Determinants of left ventricular systolic function recovery after an acute coronary syndrome.

INTRODUCTION: Ischemic heart disease is a major cause of heart failure in western societies. However, the factors that may influence left ventricular function (LVF) recovery after an acute coronary syndrome (ACS) are still unclear. OBJECTIVE: To identify variables that may influence LVF evolution one year after ACS. METHODS: 104 patients hospitalized with ACS between 7/1/2001 and 12/31/2002 and with systolic dysfunction--defined as an echocardiographic ejection fraction (EF) < or = 45%--were randomly allocated to a planned coronary follow-up program (FUP) or a general cardiology clinic (GC); patients from both groups were also randomly referred to a structured cardiac rehabilitation program (CRP). EF was re-assessed at one year. We compared differences between patients who recovered left ventricular function (EF > 45%; group 1) and those who did not (group 2). RESULTS: One year after discharge, 44.2% of the patients had recovered function. There were no significant differences between the groups in gender (77.7 vs. 76.5% male), age (56 vs. 59 years), hypertension, diabetes, dyslipidemia, smoking habits or family history. A previous history of cardiovascular events was more frequent in group 2 (11.1% vs. 35.3%, p = 0.03). Cardiac catheterization was performed before discharge in 88.8% and 88.2% in groups 1 and 2 respectively (p = NS); no differences were found in coronary anatomy between the two groups. Angioplasty was performed in 54.2% in group 1 and 50% in group 2 (p = NS). There were no differences in the use of angiotensin-converting enzyme inhibitors (83.3% vs. 87.5%), beta-blockers (87.5% vs. 87.5%), nitrates (37.5% vs. 33.3%), aspirin (95.8% vs. 95.8%), statins (79.1% vs. 75%) or diuretics (20.8% vs. 45.8%). There was no significant difference in LVF recovery between patients randomized to FUP or GC (38.5% vs. 54.5%). 87.5% of patients who completed the CRP had normal EF at one year compared to 32.7% of patients not referred to the program (p = 0.009). Although EF improved in both groups, this improvement was greater in patients who completed a CRP (EF 8% vs. 5%, p = 0.003). CONCLUSION: A previous cardiovascular event and completion of a CRP were the only variables that influenced LVF recovery. Thus, enrollment in a CRP, in addition to standard therapy, could be an important therapeutic measure in patients with systolic dysfunction after ACS; our data suggest that these programs should be more widely used.     

Reduced oligomeric and vascular amyloid-β following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine

Immunization with amyloid-β (Aβ) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Aβ. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Aβ in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Aβ and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Aβ alone. Moreover, use of Aβ with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Aβ in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Aβ. These antibodies decreased plaque load by as much as 36 ± 8% and insoluble Aβ42 levels by 56 ± 3%. Clearance of Aβ was most effective when antibodies were directed against N-terminal epitopes of Aβ. Moreover, immunization reduced CAA by as much as 69 ± 12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Aβ trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Aβ alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.     

Being on hemodialysis during the COVID‐19 outbreak: A mixed‐methods’ study exploring the impacts on dialysis adequacy,analytical data,and patients’ experiences

For individuals with end‐stage renal disease (ESRD), the novel coronavirus can present several additional challenges in disease self‐management. This study aimed to explore the impacts of the COVID‐19 pandemic in non‐COVID‐19 patients with ESRD undergoing in‐center hemodialysis (HD). A mixed‐methods study was conducted with a purposive sample recruited from one dialysis unit in Portugal. Quantitative data were collected retrospectively from patients' medical records from February 2020 (T1—before the outbreak) and from April 2020 (T2—during lockdown). Semi‐structured interviews were conducted with 20 patients (66.9 ± 11.9 years old) undergoing HD for an average of 46.1 months (±39.5) in April 2020. Overall results suggested that dialysis adequacy and serum albumin levels decreased significantly at T2, while phosphorus levels increased. The findings from thematic analysis suggested several psychosocial negative impacts and impacts on disease and treatment‐related health behaviors (eg, difficulties managing dietary restrictions during the lockdown and diminished physical activity), which can partially explain these quantitative results. However, some patients were also able to find positive impacts in this experience and problem‐focused and emotional strategies were identified to cope with the demands of COVID‐19. Several recommendations have been made to mitigate patients’ emotional, relational, and educational unmet needs during the current pandemic and in the event of new outbreaks.     

Imaging of cAMP-specific phosphodiesterase-IV: comparison of [11C]rolipram and [11C]Ro 20-1724 in rats

The phosphodiesterase type IV (PDEIV) family of enzymes contributes to the metabolism of cAMP formed by the stimulation of beta-adrenergic, A2-adenosine, and H2-histamine receptors in the brain. Disturbances in cAMP-mediated signaling have been implicated in several neuropsychiatric disorders, and there is evidence that increasing cAMP levels through PDEIV inhibition improves the symptoms of these disorders. In the present study, the selective PDEIV inhibitors rolipram and Ro 20-1724, labeled with C-11, were evaluated in vivo in rats, as potential radioligands for imaging PDEIV enzymes with positron emission tomography (PET). Biodistribution experiments revealed a greater than threefold increased regional brain retention of [11C]rolipram as compared to [11C]Ro 20-1724. [nC]Rolipram uptake was higher in rat brain areas (e.g., cortical regions and olfactory system) showing higher expression of PDEIV enzymes, as determined previously using [3H]rolipram autoradiography or molecular genetic techniques. Binding of [n1C]rolipram and [11C]Ro 20-1724 was specific, since coadministration of high doses of unlabeled rolipram (10 mg/Kg, i.v.) or Ro 20-1724 (30 mg/Kg with [11C]rolipram and 10 mg/Kg with [11C]Ro 20-1724, i.v.) reduced radioactivity uptake in brain regions. Pretreatment with high doses of the PDEI selective inhibitor vinpocetine (10 mg/Kg, i.p., 15 min prior), or the noradrenaline reuptake inhibitor desipramine (10 mg/Kg, i.p., 30 min prior), or coinjection with the adenylyl cyclase activator forskolin (6.5 or 15 mg/Kg, i.v.), did not inhibit [11C]rolipram uptake in brain areas, suggesting binding selectivity for PDEIV enzymes. We conclude that [11C]rolipram, but not [11C]Ro 20-1724, is a promising radioligand for imaging the PDEIV enzymes with PET.     

Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production.     

Does processing style affect recall of the Rey-Osterrieth or Taylor complex figures?

This study investigated the effects of visual vs. verbal processing style preferences on immediate recall accuracy for the Rey-Osterrieth and Taylor Complex Figure Tests. Undergraduates were classified as visualizers or verbalizers and asked to copy either the Rey-Osterrieth or Taylor figure and then draw it from memory. A subset of subjects reported the strategy they used to reproduce the figure. Visualizers showed better reproduction accuracy than verbalizers for the Rey-Osterrieth test, and for this test approximately 80% of verbalizers as well as visualizers reported using a visual strategy. For the Taylor, no effect of processing style was obtained, and close to half of the verbalizers (43%) reported using their preferred verbal strategy, while 82% of the visualizers used a visual strategy. These results suggest that a general preference for thinking "in images" is important for predicting visual memory accuracy only on tests such as the Rey-Osterrieth which do not lend themselves easily to a verbal strategy. In contrast, for the Taylor test, deficits to the visual imagery system may be circumvented and obscured by the verbalizers' use of verbal recall strategies. Thus, in test batteries, the Rey-Osterrieth and the Taylor Tests should not be used interchangeably.     

Induction of partial protection in mice after oral administration of Lactococcus lactis producing Brucella abortus L7/L12 antigen.

The Brucella abortus ribosomal protein L7/L12 is an immunodominant antigen and an interesting candidate for the development of oral live vaccines against brucellosis. Here, a recombinant Lactococcus lactis strain producing L7/L12 under the control of nisin inducible promoter was orally administered to BALB/c mice. Significant levels of anti-L7/L12 specific IgA detected in feces revealed an induced local humoral immune response. However, serum analysis did not reveal any anti-L7/L12 antibodies suggesting the absence of a systemic response. Nevertheless, the vaccinated mice showed a partial protective immunity against B. abortus virulent strain (S2308) challenged by intraperitoneal inoculation.     

Imaging the 5-HT(1A) receptors with PET: WAY-100635 and analogues

This paper summarizes our work on WAY-100635 and analogues, labeled either with carbon-11 or fluorine-18, as potential radioligands for the 5-hydroxytryptamine(1A) (5-HT(1A)) neuroreceptors. Other facets of our work include: (1) human studies with [O-methyl-(11)C]WAY-100634, the major radioactive metabolite of [O-methyl-(11)C]WAY-100635, and with [(11)C]CPC 222; (2) use of a human liver metabolism model to screen in vitro potential metabolic problems in humans; (3) modification of the "dry method" to prepare [carbonyl-(11)C]WAY-100635; and (4) validation studies in humans with [carbonyl-(11)C]WAY-100635.