27 research outputs found
Cell death regulation during influenza A virus infection by matrix (M1) protein: a model of viral control over the cellular survival pathway
During early infection, viruses activate cellular stress-response proteins such as heat-shock proteins (Hsps) to counteract apoptosis, but later on, they modulate these proteins to stimulate apoptosis for efficient viral dissemination. Hsp70 has been attributed to modulate viral entry, transcription, nuclear translocation and virion formation. It also exerts its anti-apoptotic function by binding to apoptosis protease-activating factor 1 (Apaf-1) and disrupting apoptosome formation. Here, we show that influenza A virus can regulate the anti-apoptotic function of Hsp70 through viral protein M1 (matrix 1). M1 itself did not induce apoptosis, but enhanced the effects of apoptotic inducers. M1-small-interfering RNA inhibits virus-induced apoptosis in cells after either virus infection or overexpression of the M1 protein. M1 binds to Hsp70, which results in reduced interaction between Hsp70 and Apaf-1. In a cell-free system, the M1 protein mediates procaspase-9 activation induced by cytochrome c/deoxyadenosine triphosphate. A study involving deletion mutants confirmed the role of the C-terminus substrate-binding domain (EEVD) of Hsp70 and amino acids 128–165 of M1 for this association. The M1 mutants, which did not co-immunoprecipitate with Hsp70, failed to induce apoptosis. Overall, the study confirms the proapoptotic function of the M1 protein during influenza virus infection
Structural Basis for Apoptosis Inhibition by Epstein-Barr Virus BHRF1
Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes
MYOCARDITIS IN BETA-THALASSEMIA MAJOR - A CAUSE OF HEART-FAILURE
Background Although acute pericarditis is a common complication of
beta-thalassemia major, the prevalence and consequences of myocarditis
in this disease have not been investigated.
Methods and Results A prospective 5-year follow-up study was carried out
in all patients with beta-thalassemia major in whom the diagnosis of
acute infectious myocarditis could be established between 1977 and 1986.
A similar number of age- and sex-matched control subjects with
beta-thalassemia and normal left ventricular function and no evidence of
myocarditis were also followed for 5 years. Of 1048 patients with
beta-thalassemia major, 47 patients (age, 15 +/- 2.5 years) with
precordial chest pain were diagnosed as having acute infectious
myocarditis. Myocardial biopsy was diagnostic in 26 patients, borderline
in 14 patients, and nondiagnostic in 7 patients. Acute heart failure
with left ventricular dysfunction (left ventricular ejection fraction,
25+/-11%) developed in 11 patients (23.4%) with myocarditis, and 8 of
them died within 1 month to 1 year after diagnosis. Thirteen patients
with myocarditis (27.6%) developed chronic heart failure (left
ventricular ejection fraction, 26+/-13%) within 3+/-1.3 years, and 10
of them died within 8+/-3 months. Left ventricular systolic and
diastolic functions of the control subjects did not change significantly
during the 5-year period (left ventricular ejection fraction, 63+/-11%
versus 65+/-7%; P=NS). However, left ventricular restrictive
abnormalities (early diastole/late diastole, >2.2; deceleration time,
<110 milliseconds) combined with right ventricular dilatation (>30 mm
internal diameter) and right-sided heart failure developed in 3 patients
with extremely high mean serum ferritin levels. No significant
difference was found in mean levels of serum ferritin and pretransfusion
hemoglobin between patients with and those without myocarditis.
Conclusions In patients with beta-thalassemia, myocarditis appears to be
involved in the pathogenesis of left ventricular systolic dysfunction,
being the main cause of death. Iron overload appears to provoke left
ventricular restrictive abnormalities combined with right ventricular
enlargement and dysfunction
Central serotonergic responsiveness in neurocardiogenic syncope - A clomipramine test challenge
Background-Central serotonergic mechanisms appear to participate in the
pathogenesis of recurrent neurally mediated syncope. The aim of the
study was to investigate the responsiveness of the central serotonergic
system by measuring the prolactin and cortisol responses to intravenous
administration of the serotonin reuptake inhibitor clomipramine.
Methods and Results-Twenty subjects free of any medical treatment were
tested. Twelve had a history of recurrent syncopal attacks and positive
tilt test (patient group, mean age 47+/-18 years, 8 men); 8 subjects
without syncope and a negative tilt test result served as control
subjects (mean age 49+/-10 years, 5 men). Twenty-five milligrams of
clomipramine was administered intravenously within 15 minutes, and blood
samples were taken at 0, 15, 30, 45, and 60 minutes. Two days later, a
tilt test was performed at 60 degrees for 30 minutes and blood samples
were taken at 0, 10, 20, and 30 minutes. During the clomipramine
challenge, plasma prolactin levels increased in both groups. The levels
at 30 minutes were higher in the patient group compared with the control
group (17.3+/-7.2 vs 9.3+/-7.6 ng/mL, P=0.05). Similar results were
observed for cortisol at 30 minutes (172+/-15 vs 118+/-21 ng/mL P=0.04)
and at 45 minutes (189+/-20 vs 116+/-23 ng/mL, P=0.03). The tilt test
was positive in 8 (67%) out of 12 of the patient group and negative in
all control subjects. In the samples taken during the tilt test,
significant increases in prolactin and cortisol were observed only in
the subjects with positive tilt test results.
Conclusions-Patients with a history of neurocardiogenic syncope show a
higher responsiveness of the central serotonergic system to clomipramine
challenge. The results support the view that central serotonergic
mechanisms are involved in the pathophysiology of the syndrome
Hormonal responses during tilt-table test in neurally mediated syncope
The hormonal profile during tilt testing was examined in syncopal
patients. An increase in the growth hormones cortisol and prolactin was
found during syncope, suggesting an implication of central serotonergic
activation
Left atrial function and atrial natriuretic factor cyclic guanosine monophosphate changes in DDD and VVI pacing modes
Left atrial systolic function and the plasma of atrial natriuretic
factor (ANF) and cyclic guanosine monophosphate (cGMP) were investigated
as possible markers for the development of pacemaker syndrome during VVI
pacing. Patients who developed pacemaker syndrome during VVI pacing had
a significant decrease in left atrial emptying fraction and a
substantial increase in ANF and cGMP plasma levels
Provocation of neurocardiogenic syncope by clomipramine administration during the head-up tilt test in vasovagal syndrome
OBJECTIVES We sought to test the hypothesis that activation of the
serotonergic system in patients with vasovagal syndrome during the
head-up tilt test provokes syncope.
BACKGROUNDCentral serotonergic activation participates in the
pathogenesis of neurocardiogenic syncope. Drugs increasing serotonin
(5-HT) in the central nervous system have not been tested as drug
challenges during the head-up tilt test with clomipramine (Clom-HUT).
METHODS The serotonergic re-uptake inhibitor clomipramine was infused (5
mg in 5 min) at the start of Clom-HUT in 55 patients (mean age 40 +/- 17
years) with a positive history of recurrent neurocardiogenic syncope and
in 22 healthy control subjects (mean age 46 +/- 15 years). Blood samples
were taken at 0, 5, 10 and 20 min for estimation of plasma prolactin and
cortisol as neuroendocrine indicators of central serotonergic
responsitivity. All subjects had been previously tested with a basic 60
degrees head-up tilt test (B-HUT) for 30 min, and if negative,
isoproterenol infusion was given at the end of the test.
RESULTS Twenty-nine (53%) of the 55 patients and none of the 22 control
subjects had a positive result in the B-HUT. With Clom-HUT, the
proportion of patients who experienced a positive response increased to
80% (n = 44), although this happened to only one control subject.
Prolactin and cortisol plasma levels increased significantly in the
positive Clom-HUT patient group only.
CONCLUSIONS The results indicate an increased responsitivity of the
central serotonergic neural system in subjects with vasovagal syndrome,
the activation of which leads to sympathetic withdrawal. The use of
clomipramine infusion with the tilt test seems to considerably improve
its diagnostic value. (C) 2000 by the American College of Cardiology