Systematic and differential myelination of axon collaterals in the mammalian auditory brainstem

A brainstem circuit for encoding the spatial location of sounds involves neurons in the cochlear nucleus that project to medial superior olivary (MSO) neurons on both sides of the brain via a single bifurcating axon. Neurons in MSO act as coincidence detectors, responding optimally when signals from the two ears arrive within a few microseconds. To achieve this, transmission of signals along the contralateral collateral must be faster than transmission of the same signals along the ipsilateral collateral. We demonstrate that this is achieved by differential regulation of myelination and axon caliber along the ipsilateral and contralateral branches of single axons; ipsilateral axon branches have shorter internode lengths and smaller caliber than contralateral branches. The myelination difference is established prior to the onset of hearing. We conclude that this differential myelination and axon caliber requires local interactions between axon collaterals and surrounding oligodendrocytes on the two sides of the brainstem. GLIA 2016;64:487–494     

Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking

Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine‐Sottas syndrome (DSS) and in the corresponding mouse model (P0^null‐mice). In the mammalian CNS, the tetraspan‐membrane protein PLP is the major structural myelin constituent and required for the long‐term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type‐2) and the relevant mouse model (Plp^null‐mice). The Plp‐gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0^null‐mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0^null*Plp^null‐double‐mutant mice. Compared with either single‐mutant, P0^null*Plp^null‐mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non‐myelinated but in a one‐to‐one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0^null*Plp^null‐mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell‐dependent support of peripheral axons and the oligodendrocyte‐dependent support of central axons. GLIA 2016;64:155–174     

经血和经性传播的人类免疫缺陷病毒感染者乙、丙型肝炎病毒重叠感染比较

我国目前传播人类免疫缺陷病毒(HIV)主要途径为经血传播,如静脉吸毒,输血等,我们曾报道了经血传播HIV和HBV/HCV重叠感染的特征[1,2 ] 。而国外报道HIV传播的主要途径为性途径,在经性途径传播的HIV感染者中HBV/HCV重叠感染状况和感染特征不甚明确,我们以HIV感染的德国男性同性恋者为研究对象,首先对其HBV/HCV重叠感染状况进行调查,并总结了经性和经血传播HIV感染者HBV/HCV重叠感染特点及差异。对象和方法一、研究对象1992年1月～2 0 0 0年12月HIV感染的德国男性同性恋者4 9例,我国经血传播HIV感染者6 2例,取静脉血3ml,- …     

Prognostic importance of plasma NT-pro BNP in chronic heart failure in patients treated with a beta-blocker: results from the Carvedilol Or Metoprolol European Trial (COMET) trial

BACKGROUND: Plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro BNP) are increased in patients with chronic heart failure (CHF). Beta-blockers (BB) may influence these levels but it is unclear whether changes in NT-pro BNP reflect concomitant changes in prognosis. OBJECTIVES: To assess the prognostic importance of NT-pro BNP at baseline and during follow-up, in patients in whom beta-blocker therapy is initiated. METHODS: In COMET, 3029 patients with CHF in NYHA class II-IV and EF<35% were randomised to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Blood samples were collected for the measurement of NT-pro BNP at baseline (n=1559) and during follow-up (n=309). RESULTS: Baseline plasma concentrations of NT-pro BNP above the median (1242 pg/ml) were associated with higher all-cause mortality (RR 2.77; 95% CI 2.33-3.3, p<0.001). Patients who achieved NT-pro BNP levels<400 pg/ml during follow-up had a lower subsequent mortality (RR 0.32; 95% CI 0.15-0.69, p=0.004). CONCLUSIONS: The plasma concentration of NT-pro BNP is a powerful predictor of mortality in patients with CHF. Patients who achieve an NT-pro BNP of <400 pg/ml subsequent to treatment with a beta-blocker have a favourable prognosis.     

Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs

Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Eμ-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Eμ-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin, which acted on lymphotoxin-β-receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-α deletion and using a lymphotoxin-β receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.     

Regulation of enterocyte apoptosis by acyl-CoA synthetase 5 splicing

BACKGROUND AND AIMS: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. METHODS: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. RESULTS: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Delta 20) are found in human enterocytes. In contrast with the splice variant ACSL5-Delta 20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-R1. Expression analyses revealed that the ACSL5-fl/ACSL5-Delta 20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell line. CONCLUSIONS: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Delta 20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia.     

Incidence and risk distribution of heart failure in adolescents and adults with congenital heart disease after cardiac surgery

Heart failure (HF) is a major problem in the long-term follow-up of adults with congenital heart disease (CHD) after cardiac surgery. The purpose of this study was to evaluate risk factors for HF in patients with CHD. N-terminal-pro-brain natriuretic peptide and maximal oxygen uptake (VO2max) were measured in 345 consecutive patients with CHD. HF was defined as an elevated N-terminal-pro-brain natriuretic peptide level (> or = 100 pg/ml) and reduced VO2max (< or = 25 ml/kg/min). The HF criteria were met by 89 patients. These patients were significantly older (mean +/- SEM 30.8 +/- 0.9 vs 24.8 +/- 0.5 years), had significantly lower maximal heart rates (149 +/- 3 vs 164 +/- 1 beats/min), and had larger end-diastolic right ventricular diameters (36 +/- 1 vs 27 +/- 1 mm) and right ventricular pressure estimated by Doppler flow velocities of tricuspid valve regurgitation (2.9 +/- 0.1 vs 2.3 +/- 0.03 m/s). Mean fractional shortening of the left ventricle was within the normal range. To estimate risk stratification, odds ratios for HF were determined for the most frequently occurring types of congenital heart defects and surgical procedures. In conclusion, HF in adults with CHD predominately depends on diagnosis, age, the frequency of reoperation, and right ventricular function and may be related to chronotropic incompetence indicated by lower maximal heart rates.     

Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutropenic systemic lupus erythematosus

OBJECTIVE: Cytokines and growth factors can be a target of autoantibodies in systemic inflammatory diseases. We examined whether patients with neutropenia and either Felty's syndrome (FS) or systemic lupus erythematosus (SLE) have autoantibodies against granulocyte colony-stimulating factor (G-CSF) and whether these autoantibodies are functionally relevant. METHODS: Fifteen patients with neutropenia due to FS were matched for age, sex, and disease activity with 16 normocytic rheumatoid arthritis (RA) control patients. Sixteen patients with SLE and neutropenia were matched with 16 normocytic SLE control patients. Antibodies against G-CSF were measured by enzyme-linked immunosorbent assay and Western blotting. Antibody specificity was verified by competitive inhibition using recombinant human G-CSF. The effect of anti-G-CSF antibodies on the functional activity of their target molecule was measured in a bioassay using G-CSF-sensitive murine 32D cells. RESULTS: IgG anti-G-CSF was found in 11 FS patients, 6 SLE patients with neutropenia, 6 SLE control patients, and none of the RA control patients. IgM anti-G-CSF was found in 6 neutropenic and 3 normocytic SLE patients. Anti-G-CSF antibodies were associated with an exaggerated serum level of G-CSF and a low neutrophil count. A neutralizing effect of anti-G-CSF antibodies on its target molecule was found in 3 of the 9 patients tested. Irrespective of the presence or absence of anti-G-CSF antibodies, neutropenic patients with FS and SLE had exaggerated serum levels of G-CSF. CONCLUSION: Anti-G-CSF autoantibodies are common in neutropenia due to FS and SLE. In individual patients, these autoantibodies have a neutralizing capacity. In patients without neutralizing antibodies, hyposensitivity of the myeloid cells to G-CSF appears to be central to the pathogenesis of the neutropenia in FS and SLE.