1%) with 20mg of omeprazole orally, and 202 (37.8%) patients had no prophylaxis. There was only one episode (0.2%) of clinically relevant bleeding. CONCLUSION In patients admitted to an internal medicine ward, incidence of upper gastrointestinal bleeding as a complication of stress-related mucosal disease is low. We found that there is no advantage in prophylaxis with omeprazole.

Extended‐release niacin increases anti‐apolipoprotein A‐I antibodies that block the antioxidant effect of high‐density lipoprotein–cholesterol: the EXPLORE clinical trial

Aims Extended‐release niacin (ERN) is the most effective agent for increasing high‐density lipoprotein–cholesterol (HDL‐C). Having previously identified anti‐HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A‐I (aApoA‐I). Methods Twenty‐one patients older than 18 years, with HDL‐C ≤40 mg dl–1 (men) or ≤50 mg dl–1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12‐week periods, with 4 weeks of wash‐out before cross‐over. Primary outcome was change of paraoxonase‐1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA‐I antibodies. Clinical Trial Unique Identifier: EudraCT 2006–006889‐42. Results The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l–1, 95% confidence interval [CI] –9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL‐C levels (coefficient estimate 5.21 mg dl–1, 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl–1, 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl–1, 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA‐I antibodies (coefficient estimate 0.25 &mgr;g ml–1, 95% CI 0.09–0.40; P = 0.001). aApoA‐I titres at baseline were correlated with decreased PON activity. Conclusions The rise in HDL‐C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA‐I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.

Persistency of low levels of anticardiolipin and anti-beta2 glycoprotein1 in thrombosis.

BACKGROUND Antiphospholipid antibodies, the hallmark of the antiphospholipid syndrome, are associated with both venous and arterial thrombosis. Despite some reports stating that this association may be present in patients with low titres of anticardiolipin antibodies, a clear association has only been established in the presence of a moderate to high concentrations (above 40 GPL or MPL). METHODS In order to study whether low antibody titres could be associated with thrombosis, we reviewed the files of 196 patients, 94 with and 102 without thrombotic events, for a period of 4.4 and 5.1 years respectively. Files from patients with persistent low titres of antiphospholipid antibodies recorded in the unit database were selected, independently of the associated clinical history or diagnosis. Epidemiology, clinical and treatment information were collected and the serum variability of the antibody titres was analysed in relation to the presence of thrombotic events. RESULTS Thrombotic events were classified as venous 81.9% and arterial 18.1%. 23/94 (24.5%) patients with thrombosis had miscarriages. There were no significant differences between serum concentrations of antiphospholipid antibodies in the thrombotic and non-thrombotic groups. However, there was a higher consistency of the antibody concentrations in patients with thrombosis, as seen by the significantly lower variability of IgG aCL and abeta2GP1 titres in patients with thrombosis when compared to non-thrombotic controls (p=0.0025 and p<0.0001, respectively). CONCLUSION Consistency of low titres of antiphospholipid antibody levels may be associated with a higher risk of thrombotic events overall.

Humoral Mechanisms of Atherogenesis

The concept that atherosclerosis is an autoimmune disease is no longer controversial. Attention has been paid to cellular immune response, but current research is now focused on the humoral component of this complex disease. Heat shock proteins, oxidized low‐density lipoproteins, β2‐glycoprotein 1, cardiolipins, and, more recently, high‐density lipoproteins have been considered to be autoantigens that play a part in atherogenesis. The characterization and understanding of the mechanisms associated with the presence of these antigens and their respective autoantibodies might contribute to elucidating the atherosclerotic process. In the near future, immune modulation might constitute a very effective therapy of atherosclerosis.

Extended Release-Niacin increases anti-ApoA-I antibodies that block the anti-oxidant effect of HDL-C: the EXPLORE clinical trial.

Aims Extended‐release niacin (ERN) is the most effective agent for increasing high‐density lipoprotein–cholesterol (HDL‐C). Having previously identified anti‐HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A‐I (aApoA‐I). Methods Twenty‐one patients older than 18 years, with HDL‐C ≤40 mg dl–1 (men) or ≤50 mg dl–1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12‐week periods, with 4 weeks of wash‐out before cross‐over. Primary outcome was change of paraoxonase‐1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA‐I antibodies. Clinical Trial Unique Identifier: EudraCT 2006–006889‐42. Results The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l–1, 95% confidence interval [CI] –9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL‐C levels (coefficient estimate 5.21 mg dl–1, 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl–1, 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl–1, 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA‐I antibodies (coefficient estimate 0.25 &mgr;g ml–1, 95% CI 0.09–0.40; P = 0.001). aApoA‐I titres at baseline were correlated with decreased PON activity. Conclusions The rise in HDL‐C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA‐I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.

Seronegative Wegener’s Granulomatosis Presenting as a Multiple Cranial Neuropathy

Wegener’s granulomatosis (WG) is an immune-mediated systemic vasculitis of unknown etiology that can be seen in almost any system. It classically affects the upper and lower airways, lungs and kidneys. Despite its possibility of generalization, neurological involvement is hardly seen. When it occurs, WG tends to affect the peripheral nervous system, often as sensory-motor polyneuropathy or mononeuritis multiplex. Involvement of cranial nerves is much less frequent, and the most affected is the optic nerve. Involvement of the central nervous system is even rarer but there are reports including cerebrovascular events, seizures, cerebritis, diabetes insipidus and pachymeningitis. In 1990, four criteria have been identified for the clinical diagnosis of WG by the American College of Rheumatology, which are still in effect and include upper airways inflammation, pulmonary nodules and microhematuria. A patient who meets at least 2 of the criteria may be diagnosed as having classical WG with a sensitivity of 88% and a specificity of 92%. Usually there is positivity for antineutrophil cytoplasmatic antigene (ANCA) but its absence does not exclude this diagnosis, especially when the clinical picture is highly suggestive. We present a case of palsy of the lower cranial nerves as the initial presentation of a seronegative WG.

Antibodies against HDL Components in Ischaemic Stroke and Coronary Artery Disease

Quantitative and qualitative defects of high-density lipoprotein (HDL) are important in atherogenesis. In this study, we investigated whether antibodies against HDL components had additional value to conventional cardiovascular risk factors for the diagnosis of ischaemic stroke (IS) and coronary artery disease (CAD). Cross-sectional study was conducted on 53 patients with IS, 51 with CAD and 55 healthy controls, and in vitro studies to validate findings of the clinical study. We determined serum immunoglobulin G (IgG) antibodies against HDL (aHDL), apolipoproteins (aApoA-I, aApoA-II and aApoC-I) and paraoxonase-1 (aPON1) as well as PON1 activity (PON1a), total antioxidant capacity and biomarkers of endothelial activation (serum nitric oxide metabolites, 3-nitrotyrosine, VCAM-1 and ICAM-1); in vitro assays tested the capacity of IgG aHDL purified from high titer patients to inhibit PON1a and to reverse protective effect of HDL on endothelial cells. IgG aHDL, aApoA-I and aPON1 were higher in IS and CAD than controls (p < 0.001), predicted negatively PON1a and positively VCAM-1 and ICAM-1. By adding IgG aHDL and aApoA-I to a traditional cardiovascular risk factors model for IS and by adding IgG aHDL in a similar model for CAD, we obtained better discrimination of IS and CAD from healthy controls. IgG aHDL purified from IS and CAD inhibited PON1a by 38% (p < 0.01) and abrogated the protective effect of HDL on VCAM-1 expression by 126% compared with non-specific human IgG (p < 0.001). IgG against HDL components interfere with the antioxidant and anti-inflammatory properties of HDL and may represent novel biomarkers for vascular disease that need to be investigated in prospective studies.

Oxidative/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial?

Abstract Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterised from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that through an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress through different agents with antioxidant properties have not translated into a sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far used to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future.

Pneumonia por Pneumocystis e citomegalovírus no doente VIH – A propósito de dois casos clínicos

Cytomegalovirus is capable of causing disease in immunocompromised patients. In people infected by the Human Immunodeficiency Virus (HIV) it becomes an important agent when there is advanced immunosupression. Its role as a pulmonary pathogen in these patients has been questioned. In the case of pneumocystosis the presence of Cytomegalovirus doesn’t seem to worsen prognosis, except in cases where corticosteroids are used. Authors present two cases of patients with HIV infection and advanced immunosupression who were admitted in the intensive care unit for respiratory failure. In both Pneumocystis jirovecii was isolated from