妊娠性肝内胆汁淤积症：一项地塞米松和熊脱氧胆酸的随机、对照试验

妊娠性肝内胆汁淤积症（ICP）的主要特征是：母体难以忍受的瘙痒症，血清胆汁酸升高（≥10μmol／L）以及胎儿死亡风险的增加。最近，确定了一个与影响胎儿损害相关的界值，即血清胆汁酸≥40μmol／L。在一项双盲、安慰剂对照试验中，作研究了熊脱氧胆酸（UDCA）和地塞米松对瘙痒症、胆汁淤积的生化指标和胎儿并发症发生率的影响。为此，选取了130例患有ICP的妇女，随机分到UDCA组（1g／d，使用3周），地塞米松组（12mg／d使用1周，第2周、第3周使用安慰剂）和安慰剂组（使用3周）进行治疗。在治疗期间和治疗3周后对瘙痒症和胆汁淤积的生化指标进行分析。在分娩时记录胎儿的并发症（自发性早产，新生儿窒息，羊水、胎盘、胎膜的胎粪染色）。意向治疗分析显示仅在UDCA组中，丙氨酸转氨酶（ALT）（P=0．01）和胆红素（P=0．002）明显减少。在血清胆汁酸≥40μmol／L的ICP妇女的亚群分析中发现（n=34）UDCA对瘙痒症（减轻75％）、胆汁酸（下降79％）、ALT（降低80％）和胆红素（降低50％）也有明显效果，但对胎儿并发症发生率无影响。地塞米松并无减轻瘙痒症或降低ALT的作用，在降低胆汁酸和胆红素方面比UDCA效果差。     

Renal growth after neonatal urinary tract infection

This study presents the result of 12–21 years' follow-up in a group of children with neonatal urinary tract infection (onset within 1 month after birth) in whom early renal growth retardation was noted without concomitant classical renal scarring. In all cases the neonatal infection was diagnosed and treated within a few days of onset and the patients were closely supervised thereafter. Renal length, parenchymal thickness and area were measured at urography. At first follow-up (22 children, mean age 4.1 years) a significant reduction of renal parenchymal thickness was noted. Long-term follow-up (18 patients, mean age 17 years) demonstrated a normalization of renal size in the entire group, although less complete in the subgroup with reflux. There were two major findings in the present study. Firstly, renal growth retardation was seen after neonatal infection, both with and without reflux. Secondly, normalization of renal size in previously small kidneys was demonstrated, suggesting that growth retardation can be a reversible phenomenon. The tendency for such normalization was slightly more marked in children without reflux. Reduction of parenchymal thickness without calyceal deformity, therefore, does not necessarily mean irreversible damage, and differentiation between permanent scarring and temporary growth retardation can thus only be made at later follow-up, possibly not until after puberty. The demonstration of renal growth retardation in spite of early diagnosis and treatment emphasizes the great vulnerability of the kidney in the newborn.     

5-HT-receptor-induced changes of the intracellular cAMP level monitored by a hyperpolarization-activated cation channel

The HvCNG channel from the moth Heliothis virescens is highly sensitive to cAMP concentrations ranging between 0.1 microM and 5 microM. This HvCNG channel was over-expressed in Spodoptera frugiperda (Sf.9) cells to measure endogenous cAMP levels. Hyperpolarization-activated inward currents were measured in the whole-cell patch-clamp configuration with pipettes filled with different cAMP concentrations to calibrate the system. Varying the cAMP concentration between 0 microM and 100 microM in the pipette, the half-maximal activation voltage ( V1/2) was shifted by +28.5+/-1.7 mV. The activation time constant (tau(a)) was used as a parameter for cAMP quantification because it was independent of the expression level of HvCNG channels. tau(a) changed from 1106+/-60 ms at 0 microM cAMP to 265+/-7 ms at a saturating concentration of 1 mM cAMP. A dose-response relationship yielded values of 0.6 microM for the half-maximal cAMP concentration and 1.5 for the Hill coefficient. Activation of endogenous adenylyl cyclases by 50 microM forskolin induced an elevation of the cAMP level by about 1.6+/-0.2 microM. Co-expressions of HvCNG channels in combination with the mouse 5-HT4a- or 5-HT1A- receptors and the corresponding Gs- or Gi-proteins were successful and allowed us to also verify receptor-induced changes of the cAMP level. Stimulation of m5-HT4a-receptors by 0.1 microM 5-HT induced an increase of cAMP of about 4.6+/-1.5 microM, whereas cAMP levels decreased from a control value of 1+/-0.2 microM to 0.41+/-0.1 microM after stimulation of the m5-HT1A-receptors.     

25 years experience of the surgical treatment of phaeochromocytoma.

OBJECTIVE: To assess the outcome of the surgical treatment of patients who had adrenalectomy for phaeochromocytoma. DESIGN: Retrospective clinical study. SETTINGS: University hospital, Germany. SUBJECTS: 87 consecutive patients with phaeochromocytoma who were operated on. INTERVENTIONS: 29 flank and 58 transabdominal adrenalectomies between 1974 and 2000. RESULTS: The mean tumour diameter was 5 cm (range 2-13), and the mean weight 91 g (range 7-550). The postoperative hospital stay was 11 days. The flank incision entailed the shortest operating time (95 minutes). Two of the phaeochromocytomas were malignant. There were two wound infections but no deaths. With a correct selection of patients, a flank incision is safe. Endoscopic retroperitoneal adrenalectomies should be preferred.     

Ischemia independent lesion evolution during focal stroke in rats

Lesion evolution during focal cerebral ischemia may depend on flow restrictions or on accumulation of toxic mediators within the infarct and expansion of these factors to the periinfarct region. So far, the precise contribution of flow dependent versus spreading-mediated impairment of viable periinfarct tissue has not been determined. Therefore, we measured lesion expansion, flow restrictions and glutamate distribution on serial brain sections at different time points after experimental focal ischemia.Permanent focal ischemia was induced by occlusion of the right middle cerebral artery in male rats and the flow reduction was subsequently measured at 1, 12 and 24 h using iodo[¹⁴C]antipyrine autoradiography. Additionally, the necrotic volume was determined on serial brain sections and the glutamate content was measured in tissue samples from adjacent microdissections.Twelve hours after focal ischemia no noteworthy viable areas with blood flow restrictions of 20-40 ml 100 g^− 1 min^− 1 existed but at 24 h the necrotic tissue exceeded the hemodynamically compromised region by 40 ± 21 mm³ (24%). Furthermore, at 12 and 24 h the glutamate content was elevated in areas surrounding the infarct.Relevant flow restrictions are detectable only during early stages of infarct maturation, whereas the propagation of secondary factors may be the predominant mechanism for delayed infarct evolution.     

Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size.     

First-pass effects of verapamil on the intestinal absorption and liver disposition of fexofenadine in the porcine model.

The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E(H); mean +/- S.E.M.), and the given doses of verapamil did not affect the E(H) (0.13 +/- 0.04, 0.16 +/- 0.03, and 0.12 +/- 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E(H) for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E(H) values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.     

The alpha2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition.

OBJECTIVE: To test the acute effects of the alpha2-adrenoceptor agonist guanfacine (GFC) on motor excitability in intact humans. METHODS: Eight healthy right-handed adults received a single oral dose of 2 mg of GFC. Motor cortex excitability was tested by focal transcranial magnetic stimulation of the hand area of the left motor cortex. Motor evoked potentials (MEP) were recorded from the right abductor pollicis brevis muscle. In addition, spinal and neuromuscular excitability were tested. All measures were obtained immediately before GFC intake (baseline), and 2, 6, and 24 h later. RESULTS: GFC decreased the slope of the MEP intensity curve, increased paired-pulse short-interval intracortical inhibition, and decreased paired-pulse intracortical facilitation and I-wave facilitation. These effects were maximal at 2-6 h and returned to baseline at 24 h. Motor threshold, cortical silent period, and the measures of spinal (peripheral silent period, F waves) and neuromuscular excitability (maximum M wave) remained unaffected. CONCLUSIONS: This is the first study on the effects of an anti-noradrenergic drug on human motor cortex excitability. GFC reduced cortical excitability by disfacilitation and increased inhibition. These findings support the idea that anti-noradrenergic drugs are detrimental for cortical plasticity and learning which are down-regulated by disfacilitation or increased inhibition.     

Adjuvant TACE inhibitor treatment improves the outcome of TLR2<Superscript>-/-</Superscript>mice with experimental pneumococcal meningitis

Background  

Streptococcus (S.) pneumoniae meningitis has a high lethality despite antibiotic treatment. Inflammation is a major pathogenetic factor, which is unresponsive to antibiotics. Therefore adjunctive therapies with antiinflammatory compounds have been developed. TNF484 is a TNF-alpha converting enzyme (TACE) inhibitor and has been found efficacious in experimental meningitis. Toll-like receptor 2 (TLR2) contributes to host response in pneumococcal meningitis by enhancing bacterial clearing and downmodulating inflammation. In this study, TNF484 was applied in mice, which lacked TLR2 and exhibited a strong meningeal inflammation.