Changes in Neuron-Specific Enolase are More Suitable Than Its Absolute Serum Levels for the Prediction of Neurologic Outcome in Hypothermia-Treated Patients with Out-of-Hospital Cardiac Arrest

Background

To determine neurologic outcome in patients with out-of-hospital cardiac arrest (OHCA) and treatment with mild therapeutic hypothermia (MTH).

Methods

Seventy-three consecutive OHCA patients treated with MTH were retrospectively analyzed. Serum neuron-specific enolase (NSE) was measured 24, 48, and 72 h after admission. In patients with no motor response 48 h after termination of analgosedation (n = 40), clinical neurological examination and evoked potentials (EPs) were determined. Neurological outcome was assessed after 2 months based on the cerebral performance categories (CPC), and categorized as good (CPC 1–3) or poor (CPC 4 and 5).

Results

Forty-three patients had a CPC score of 1–3 and 30 patients had a CPC 4–5. The best predictive value for poor neurologic outcome was an increase of NSE by ≥4.3 ng/mL between day 1 and day 2 (sensitivity 80 %, specificity 100 %, positive predictive value (PPV) 100 %, negative predictive value 86 %). Absolute NSE values were less reliable in the prediction of poor outcome with the highest sensitivity (88 %) and specificity (95 %) if values reached ≥36.3 ng/mL on day 3. Somatosensory EPs (SSEPs) showed a specificity of 100 % and PPV of 100 %; however, sensitivity for evoked potentials was low (29 %). Intriguingly, two initially comatose patients with excessive NSE values (24 h NSE: 101 and 256 ng/mL, and 48 h NSE: 93 and 110 ng/mL, respectively) had physiological SSEPs and regained a CPC score of 1.

Conclusion

In patients treated with MTH after OHCA changes in NSE are more suitable than its absolute serum levels for the prediction of poor neurologic outcome. Since unequivocal prediction of poor neurologic outcome is of utmost importance in these patients the decision to limit therapy must be based on several prediction tools with the highest PPV and specificity including SSEPs.     

Coffee,caffeine, and risk of completed suicide: Results from three prospective cohorts of American adults

Objective.To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of US men and women. Methods. We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988–2008), 73,820 women in the Nurses’ Health Study (NHS, 1992–2008), and 91,005 women in the NHS II (1993–2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. Results. We documented 277 deaths from suicide. Compared to those consuming ≤ 1 cup/week of caffeinated coffee (< 8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38–0.78) for those consuming 2–3 cups/day and 0.47 (0.27–0.81) for those consuming ≥ 4 cups/day (P trend < 0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63–0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63–0.93) for each increment of 300 mg/day of caffeine. Conclusions. These results from three large cohorts support an association between caffeine consumption and lower risk of suicide.     

PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells

Background

Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells.

Methods and results

Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers.

Conclusion

Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.     

Comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies

Phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) were strongly correlated with the presence of lupus anticoagulant showing a high specificity for the diagnosis of antiphospholipid syndrome. However, the main criticism for the clinical applicability of aPS/PT testing is the lack of reproducibility of the results among laboratories. In this study, we measured IgG and IgM aPS/PT using our original in-house enzyme-linked immunosorbent assays (ELISA) and commercial ELISA kits to assess the assay performance and to evaluate the accuracy of aPS/PT results. The study included 111 plasma samples collected from patients and stored at our laboratory for aPS/PT assessment. Sixty-one samples were tested for IgG aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite? aPS/PT IgG ELISA kit (INOVA Diagnostics, Inc., USA). Fifty samples were evaluated for IgM aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite? aPS/PT IgM ELISA kit (INOVA Diagnostics). Ninety-eight percent of samples yielded concordant results for IgG aPS/PT and 82 % for IgM aPS/PT. There was an excellent agreement between the IgG aPS/PT assays (Cohen κ = 0.962) and moderate agreement between the IgM aPS/PT assays (κ = 0.597). Statistically significant correlations in the aPS/PT results were obtained from both IgG and IgM aPS/PT assays (r = 0.749, r = 0.622, p < 0.001, respectively). In conclusion, IgG and IgM detection by ELISA is accurate. The performance of aPS/PT is reliable, and concordant results can be obtained using different ELISA methods.     

The past and future of CD33 as therapeutic target in acute myeloid leukemia

CD33 is a myeloid differentiation antigen with endocytic properties. It is broadly expressed on acute myeloid leukemia (AML) blasts and, possibly, some leukemic stem cells and has therefore been exploited as target for therapeutic antibodies for many years. The improved survival seen in many patients when the antibody-drug conjugate, gemtuzumab ozogamicin, is added to conventional chemotherapy validates this approach. However, many attempts with unconjugated or conjugated antibodies have been unsuccessful, highlighting the challenges of targeting CD33 in AML. With the development of improved immunoconjugates and CD33-directed strategies that harness immune effector cells, therapeutics with enhanced efficacy may soon become available. Toxic effects on normal hematopoietic cells may increase in parallel with this increased efficacy and demand new supportive care measures, including possibly rescue with donor cells, to minimize morbidity and mortality from drug-induced cytopenias and to optimize treatment outcomes with these agents in patients with AML.     

The efficacy and safety of venetoclax therapy in elderly patients with relapsed,refractory chronic lymphocytic leukaemia

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.