Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice.

Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum, and reduced levels of dopamine in the mesolimbic system. The present study confirms that SNCA plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age-related decline in specific motor performance. The generated mouse line has a potential to become a model for PD with comparable time course and phenotype.

[Mathematical model for cooperation of ion pump, symport, and antiport in epithelial cells].

Transcellular transport in epithelial cells plays an important role in providing such physiological functions as excretion of cytotoxic substances or reabsorption of metabolites useful for the body life activity. These functions have been shown to be performed by the mechanisms - symport, antiport, ion pumps, and channels - that often function cooperatively. Kinetic models of the substrate transport with the aid of the above mechanisms are widely described in the literature. Much less attention is paid to modeling of cooperative activity of transporters that have different transport mechanisms. In this work we propose a mathematical model for flux coupling of three transporters - the ion pump, symporter, and antiporter as well as of two substrates, one of which (A) can be transported simultaneously by the symport and antiport mechanisms, while the other (B) - only by the latter mechanisms. Analysis of the model has shown that for the pair of substrates (A and B) the flux coupling becomes possible if the following conditions are met: (1) the substrate A flux into the internal cell volume using the symport mechanism is to exceed its antiporter-realized flux in the opposite direction; (2) probability of reorientation from one side of membrane to the other side for the antiporter loaded with the substrate is to be essentially higher than that for empty transporter. The proposed model can be used for comparing efficiency both of excretion and of reabsorption of cell metabolites in representatives of different taxa.

Primary aortoduodenal fistula: successful grafting with axillo-bifemoral bypass.

Primary aortoduodenal fistula (PADF) is uncommon direct pathological communication between the abdominal aorta and duodenum, which may cause life-threatening gastrointestinal bleeding. PADF leads to high mortality and morbidity unless it is promptly evaluated and appropriate surgical intervention performed. We present a case report describing PADF treated successfully with axillobifemoral bypass. A 70-year-old male was admitted in our hospital with severe back and abdominal pain. A pulsative tumor mass was palpated in the middle abdomen. Previous ultrasonography had shown abdominal aortic aneurysm. There were no symptoms of active gastrointestinal bleeding, but the patient had moderate anaemia. Computer tomography revealed infrarenal abdominal aortic aneurysm. Intraoperatively, PADF was diagnosed. The duodenum was repaired and the abdominal aorta was closed directly below the renal arteries. At the next stage, extra-anatomic grafting was performed, because frank pus was found in the abdominal cavity. By present time, the axillobifemoral bypass has been patent for 2 years.

[Minimal mathematical model of the energetic coupling of cotransport and anion-exchange mechanisms for transport in biological membranes]. / Minimal'naia matematicheskaia model' énergeticheskogo sopriazheniia kotransportnogo i anionoobmennogo mekhanizmov perenosa v biologicheskikh membranakh.

A minimal model for the coupling of fluxes of two different anions was constructed, in which one anion Y, is transferred by both the cotransport and anion-exchange pathways, whereas the other anion, Z, only by the anion-exchange mechanism. The possibilities of the model for describing the cooperativity of cotransport and anion-exchange pathways are demonstrated by using the computer simulation approach. It is shown that the energetic coupling of Y and Z anion fluxes becomes possible when the following conditions are fulfilled: (1) The inward-directed flux of Y by the cotransport pathway exceeds its anion-exchange flux directed outward; (2) the reorientation probability of the Y-loaded anion-exchanger is higher than that of the unloaded exchanger.

Sugiura procedure in the treatment of bleeding esophageal varices.

AIM OF THE STUDY: The aim of this study was to report our results and to make an attempt to define the possible role of Sugiura procedure in the treatment of variceal bleeding. MATERIAL AND METHODS: From January 1979 to December 1997, 39 patients with portal hypertension and acute variceal bleeding (17 patients) or previous variceal bleeding (22 patients) underwent Sugiura procedure. Operations were performed in two stages. When performed in an emergency situation (17 patients) thoracic operation was performed first. In elective cases abdominal operation was usually preferred. Complete two-stage operation was performed in 16 patients. Twenty-three patients did not undergo the second stage because of early postoperative death, deterioration of condition or refusal. There were 17 men and 22 women, aged 41.7 +/- 18.3 years (range 8-71 years). According to the Child--Turcotte classification of hepatic function there were 23 Child class A, 13 Child class B and 3 Child class C patients. SUMMARY OF RESULTS: Overall operative mortality was 10.3% (4 deaths per 39 patients with 54 operations), mortality in an emergency situation was 17.6% (3 deaths per 17 patients) and in elective cases 4.3% (1 death per 22 patients with 37 operations). Variceal rebleeding occurred in 4 survivors (11.4%) at an average follow-up of 6.1 +/- 4.3 years. Survival rate was 84.6% at 1 year, 71.8% at 5 years and 64.1% at 10 years. CONCLUSIONS: Sugiura operation carries low operative risk in an elective situation and results in an effective prevention of recurrent variceal bleeding.

The mechanism of coupling of the organic anion exchange to Na(+)-dicarboxylate symport in basolateral membrane vesicles.

The rates of p-aminohippurate (PAH) and of uric acid uptake by basolateral membrane vesicles isolated from proximal tubules of rat kidney have been investigated. Accumulation of both substrates against the concentration gradient within the vesicles was shown to occur in the presence of alpha-ketoglutarate (alpha-KG) and Na+ gradient in the incubation medium. The mechanism of the coupling between Na(+)-dicarboxylate symport and organic anion transport is discussed based on the differences between the rates of PAH and of uric acid uptake. It is proposed that the limiting step of coupling between two transporters is the step of alpha-KG-organic anion exchange.

Venous allografts for infrainguinal vascular bypass.

Between 1978 and 1993, 107 patients received venous allografts for infrainguinal revascularization because autogenous material was unavailable. These operations comprised 7.4% of 1442 reversed vein bypass procedures performed during the same period. Alloveins were harvested during varicose vein stripping and stored up to 10 days in saline solution containing heparin and antibiotics. Veins with or without minimal degenerative changes were used and when necessary segments were sutured end-to-end to obtain a convenient length. The patients comprised 95 men and 12 women of age range 44-87 years. All operations were performed for limb salvage (rest pain and gangrene); 40 femoropopliteal and 67 femorocrural bypasses were performed; 66 were primary reconstructions and 41 secondary reconstructions. The operative mortality rate was 3.7%. Early thrombosis occurred in 18 patients (16.8%), nine of whom were successfully reoperated upon. The cumulative patency rates for all bypass operations was 82.9%, 38.7% and 21.3% at 30 days, 3 and 5 years, respectively, the limb salvage rates being 84.8%, 48.0% and 29.2%, respectively. Allografts may have a place in lower-limb bypass surgery in the absence of veins, polytetrafluoroethylene or human umbilical vein.

[Sugiura's operation in the treatment of hemorrhage from esophageal varicose veins]. / Operatsiia Sugiura pri lechenii krovotechenii iz varikozno-rasshirennykh ven pishchevoda.

The authors have performed Sugiura's operation since 1979 in 17 patients in bleeding from varicose veins of the esophagus. The patient's ages ranged from 14 to 69 years. Portal hypertension was caused by hepatic cirrhosis in 14 and extrahepatic blockade in 3 patients. Emergency operations were carried out in 12 and planned interventions on 5 patients. The 3 patients with extrahepatic blockade and 7 patients with Groups A and B hepatic cirrhosis (according to Child's classification) recovered. Among 7 patients with group C 4 died (total mortality, 24%). Recurrent bleeding was not encountered in long-term postoperative follow-up periods of up to 10 years.

[Effect of functional loading on the operation of the active transport system for organic acids in the proximal kidney tubules of rats after unilateral nephrectomy and in the early postnatal period]. / Vliianie funktsional'noi nagruzki na rabotu sistemy aktivnogo transporta organicheskikh kislot v proksimal'nykh kanal'tsakh pochki krys posle odnostoronnei nefréktomii i v rannem postnatal'nom periode.

The influence of a prolonged introduction of exogenic organic acid penicillin (that is functional loading) on the level of accumulation of an anionic dye (fluorescein) in renal proxima tubules was studied after unilateral nephrectomy and early postnatal period. Injection of penicillin 2 days after unilateral nephrectomy slowly increased Na-independent and strongly increased Na-dependent component of active fluorescein transport in renal proximal tubules of randombred, but strongly decreased both Na-independent and Na-dependent transport in renal tubules of the Campbell rats. When newborn random-bred, Wistar and Campbell rats were pretreated with penicillin, we obtained a slow increase in Na-independent and a strong increase in Na-dependent component of fluorescein transport in renal tubules of random-bred and Wistar rats, but a significant reduction in both Na-independent and Na-dependent transport. It is concluded that the ability for adaptive (or substrate) stimulation of active transport of organic anion in renal proximal tubules is controlled genetically. Adaptive stimulation of organic acid transport in renal tubules referred to in literature as "carried induction", was accomplished apparently by the increase in driving force of the active transport, that is evidently the level of electrochemical Na+-gradient.

[Work of the active transport system of organic acids in the kidney proximal tubules of rats with compensatory hypertrophy]. / Rabota sistemy aktivnogo transporta organicheskikh kislot v proksimal'nykh kanal'tsakh pochki krys pri kompensatornoi gipertrofii.

The active transport of organic acids in proximal renal tubules of the Campbell, Wistar and random-bred rats was studied by contact microfluorometry with anion dye fluorescein as a marker, on 1, 2, 3, 5, 10, 30 and 90 days after a unilateral nephrectomy. Sham-operated rats were used as a control. Transport was investigated under certain conditions when fluorescein was transported by Na-dependent (at 30 degrees C) or Na-independent (at 20 degrees C) systems. It is shown that fluorescein accumulation in renal tubules of operated random-bred rats at 30 degrees C is (if compared to the corresponding control) 81, 105 and 75% on 1, 2 and 3-10 days, resp., and about 90% on 30 and 90 days. Fluorescein accumulation at 20 degrees C in all investigated rats was about 90% of the corresponding control. A specific poison of Na+, K+-ATPase = ouabain inhibited fluorescein accumulation on day 1 after sham-operation by 70% to control, but there was no inhibition on day 1 after the operation (unilateral nephrectomy). P-aminohippuric acid in both media inhibited fluorescein accumulation in renal tubules of sham-operated rats better than in operated rats. It is concluded that either the amount of the carried of transport system for organic acids decreased in membranes of renal tubules of operated rats, or the affinity of carrier to organic acids is aggravated.

[The system of active transport of organic acids in the proximal tubules of rats with hereditary retinal degeneration (Campbell strain)]. / Sostoianie sistemy aktivnogo transporta organicheskikh kislot v proksimal'nykh kanal'tsakh krys s nasledstvennoi degeneratsiei setchatki (liniia Kempbell).

Active transport of organic acids (ATOA) in proximal renal tubules of Campbell, Wistar and random-bred rats was studied by contact microfluorometry with anion fluorescein as a marker. Beginning with the 60th day of life this transport in Campbell rats was characterized by a lower equilibrium uptake of fluorescein by the tubules, by altered sensitivity to AMP and adenosine, and by no response to unilateral nephrectomy. It is assumed that ATOA in Campbell rats plays a certain role in the pathogenesis of retinitis pigmentosa.