PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of beta1-adrenergic preconditioning

OBJECTIVE: Using an isolated non-working rat heart model, this study investigated the mechanisms of pharmacological preconditioning (PC) induced by transient beta1-adrenoreceptor (beta1-AR) stimulation with xamoterol (XA). METHODS: After 6-hydroxydopamine (6-OHDA) pretreatment and a 20-min stabilization period, hearts were perfused at constant pressure for 20 min then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R, Ctrl); exposed to 0.01 microM XA for 5 min with or without 10 microM atenolol (ATE), a specific antagonist of beta1-AR, followed by a 15-min XA-free perfusion before I/R (PC, ATE-PC, respectively); treated during 20 min with either phosphoinositide (PI) 3-kinase inhibitors, LY-294002 (LY, 15 microM), or wortmaninn (WO, 0.1 microM); protein kinase C (PKC) inhibitor, GF-109203X (GF, 4 nM); or protein kinase A (PKA) inhibitor, H89 (H89, 1 microM), with an infusion starting 3 min before XA (LY-PC, WO-PC, GF-PC, and H89-PC, respectively). The main endpoints were the mean coronary flow (MCF), the left ventricular end-diastolic pressure (LVEDP), rate-pressure product (RPP), and creatine kinase (CK) release. RESULTS: XA induced an increase in the MCF after I/R (t 105 min) and a protective effect on the LVEDP, which were blocked by ATE and abolished with the different inhibitors. The transient increase in RPP following XA infusion was blocked by ATE and was not modified by the inhibitors except for H89. Recovery of RPP, measured 25 min after reperfusion, was improved by XA, blocked by ATE, and decreased with the different inhibitors. Fifteen minutes after the end of ischemia, CK release reached maximal values in all groups. XA provided significant protection whereas ATE and the four inhibitors suppressed XA-induced protection. CONCLUSION: The transient preischemic exposure to nanomolar concentrations of a beta1-AR agonist is protective against I/R. PI 3-kinase, PKC, and PKA are implicated in the trigger phase of PC. These observations were confirmed by Western blots.     

Non Hodgkin’s lymphoma presenting as neutropenia related to an IgM monoclonal anti-i antibody

A sixty-year old female was referred to the Internal Medicine Department for the treatment of a diffuse high-grade non Hodgkin’s lymphoma. She presented episodes of fever in a context of neutropenia (neutrophils 0.35 × 10⁹/l from 1.6 × 10⁹/l white blood cells). Hemoglobin level was 8.2 g/dl and platelets 132 × 10¹²/l. A monoclonal IgM-(kappa) protein (48 g/l) was detected in her serum. A direct antiglobulin test on the red cells proved positive with anti-C3d but not with anti-IgG antiglobulin, due to the presence of an IgM cold antibody with a serological anti-i specificity. The IgM antibody was found on the patient’s neutrophils as well as in her serum. This antibody recognized all neutrophils tested in conventional serological tests whatever the neutrophil phenotypes in systems NA, NB, and 5. It was demonstrated that it recognized the i antigen expressed on the neutrophils. These results suggest that a cold agglutinin anti-i might be responsible for neutropenia in some patients.     

Face recognition in schizophrenia: do individual and average ROCs tell the same story?

Introduction. Many studies have shown that recollection process is impaired in patients with schizophrenia, whereas familiarity is generally spared. However, in these studies, the Receiver Operating Characteristic (ROC) presented is average ROC likely to mask individual differences.

Methods. In the present study using a face-recognition task, we computed the individual ROC of patients with schizophrenia and control participants. Each group was divided into two subgroups on the basis of the type of recognition processes implemented: recognition based on familiarity only and recognition based on familiarity and recollection.

Results. The recognition performance of the schizophrenia patients was below that of the control participants only when recognition was based solely on familiarity. For the familiarity-alone patients, the score obtained on the Scale for the Assessment of Positive Symptoms (SAPS) was correlated with the variance of the old-face familiarity. For the familiarity-recollection patients, the score obtained on the Scale for the Assessment of Negative Symptoms (SANS) was correlated with the decision criterion and with the old-face recollection probability.

Conclusions. These results show that one cannot ascribe the impaired recognition observed in patients with schizophrenia to a recollection deficit alone. These results show that individual ROC can be used to distinguish between subtypes of schizophrenia and could serve as a basis for setting up specific cognitive remediation therapy for individuals with schizophrenia.     

Chronic restraint-induced stress has little modifying effect on radiation hematopoietic toxicity in mice

Both radiation and stresses cause detrimental effects on humans. Besides possible health effects resulting directly from radiation exposure, the nuclear plant accident is a cause of social psychological stresses. A recent study showed that chronic restraint-induced stresses (CRIS) attenuated Trp53 functions and increased carcinogenesis susceptibility of Trp53-heterozygous mice to total-body X-irradiation (TBXI), having a big impact on the academic world and a sensational effect on the public, especially the residents living in radioactively contaminated areas. It is important to investigate the possible modification effects from CRIS on radiation-induced health consequences in Trp53 wild-type (Trp53wt) animals. Prior to a carcinogenesis study, effects of TBXI on the hematopoietic system under CRIS were investigated in terms of hematological abnormality in the peripheral blood and residual damage in the bone marrow erythrocytes using a mouse restraint model. Five-week-old male Trp53wt C57BL/6J mice were restrained 6 h per day for 28 consecutive days, and TBXI (4 Gy) was given on the 8th day. Results showed that CRIS alone induced a marked decrease in the red blood cell (RBC) and the white blood cell (WBC) count, while TBXI caused significantly lower counts of RBCs, WBCs and blood platelets, and a lower concentration of hemoglobin regardless of CRIS. CRIS alone did not show any significant effect on erythrocyte proliferation and on induction of micronucleated erythrocytes, whereas TBXI markedly inhibited erythrocyte proliferation and induced a significant increase in the incidences of micronucleated erythrocytes, regardless of CRIS. These findings suggest that CRIS does not have a significant impact on radiation-induced detrimental effects on the hematopoietic system in Trp53wt mice.     

Functional Electrical Stimulation—A New Therapeutic Approach to Enhance Exercise Intensity in Chronic Obstructive Pulmonary Disease Patients: A Randomized,Controlled Crossover Trial

Objective

To evaluate the effect of quadriceps functional electrical stimulation (FES)-cycling on exertional oxygen uptake ($\dot{\text{V}}$o₂) compared with placebo FES-cycling in patients with chronic obstructive pulmonary disease (COPD).

Infection-related ventilator-associated complications in ICU patients colonised with extended-spectrum β-lactamase-producing Enterobacteriaceae

Purpose

To investigate the clinical significance of infection-related ventilator-associated complications (IVAC) and their impact on carbapenem consumption in mechanically ventilated (MV) patients colonised with extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBLE).

Methods

Inception cohort study from the French prospective multicenter OUTCOMEREA database (17 ICUs, 1997–2015) including all ESBLE carriers (systematic rectal swabbing at admission then weekly and/or urinary or superficial surgical site colonisation) with MV duration?>?48 h and?≥?1 episode of IVAC after carriage documentation. All ICU-acquired infections were microbiologically documented.

Results

The 318 enrolled ESBLE carriers (median age 68 years; males 67%; medical admission 68%; imported carriage 53%) experienced a total of 576 IVAC comprising 361 episodes (63%) without documented infection, 124 (21%) related to infections other than ventilator-associated pneumonia (VAP), 73 (13%) related to non-ESBLE VAP and 18 (3%) related to ESBLE VAP. Overall, ESBLE infections accounted for only 43 episodes (7%). Carbapenem exposure within the preceding 3 days was the sole independent predictor of ESBLE infection as the causative event of IVAC, with a protective effect (adjusted odds ratio 0.2, 95% confidence interval 0.05–0.6; P?<?0.01). Carbapenems were initiated in 9% of IVAC without infection, 15% of IVAC related to non-VAP infections, 42% of IVAC related to non-ESBLE VAP, and 56% of IVAC related to ESBLE VAP (ESBLE VAP versus non-ESBLE VAP: P?=?0.43).

Conclusions

IVAC in ESBLE carriers mostly reflect noninfectious events but act as a strong driver of empirical carbapenem consumption. ESBLE infections are scarce yet hard to predict, strengthening the need for novel diagnostic approaches and carbapenem-sparing alternatives.