Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Distribution of glial cell line-derived neurotrophic factor receptor alpha-1 in the brain of adult zebrafish.

Abstract Glial cell line-derived neurotrophic factor (GDNF) is a potent trophic factor for several types of neurons in the central and peripheral nervous systems. The biological activity of GDNF is mediated by a multicomponent receptor complex that includes a common transmembrane signaling component (the rearranged during transfection (RET) proto-oncogene product, a tyrosine kinase receptor) as well as a GDNF family receptor alpha (GFRalpha) subunit, a high-affinity glycosyl phosphatidylinositol (GPI)-linked binding element. Among the four known GFRalpha subunits, GFRalpha1 preferentially binds to GDNF. In zebrafish (Danio rerio) embryos, the expression of the GFRalpha1a and GFRalpha1b genes has been shown in primary motor neurons, the kidney, and the enteric nervous system. To examine the activity of GFRalpha in the adult brain of a lower vertebrate, we have investigated the localization of GFRalpha1a and GFRalpha1b mRNA and the GFRalpha1 protein in zebrafish. GFRalpha1a and GFRalpha1b transcripts were observed in brain extracts by reverse transcription-polymerase chain reaction. Whole-mount in-situ hybridization experiments revealed a wide distribution of GFRalpha1a and GFRalpha1b mRNAs in various regions of the adult zebrafish brain. These included the olfactory bulbs, dorsal and ventral telencephalic area (telencephalon), preoptic area, dorsal and ventral thalamus, posterior tuberculum and hypothalamus (diencephalon), optic tectum (mesencephalon), cerebellum, and medulla oblongata (rhombencephalon). Finally, expression patterns of the GFRalpha1 protein, detected immunohistochemically, correlated well with the mRNA expression and provided further insights into translational activity at the neuroanatomical level. In conclusion, the current study demonstrated that the presence of GFRalpha1 persists beyond the embryonic development of the zebrafish brain and, together with the GDNF ligand, is probably implicated in the brain physiology of an adult teleost fish. PMID: 20572899 [PubMed - indexed for MEDLINE

PROCEEDINGS OF THE 33rd NATIONAL CONGRESS OF THE ITALIAN SOCIETY OF HISTOCHEMISTRY

Ulcerative colitis (UC) is an inflammatory bowel disease associated with dysfunctional colonic motility which is responsible for abdominal pain and diarrhoea. These changes may be mediated by prostaglandins which are increased in this condition. Increased expression of the constitutive and inducible isoform of cyclo-oxygenases (COX-1 and COX-2, respectively) has been found in active inflammatory bowel disease although their cellular distribution remains uncertain at the level of the colonic neuromuscular compartment. Aim. To evaluate the cellular distribution of COX-1 and COX-2 in the neuromuscular tissues from patients with UC. Patients and Methods. Using immunohistochemistry, COX-1 and COX-2 expression was evaluated in 8 full-thickness colectomy specimens from patients with UC who had failed medical therapy. Histologically normal colon full-thickness specimens was obtained from 10 patients having resection for colorectal neoplasia and evaluated as above. Results. All specimens expressed both COX isoforms although with different cellular distribution and intensity degrees. In control tissues COX-1 was detected in myenteric neurons and circular layer myocytes; COX-2 was expressed mainly in longitudinal layer with little immunoreactivity in neurons. Although a pronounced cell depletion was observed in myenteric ganglia in all inflamed specimens, neurons maintained appreciable COX-1 labelling; COX-2 was significantly upregulated in UC, being localized in cells infiltrating the myenteric plexus and both muscle layers. Conclusions. These findings provide the first evidence that COX-1 and COX-2 are expressed in myenteric neural cells and muscle layers of colon in UC and may contribute to the colonic dysmotilty associated with this pathological condition

Investigating attachment, caregiving, and mental health: a model of maternal-fetal relationships

Background Maternal-fetal relationships have been associated with psychosocial outcomes for women and children, but there has been a lack of conceptual clarity about the nature of the maternal relationship with the unborn child, and inconsistent findings assessing its predictors. We proposed and tested a model whereby maternal-fetal relationship quality was predicted by factors relating to the quality of the couple relationship and psychological health. We hypothesized that the contribution of individual differences in romantic attachment shown in past research would be mediated by romantic caregiving responsiveness, as maternal-fetal relationships reflect the beginnings of the caregiving system. Methods 258 women in pregnancy (13, 23, and 33-weeks gestation) completed online measures of attachment to partner, caregiving responsiveness to partner, mental health, and thoughts about their unborn baby. Structural equation modeling was used to test a model of maternal-fetal relationships. Results Maternal-fetal relationship quality was higher for women at 23-weeks than 13-weeks gestation. Women in first pregnancies had higher self-reported scores of psychological functioning and quality of maternal-fetal relationships than women in subsequent pregnancies. Structural equation models indicated that the quality of the maternal-fetal relationship was best predicted by romantic caregiving responsiveness to partner and women's own psychological health, and that the association between adult romantic attachment avoidance and maternal-fetal relationships was fully mediated by caregiving responsiveness to partner, even after controlling for other factors. These data support the hypothesis that maternal-fetal relationships better reflect the operation of the caregiving system than the care-seeking (i.e., attachment) system. Conclusions Models of maternal-fetal relationships and interventions with couples should consider the role of caregiving styles of mothers to partners and the relationship between expectant parents alongside other known predictors, particularly psychological health