Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how?

Plasma provided by COVID-19 convalescent patients may provide therapeutic relief as the number of COVID-19 cases escalates steeply worldwide. Prior findings in various viral respiratory diseases including SARS-CoV-related pneumonia suggest that convalescent plasma can reduce mortality, although formal proof of efficacy is still lacking. By reducing viral spread early on, such an approach may possibly downplay subsequent immunopathology. Identifying, collecting, qualifying and preparing plasma from convalescent patients with adequate SARS-CoV-2-neutralizing Ab titres in an acute crisis setting may be challenging, although well within the remit of most blood establishments. Careful clinical evaluation should allow to quickly establish whether such passive immunotherapy, administered at early phases of the disease in patients at high risk of deleterious evolution, may reduce the frequency of patient deterioration, and thereby COVID-19 mortality.     

Episodic memory bias and the symptoms of schizophrenia.

Much of the research on episodic memory in schizophrenia spectrum disorders has focused on memory deficits and how they relate to clinical measures such as outcome. Memory bias refers to the modulatory influence that state or trait psychopathology may exert on memory performance for specific categories of stimuli, often emotional in nature. For example, subjects suffering from depression frequently have better memory for negative stimuli than for neutral or positive ones. This dimension of memory function has received only scant attention in schizophrenia research but could provide fresh new insights into the relation between symptoms and neurocognition. This paper reviews the studies that have explored memory biases in individuals with schizophrenia. With respect to positive symptoms, we examine studies that have explored the link between persecutory delusions and memory bias for threatening information and between psychosis and a memory bias toward external source memory. Although relatively few studies have examined negative symptoms, we also review preliminary evidence indicating that flat affect and anhedonia may lead to some specific emotional memory biases. Finally, we present recent findings from our group delineating the relation between emotional valence for faces and memory bias toward novelty and familiarity, both in schizophrenia patients and in healthy control subjects. A better understanding of the biasing effects of psychopathology on memory in schizophrenia (but also on other cognitive functions, such as attention, attribution, and so forth) may provide a stronger association between positive and negative symptoms and memory function. Memory measures sensitive to such biases may turn out to be stronger predictors of clinical and functional outcome.     

Generalization of Frequency Discrimination Learning Across Frequencies and Ears: Implications for Underlying Neural Mechanisms in Humans

Frequency discrimination thresholds (FDTs) at 750, 1500, 3000, and 6000 Hz were measured in 32 normal-hearing listeners before and after each listener practiced the task for 12 h at one of the above frequencies using a single ear. Marked improvements in thresholds taking place over several hours were observed during the frequency- and ear-specific training period. Comparisons between pre- and posttraining thresholds showed large improvements at the trained frequency, but also at other frequencies. The improvements were initially slightly—but significantly—larger at the trained frequency than at untrained frequencies. However, this trained-frequency advantage disappeared rapidly during the course of the two-hour multifrequency posttraining session, suggesting rapid relearning or learning generalization across frequencies. In contrast, no significant ear specificity was found, not even at early stages of the posttraining session. These findings add to earlier results suggesting that, in humans, frequency discrimination learning is only weakly frequency-specific, and they reveal that a complete generalization across frequencies can occur rapidly with little retraining at the initially untrained frequencies. Implications regarding underlying mechanisms are discussed.     

Effects of Intermittent Femoral Nerve Injections of Bupivacaine, Levobupivacaine, and Ropivacaine on Mitochondrial Energy Metabolism and Intracellular Calcium Homeostasis in Rat Psoas Muscle

Background: Long-acting local anesthetics cause muscle damage. Moreover, long-acting local anesthetics act as uncoupler of oxidative phosphorylation in isolated mitochondria and enhance sarcoplasmic reticulum Ca2+ release. The aim of the study was to evaluate effects of perineural injections of local anesthetics on mitochondrial energetic metabolism and intracellular calcium homeostasis in vivo.

Methods: Femoral nerve block catheters were inserted in adult male Wistar rats. Rats were randomized and received seven injections (1 ml/kg) of bupivacaine, levobupivacaine, ropivacaine, or isotonic saline at 8-h intervals. Rats were killed 8 h after the last injection. Psoas muscle was quickly dissected from next to the femoral nerve. Local anesthetic concentrations in muscle were determined. Oxidative capacity was measured in saponin-skinned fibers. Oxygen consumption rates were measured, and mitochondrial adenosine triphosphate synthesis rate was determined. Enzymatic activities of mitochondrial respiratory chain complexes were evaluated. Local calcium release events (calcium sparks) were analyzed as well as sarcoplasmic reticulum calcium content in saponin-skinned fibers.

Results: Eight hours after the last injection, psoas muscle concentration of local anesthetics was less than 0.3 [mu]g/g tissue. Adenosine triphosphate synthesis and adenosine triphosphate-to-oxygen ratio were significantly decreased in the muscle of rats treated with local anesthetics. A global decrease (around 50%) in all of the enzyme activities of the respiratory chain was observed. Levobupivacaine increased the amplitude and frequency of the calcium sparks, whereas lower sarcoplasmic reticulum calcium content was shown.     

Preliminary experience with inhaled milrinone in cardiac surgery

Background: Inhaled administration of milrinone reduces pulmonary artery pressure. Pulmonary hypertension (PH) and right heart failure are associated with difficult separation from cardiopulmonary bypass (CPB). Therefore, inhaled milrinone could facilitate separation from CPB. Objective: To determine the impact and timing of administration of inhaled milrinone. Methods: A retrospective analysis of our experience on high-risk patients receiving inhaled milrinone was conducted to evaluate the postoperative course after administration of the drug. Results: Seventy-three patients received inhaled milrinone from June 2002 to February 2005. Mean age was 64 ± 13 years, with a mean preoperative Parsonnet score of 27 ± 14. Inhaled milrinone (5 mg) was administered before (n = 30) or after (n = 40) CPB, three patients had off-pump procedures and were excluded. CPB time was 145 ± 78 min with cross-clamping times of 91 ± 56 min without any significant difference between groups. Fifty-four patients (74%) had difficult separation from CPB, 14 patients (19%) required an intra-aortic balloon pump and 10 patients (14%) needed emergency reinitiation of CPB for hemodynamic instability. Ten patients died in the perioperative period (13.7%). Patients receiving inhaled milrinone prior to CPB initiation had a lowering pulmonary artery pressure after CPB (p < .01) and had less emergency reinitiation of CPB after weaning (3% vs 23%, p = .02) as compared to those with administration after CPB. No detectable side effects were directly linked to the administration of the drug. Conclusion: In this high-risk cohort, use of inhaled milrinone was well tolerated. Administration before initiation of CPB could help weaning from CPB.     

Intrahepatic cytokine profile in renal-transplant patients infected by hepatitis C virus

In order to examine the immunopathogenesis of hepatitis C virus (HCV)-related liver injury in renal-transplant patients, intra-hepatic cytokine profiles were examined in 38 liver biopsies from 38 patients by measuring messenger RNA (mRNA) concentrations by a real-time PCR method of a Th1 cytokine (i.e., interferon (IFN)-gamma), a Th2 cytokines (i.e., interleukine (IL)-10), a proinflammatory cytokine (i.e., IL-8), and a potent fibrogenic factor (transforming growth factor [TGF]-beta). There was no significant difference in TGF-beta, IFN-gamma, IL-10, or IL-8 levels of expression according to liver-activity grade, liver-fibrosis stage, the concentration of HCV RNA at liver biopsies, or the HCV genotype. However, IFN-gamma/beta-actin mRNA concentration was higher than the IL-10/beta-actin mRNA concentration in patients with F3 Metavir score. Median IFN-gamma/beta-actin mRNA concentration tended to be higher in patients with A3 and A4 Metavir activity grades compared with those with A0 and A1 activity grades. There was a significant correlation between the duration of HCV infection and both TGF-beta/beta-actin (r(2)=0.19, P=0.04) and IL-8/beta-actin mRNA concentrations (r(2)=0.19, P=0.03). IFN-gamma/beta-actin mRNA concentration also increased according to the duration of HCV (r(2)=0.19, P=0.07). Finally, there was a significant correlation between the duration of HCV infection and liver fibrosis stage (r(2)=0.17, P=0.045). Intrahepatic Th1 cytokine profile seems to be predominant in patients with extensive fibrosis and activity scores, suggesting that it might be responsible for liver injury in renal transplant patients.     

Differences in virulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men

Differences in the presence of nine urovirulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men have been studied. Hemolysin and necrotizing factor type 1 occur significantly more frequently among isolates causing prostatitis than among those causing cystitis (P < 0.0001) or pyelonephritis (P < 0.005). Moreover, the papGIII gene occurred more frequently in E. coli isolates associated with prostatitis (27%) than in those associated with pyelonephritis (9%) (P < 0.05). Genes encoding aerobactin and PapC occurred significantly less frequently in isolates causing cystitis than in those causing prostatitis (P < 0.01 and P < 0.0001, respectively) and pyelonephritis (P < 0.01 and P < 0.0001, respectively). No differences in the presence of Sat or type 1 fimbriae were found. Finally, AAFII and Bfp fimbriae are no longer considered uropathogenic virulence factors since they were not found in any of the strains analyzed. Overall, the results showed that clinical isolates producing prostatitis need greater virulence than isolates producing pyelonephritis in women or, in particular, cystitis in women (P < 0.05). Overall, the results suggest that clinical isolates producing prostatitis are more virulent that those producing pyelonephritis or cystitis in women.     

Amantadine therapy in renal transplant patients with hepatitis C virus infection.

BACKGROUND: To date, there is no safe and efficient treatment of hepatitis C virus (HCV) infection after renal transplantation. Recently, there were encouraging reports after using amantadine in HCV-positive immunocompetent patients. OBJECTIVES: In an open pilot study, we evaluated the efficacy and the safety of amantadine monotherapy in 8 HCV positive renal-transplant patients with chronic active hepatitis and increased alanine aminotransferase (ALT) levels. RESULTS: After 6 months of amantadine therapy (200 mg per day), there were no decrease in HCV viremia (5.87 +/- 0.37 log copies/ml at M6 versus 5.71 +/- 0.5 log copies/ml at baseline; P > 0.05). However, we found a significant decrease in ALT activity (71 +/- 17 IU/l at M6 versus 100 +/- 9 IU/l at baseline; P = 0.04), whereas the decrease in aspartate aminotransferase activity did not reach statistical significance. There were no significant changes in liver histology. The clinical and biological tolerance was very good. Finally, there were a significant decrease in cyclosporine A whole blood trough levels during therapy. CONCLUSIONS: Our study is the first one to demonstrate that amantadine monotherapy lack of efficacy in HCV renal-transplant patients. It is able to improve liver enzymes but it has no impact neither upon HCV viremia nor upon liver histology.     

A gene signature of inhibitory MHC receptors identifies a BDCA3(+) subset of IL-10-induced dendritic cells with reduced allostimulatory capacity in vitro

Dendritic cells (DC) are crucial gatekeepers in regulating immunity. Whereas mature immunostimulatory myeloid DC (DC(ims)) potently promote immune responses, IL-10-induced myeloid DC (DC-IL-10) counteract T cell activation. To elucidate the molecular repertoire by which DC-IL-10 secure reduced T cell activation, comparative gene expression profiling was done using Affymetrix U133A microarrays. Among the genes overexpressed in DC-IL-10, eight immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing inhibitory molecules (ILT2, ILT3, ILT4, ILT5, DCIR, PILRA, FcgammaRIIB, SLAM) were found. Phenotypic analysis of DC-IL-10 defined an ILT(high) DC subset further characterized by expression of CD14, TLR2, DC-SIGN, and CD123 and the lack of lymphocyte, monocyte/macrophage, and plasmacytoid DC markers such as CD3, CD8, and CD68. A unique feature of the ILT(high) DC subset was expression of the novel DC marker BDCA3, which was not detected on monocytes, immature DC, DC(ims), or ILT(low) DC-IL-10. While the allogeneic T cell proliferation induced by the entire DC-IL-10 population was approximately 30% of that stimulated by DC(ims), allogeneic MLR responses driven by the ILT(high) DC subset were reduced to 8% of the allostimulatory capacity of DC(ims), although secretion of the inhibitory cytokine IL-10 and other Th1/Th2-associated cytokines was similar in these cells.     

Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes.

Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4(+) lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4(+) populations in blood, as well as by tissue-infiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4(+) lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69(+)). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in alpha(4)beta(7) expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation.