Acceleration of peripheral nerve regeneration after crush injury in rat

It the sciatic nerve of a rat is crushed in the thigh, axons from the proximal side of the crush will regenerate so that the toe-spreading reflex becomes observable again after 10.4 +/- 1.7 (mean +/- S.D.) days. If the nerve is electrically stimulated for 0.25-1.0 h at the crush site, just after the crush occurs, the toe-spreading reflex first becomes observable 4.14 +/- 1.6 (mean +/- S.D.) days after the crush. Stimulation is most effective if delivered immediately after the crush but can be delayed up to an hour and still cause significantly faster regeneration. This phenomenon could be useful in clinical management of crushed peripheral nerves.     

不同全麻药对小鼠周围神经电生理的影响

目的：探讨全麻药对小鼠周围运动神经和感觉神经的影响。方法：将50只小鼠分为5组，分别是用α-氯醛糖、戊巴比妥钠、氨基甲酸乙酯、水合氯醛、氯胺酮进行腹腔麻醉后，测定坐骨神经感觉神经动作电位(SNAP)和腓肠肌复合肌肉动作电位(CMAP)，并比较其潜伏期、波幅、传导速度。结果：氯胺酮组的SNAP和CMAP的传导速度都最快，而α-氯醛糖组的SNAP的潜伏期、波幅、传导速度都最差。结论：在实验性研究或临床应用周围神经电生理检测时，选用氯胺酮或戊巴比妥钠麻醉较为理想。     

Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells

We studied the in vitro effect of testosterone on spontaneous immunoglobulin production by human peripheral blood mononuclear cells (PBMC). Testosterone inhibited IgG and IgM production by PBMC both from males and females. The inhibitory effect of testosterone was revealed at doses more than 1 nm, increased dose-dependently, and reached a plateau at 100 nm. At doses <1000 nm, testosterone did not reduce cell viability. Testosterone treatment reduced IgG production by 59.0% and that of IgM by 61.3% compared with control. Immunoglobulin production by B cells was also suppressed by testosterone, though the magnitude of the suppressive effect on B cells was lower than that on whole PBMC; testosterone-induced decrease of IgG production compared with control was 26.9% and that of IgM was 24.9%. Exogenous IL-6 partially restored the impaired immunoglobulin production of testosterone-treated PBMC; IgG production in testosterone culture was increased by IL-6 from 35.6% to 66.5% of control and that of IgM was also increased from 38.9% to 71.2%, respectively. Testosterone treatment reduced IL-6 production of monocytes by 78.4% compared with control, but neither affected that of T cells or B cells. These results suggest that testosterone may suppress immunoglobulin production of human PBMC directly by inhibiting B cell activity and indirectly by reducing IL-6 production of monocytes. It is thus indicated that this hormone may have protective and therapeutic effects on human autoimmune diseases.     

Effects of tryptophan depletion on central and peripheral chemoreflexes in man

Klein (Arch. Gen. Psychiatry 50, 306-317, 1993) suggests that panic attacks are the result of a defective 'suffocation alarm' threshold that presents with carbon dioxide (CO(2)) hypersensitivity, exaggerated ventilatory response and panic in panic disorder (PD) patients. Serotonergic deficiencies enhance this ventilatory response in PD patients, as per 'suffocation alarm' theory predictions, suggesting that serotonin (5-HT) normalizes the ventilatory response. Other research supports a serotonin system-mediated stimulation of ventilation. Knowledge of 5-HT's role on ventilatory output and its neurophysiological sources impacts on the 'suffocation alarm' theory validity and predictive value. We used tryptophan depletion (TRP-) in concert with a modified Read rebreathing test to determine the effect of deficient serotonergic modulation on the central and peripheral chemoreflex threshold and sensitivity of response to CO(2) in 11 healthy men. TRP- did not affect central or peripheral chemoreflex threshold or sensitivity of response to CO(2). However, basal ventilation was significantly elevated during TRP-. In contrast to 'suffocation alarm' theory predictions, decreased 5-HT neurotransmission does not significantly affect the respiratory chemoreflex response to CO(2), impacting on non-chemoreflex drives to breathe. Panic associated respiratory abnormalities may be related to defective 5-HT modulation of non-chemoreflex drives to breathe, unrelated to any respiratory chemoreflex abnormality.     

Pressure-flow relationships of the canine iliac periphery and systemic hemodynamics: Effects of sodiumnitroprusside and adenosine

It has been reported that sodiumnitroprusside (SNP) decreases mean systemic pressure and simultaneously increases pressure pulse amplification towards the iliac periphery (Kenner and van Zwieten 1982). This unexpected finding was suggested to be due to a decrease in iliac peripheral resistance but an increase in iliac differential resistance. In order to investigate this apparent contradiction, the iliac periphery was hemodynamically isolated from the rest of the circulation and perfused with the dog's own blood by means of a pump. Perfusion pressure (P) and flow (F), femoral venous pressure (P_v), systemic pressure (P_s) and cardiac output (CO) were measured. Steady state pressure-flow relations of the isolated bed were obtained during control and during various i.v. infusion rates of SNP and adenosine (ADS) and were found to be straight (meanr=0.99). Their slope (P/F) was defined as differential resistance (R_d). Peripheral resistance (R_p) of the iliac bed was defined as R_p=(P-P_v)/F, calculated at the flow value where perfusion pressure equalled the prevailing systemic pressure. Total peripheral resistance (TPR) was defined as TPR=P_s/CO. The changes of R_d, R_p, P_s, CO and TPR with respect to control show that during low SNP infusion rates R_d and R_p were both increased while TPR was decreased. During all infusion rates of SNP CO did not change while P_s decreased. During low infusion rates of adenosine CO increased while P_s, R_d and R_p did not change and TPR decreased. During high infusion rates of ADS CO decreased again, R_d, R_p and P_s decreased, and TPR remained constant but at a decreased level.It is concluded that: (1) the suggestion of Kenner and van Zwieten is not supported, since SNP (as well as ADS) affects iliac peripheral and iliac differential resistance in a similar way; (2) SNP (as well as ADS) affects iliac peripheral resistance and total peripheral resistance in a differentiated way, and even in an opposite way during low infusion rates of SNP; (3) it is this opposite effect that explains the paradoxical observations of Kenner and van Zwieten; (4) for comparable reductions of TPR, CO is better maintained during infusion of SNP, while P_s is better maintained during infusion of ADS.     

Fibroblast growth factor 2 induces differentiation and apoptosis of Askin tumour cells

Peripheral primitive neuroectodermal tumour (PNET)/Ewing's sarcoma (ES) and neuroblastoma (NB) are related tumours of neural crest origin with primitive neural characteristics. Fibroblast growth factor 2 (FGF2) is a critical signalling molecule for primitive neural crest cells. The treatment of NB cells with FGF2 variably affects biological characteristics such as growth and differentiation, while in PNET/ES, FGF2 predominantly induces apoptosis. The JK-GMS Askin tumour cell line can be induced to differentiate upon treatment with nerve growth factor (NGF), indicating the integrity of the cellular machinery necessary for differentiation. The present study assesses whether FGF2 can induce differentiation in JK-GMS cells. JK-GMS cells expressed high-affinity FGF receptors (FGFRs), and treatment with FGF2 induced phosphorylation of FGFR1 together with activation of extracellular signal-regulated kinases (ERK1/ERK2) and c-Jun N-terminal kinase (JNK). Subsequent biological effects were growth inhibition, neuronal differentiation, and apoptosis, and these changes were associated with increased expression of neurofilaments, reduction of c-myc and bcl-2 expression, and activation of caspase 3. Treatment of the cells with a specific inhibitor of the MAPK/extracellular signal-regulated kinase (MEK)-1, PD98059, predominantly inhibited the effects of FGF2 on growth, differentiation, and apoptosis, while an inhibitor of JNK reduced apoptosis, indicating that the ERK1/2 and JNK pathways are critical components of FGF2-mediated effects in JK-GMS cells. Additional comparative analyses of FGF2-mediated effects in two ES cell lines (CADO-ES, RD-ES) and a PNET cell line (SK-N-MC) showed pronounced differentiation in SK-N-MC, but not in CADO-ES or RD-ES cells. This study demonstrates that FGF2 can induce neuronal differentiation of PNET including Askin tumour. These findings clearly indicate that the FGF2-mediated signalling pathway plays a critical role in controlling the major properties of PNET cells and may provide a potential therapeutic target for PNET.     

A monoclonal antibody (RH1-38) which inhibits multiple systems of cell-mediated cytotoxicity--II. Evidence that the epitope recognized is involved in a late step in the cytolytic mechanism

A monoclonal antibody (RH1-38) which blocks multiple systems of cell-mediated cytotoxicity was functionally characterized. RH1-38 specifically blocks, in the absence of complement, natural killer (NK) activity (K562 targets) without any effect on NK-K562 conjugate formation. Kinetic studies suggested that the antibody blocks a step that occurs 30-120 min after effector populations are mixed with target cells. Single-cell cytotoxicity assays in agarose, combined with standard 51Cr release assays and Michaelis-Menten analysis revealed that RH1-38 markedly decreases Vmax and the number of active NK cells, again without any effect on the number of target-binding cells. The maximum recycling capacity was usually decreased, but in some experiments unchanged, in the presence of the monoclonal antibody. RH1-38 inhibited equally well whole peripheral blood mononuclear leukocytes (PBML), Percoll-fractionated lymphocytes enriched for NK activity, and interferon (IFN)-boosted NK activity. PBML exposed to RH1-38 and then washed mediated depressed NK activity which was partially reversed by subsequent treatment with IFN. These studies are most consistent with the hypothesis that RH1-38 inhibits a step late in the NK cytolytic mechanism rather than through an effect on conjugate formation. The primary effect is probably not on the IFN-generating or boosting mechanism, but a secondary effect on IFN-related mechanisms cannot be ruled out. Inhibition through an effect on a small lymphocyte modulator of NK activity is also unlikely but not rigorously excluded. Thus, RH1-38 appears to inhibit NK activity through a direct effect on NK effector cells, probably by interfering with a cell-surface molecule which is important in the expression of NK activity. The companion paper demonstrates that this monoclonal antibody immunoprecipitates a molecule which is very similar or identical to the LFA-1 antigen. Thus, RH1-38 recognizes either a novel epitope on the LFA-1 molecule or alternatively a distinct, functional killer cell surface molecule. The epitope appears to be involved in a late step in the cytolytic mechanism, possibly part of the effector cell lytic machinery.     

Production of transforming growth factor-beta 1 (TGF-beta1) by blood monocytes from patients with different clinical forms of leprosy

In the present study, the concentration of TGF-beta1 secreted by adherent cells isolated from human peripheral blood mononuclear cells (PBMC) and either stimulated with PGL-1 or lipopolysaccharide (LPS) or left unstimulated was determined by ELISA. The cells were isolated from untreated patients with different clinical forms of leprosy and healthy individuals. The adherent cells exhibited spontaneous release of TGF-beta1 in all clinical forms of leprosy and in healthy individuals; however, lepromatous leprosy/borderline leprosy (LL/BL) patients presenting erythema nodosum leprosum (ENL) displayed significantly higher concentrations of TGF-beta1 than either the other patients studied or the controls. These high TGF-beta1 levels were consistently observed when LL/BL ENL cells were stimulated with phenolic glycolipid (PGL-1) or LPS, and even in the absence of a stimulus (P < 0.01). The most significant differences in TGF-beta1 levels were observed when comparing the results in the presence of PGL-1 from ENL with, in order of significance: tuberculoid leprosy (TT) patients (P < 0.001), LL/BL patients without ENL (P < 0.01), healthy individuals (P < 0.01) and borderline-borderline/borderline-tuberculoid (BB/BT) patients with reversal reaction (RR) (P < 0.01). The BB/BT patients produced equivalent levels of TGF-beta1 compared with LL/BL patients without ENL, for all types of stimuli (P > 0.05). In contrast, TT patients produced the lowest levels of TGF-beta1 among all the subjects studied (both patients and healthy controls), especially following PGL-1 stimulation (P < 0.001, and P < 0.05, respectively). In conjunction with our previous data regarding TGF-beta1 expression in dermal lesions, it appears that TGF-beta1 probably plays different roles in leprosy: (i) to mediate a suppressive action locally, associated with the presence of PGL-1, and (ii) to induce proinflammatory effects when secreted systemically by monocytes, thereby acting as a modulatory cytokine in the acute inflammatory reactions of ENL and associated with the Th2 immune response in multibacillary forms of leprosy.