Plasma kallikrein activates the epithelial sodium channel in vitro but is not essential for volume retention in nephrotic mice.

AIM: Recent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (PKLK) as a candidate serine protease in this context. METHODS: We analysed PKLK in the urine of patients with chronic kidney disease (CKD, n = 171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK-deficient mice (klkb1-/- ) with experimental nephrotic syndrome induced by doxorubicin injection. RESULTS: In patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2 µg mL-1 which was correlated with albuminuria (r = .71) and overhydration as assessed by bioimpedance spectroscopy (r = .44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67 kDa γ-ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in γ-ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome, active PKLK was present in nephrotic urine of klkb1+/+ but not of klkb1-/- mice. However, klkb1-/- mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1+/+ mice. CONCLUSION: Plasma kallikrein is detected in the urine of proteinuric patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice.

Effects of prior arm exercise on pulmonary gas exchange kinetics during high-intensity leg exercise in humans.

For moderate work rates (i.e. below the lactate threshold, theta), oxygen uptake (Vo2) approaches the steady state mono-exponentially. At higher work rates, the Vo2 kinetics are more complex, reflecting the delayed superimposition of an additional, slow component. The mechanisms of this 'slow' component are poorly understood. It has been demonstrated, however, that while a prior bout of supra theta L cycling (with a 6 min recovery) does not significantly affect the V02 time course for a subsequent sub-theta L bout, it significantly speeds the V02 response to a subsequent supra-theta L bout (Gausche, Harmon, Lamarra & Whipp, 1989; Gerbino, Ward & Whipp, 1996). These investigators proposed that this speeding was a result of improved muscle perfusion during the exercise transient, possibly related to the residual metabolic acidaemia still present at the start of the subsequent exercise bout. To determine whether speeding of the V02 kinetics could also be induced by a bout of prior high-intensity exercise performed at a remote site (e.g. the arms), subjects each performed two 6 min bouts of high-intensity cycling (leg exercise: LE) at a work rate equivalent to 50% of lambda le' (the difference between maximum V02,LE and theta L,LE). On one occasion this was preceded by a 6 min period of cycling at 50% lambda LE and, on another, by a similar period of arm-crank exercise (arm exercise: AE) at 50% lambda LE in each case, the work bouts were separated by 6 min of unloaded pedalling. Pulmonary gas exchange variables were derived breath-by-breath. During unloaded pedalling and at minute 6 of each work bout, arterialized venous blood samples were drawn from the dorsum of the heated hand or at the wrist for analysis of PH, lactate, pyruvate, noradrenaline (NAdr), adrenaline (Adr), and potassium (K+). The difference in V02 between minute 6 and 3 of each work bout (lambda V02 ¿6-3] and the 'partial' O2 deficit (O2 Def) provided indices of the slow phase of V02 kinetics. The initial AE and LE bouts resulted in similar degrees of metabolic (lactic) acidaemia; the residual acidaemia at the end of the subsequent 6 min recovery phase was also similar for the two protocols, as were [K+], [Adr¿ and [NAdr]. The subsequent LE bouts were associated with reductions in both lambda V02[6-3] and O2 Def, relative to control, with the effect being more marked when the work was preceded by a prior LE bout than a prior AE bout: lambda V02[6-3] averaging 32 and 56% of control, respectively, and O2 Def 71 and 81%. Consequently, the increase in [lactate] and decrease in PH induced in this second LE bout were smaller when preceded by prior leg exercise than prior arm exercise. It is therefore concluded that while metabolic acidaemia induced at a site remote from the legs is associated with a less prominent slow phase of the V02 kinetics for high-intensity leg exercise, a component specific to the involved contractile units appears to exert the dominant effect. The mechanisms underlying this response are, however, presently uncertain.

[Wernicke's encephalopathy in chronic gastropancreatic disease with pyloric stenosis]. / Wernicke-Enzephalopathie bei chronischer gastropankreatischer erkrankung mit Pylorusstenose.

The acute symptomatology of Wernicke's syndrome was observed in a 17-year-old female patient and a 48-year-old male patient. They were both affected by chronic gastropancreatic disease with pyloric stenosis and showed already subclinical thiamine deficiency. Symptoms occurred within 4 weeks of an infusion regime rich in carbohydrates. Parenteral administration of high doses of thiamine (200 mg/d and 360 mg/d) led to clear-cut regression of symptoms. Due to the unfavourable prognosis of Wernicke's encephalopathy prophylactic administration of thiamine in a daily dosage of 50-100 mg is recommended in patients with chronic intestinal disease and parenteral nutrition.

Neurologic symptoms of basal cell nevus syndrome.

The neurological symptomatology of the basal cell nevus syndrome (Gorlin-Goltz syndrome) is described based on a personal observation and previously published cases. The case presented here, with dominant cerebellar symptomatology, optic atrophy and pyramidal signs, is discussed pathophysiologically either as a primary central nervous manifestation of the basic disturbance or as a secondary cerebral paraneoplastic process.

[Basilar artery thrombosis (author's transl)]. / Basilaristhrombose.

Arteriosclerosis is the most common cause of basilar artery thrombosis. Rarely basilar occlusions are observed after cerebral concussion and hyperextension of the neck; occasionally they are founded in craniocervical dysplasia, arteritis and hypercoagulability of blood.--Clinical data and differential diagnostic aspects are demonstrated in 4 own cases and the present literature. Characteristics of clinical symptomatology are discussed with respect to the sites of predilection in distal and proximal part of basilar artery. Angiography examination is the most important diagnostic method and shows prognostic indications by demonstration of collaterals.--The treatment consists of inhibition of blood viscosity, reduction of perifocal edema and stabilization of blood-pressure.

[Contribution to facial spasm (author's transl)]. / Beitrag zum Spasmus facialis.

Clinical, electromyographic, neurographic, and nystagmographic results of 20 cases of facial spasm are reported. The syndrome is discussed with reference to parabiosis of the facial nerve and the "ephapse" theory, the localization of facial nerve lesions, and possible etiologic factors of parabiotic changes. For the pathogenesis chronic and subclinical preimpairments of facial nerve axons are postulated as causing, after subsequent additional affections, an "ephaptic" transfer to neighboring fibers. Therapeutic possibilities are discussed.