Kidney Transplantation Substantially Improves Endothelial Progenitor Cell Dysfunction in Patients with End-Stage Renal Disease

Endothelial progenitor cells (EPC) are involved in endothelial repair and maintenance. Dysfunction of EPC may contribute to accelerated arteriosclerosis in chronic kidney disease. Kidney transplantation (KTx) improves both survival and endothelial function of dialysis patients. In a prospective study, we tested to which extent KTx changes EPC biology. We studied number and function (migratory activity, adhesion to extracellular matrix proteins and to mature endothelial cells [EC]) of EPC in 20 patients during dialysis and 3, 6, 9 and 12 months after KTx. Twenty-two healthy volunteers served as matched controls. Circulating precursor populations were measured by flow cytometric analysis. Cytokines relevant for EPC mobilization were monitored. Compared to the dialysis state, KTx increased the migration of EPC to approximately 2-fold. Adhesion to fibronectin and to collagen type IV was significantly increased after KTx. An improved adhesion rate of EPC to mature EC was observed. The number of EPC decreased. The amount of precursor populations showed no difference compared to the pretransplant state. Our study shows an improved function of EPC after KTx. This finding indicates an improved potential for endothelial repair which in turn may contribute to enhanced endothelial function and reduced cardiovascular morbidity after KTx.     

Anulus fibrosus in bulging intervertebral disks

In this investigation the association of radial tears of the anulus fibrosus and bulging of the intervertebral disk was studied. An index of disk bulging was measured in sagittal anatomic sections in 149 lumbar disks from 31 cadavers. The indexes of disk bulging were correlated with stages of disk development and the presence of an annular tear. The largest disk-bulging indexes were always associated with radial tears of the anulus. Eighty-four percent of the disks with radial tears had disk-bulging indexes greater than 2.5 mm. Most normal adult disks had an index of less than 2.5 mm. The results challenge the concept that the anulus fibrosus is intact in bulging disks, although ruptured in herniated disks.     

A pathway for the biosynthesis of straight and branched, odd- and even-length, medium-chain fatty acids in plants.

Pathways and enzymes of fatty acid synthase-mediated, long-even-chain (generally C16-C20) fatty acid synthesis are well studied, and general metabolism involved in short-chain (C4-C7) fatty acid biosynthesis is also understood. In contrast, mechanisms of medium-chain (C8-C14) fatty acid synthesis are unclear. Recent work suggests involvement of chain-elongation-terminating thioesterases in medium-chain fatty acid formation in oilseeds and animals. We have shown that iso- and anteiso-branched and straight, odd- and even-length, short-chain fatty acids esterified in plant-trichome-gland-produced sucrose esters are synthesized by using carbon skeletons provided by modified branched-chain amino acid metabolism/catabolism. The principal enzymes involved are those catalyzing leucine biosynthesis in all organisms and those leading to short-chain alcohols in mutant yeasts and alkyl acids in Clostridium species (products often serving as mammalian pheromones). Here we provide evidence that C10-C12 straight medium-chain and C10-C12 branched medium-chain acyl acids of tomato, C6-C8 straight-chain acyl acids of Petunia, and C6 and C8 branched acyl acids of Nicotiana glutinosa are formed by alpha-ketoacid elongation without participation of fatty acid synthase-mediated reactions or -independent thioesterases. This different metabolism suggests greater integration of amino acid and fatty acid metabolism than previously considered and provides other avenues to study and manipulate not only straight even-length but also odd- and even-length straight and branched medium-chain fatty acid biosynthesis.     

Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.

MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extrapulmonary location of sarcoidosis.

Two cases of sarcoidosis located outside the lungs are reported. In both cases the symptoms of the sicca syndrome were in the foreground. In the first case other clinical manifestations included mediastinal and retroperitoneal lymphadenopathy, and lacrimal gland impairment. In the other case the symptoms of the sicca syndrome were associated with polyneuropathy and maculopapular skin rash. The diagnosis of sarcoidosis was confirmed by histological examination of a biopsy specimen of lower lip mucosa in the first case, and biopsy of skin lesion in the second case. Abnormal results of laboratory tests included only raised erythrocyte sedimentation rate, in both cases and presence of circulating immune complexes in one case. Serological tests failed to demonstrate the presence of rheumatoid factor, antinuclear and anti-ds DNA antibodies. No decrease was observed also in the haemolytic activity of the complement, and cryoglobulins were absent. Regression of clinical signs was obtained in both cases after treatment with glucocorticosteroids.     

The circadian component of spinule dynamics in teleost retinal horizontal cells is dependent on the dopaminergic system.

During the light phase of a light/dark cycle, dendrites of teleost cone horizontal cells display numerous finger-like projections, called spinules, which are formed at dawn and degraded at dusk, and are thought to be involved in chromatic feedback processes. We have studied the oscillations of these spinules during a normal light/dark cycle and during 48 h of constant darkness in two groups of strongly rhythmic, diurnal fish, Aequidens pulcher. In one group the retinal dopaminergic system had been destroyed by the application of 6-OHDA, while in the other (control) group, the dopaminergic system was intact. In control fish, oscillations of spinule numbers were observed under both normal and constant dark conditions, indicating the presence of a robust circadian rhythm. However, spinule dynamics were severely affected by the absence of retinal dopamine. During the normal light phase, the number of spinules in 6-OHDA injected retinae was strongly reduced, and throughout continual darkness, spinule formation was almost completely suppressed. These results indicate that dopamine is essential for both light-evoked and circadian spinule formation; furthermore, we conclude that there is no circadian oscillator within horizontal cells controlling the formation of spinules.     

Betahistine: a retrospective synopsis of safety data.

Betahistine is a structural analogue of histamine that is prescribed for the treatment of vestibular disorders such as Ménière's disease and the symptomatic treatment of vertigo. It is estimated from sales information that >130 million patients have been exposed to the drug since its registration in 1968. In this review we analyse the safety profile of betahistine based on data obtained during >35 years of worldwide postmarketing surveillance. Until 31 December 2005, 554 adverse drug reaction (ADR) reports with 994 individual signs and symptoms were received by the marketing authorisation holder from worldwide sources and were reviewed and evaluated. Signs and symptoms of cutaneous hypersensitivity reactions during betahistine therapy were the most frequently reported complaints. They consisted of usually mild and self-limiting rash, pruritus and urticaria, and all symptoms were reversible after drug discontinuation. Betahistine was reported to be involved in one anaphylactoid reaction and one case of Stevens-Johnson syndrome. Anaphylactic reactions with fatal outcome were not reported. The reports that describe gastrointestinal complaints mostly concern nausea and vomiting or unspecific abdominal pain. These were typically non-serious complaints. Hepatobiliary involvement was reported 25 times, including increases in alkaline phosphatase, gamma-glutamyltransferase, and alanine and aspartate aminotransferase levels. None of the patients concerned developed severe liver failure or died. ADRs related to the nervous system predominantly reveal heterogeneous events that are not suggestive of a specific adverse reaction profile for betahistine. A clinical intolerance to betahistine that gave rise to asthma or bronchospasm was only reported in eight ADRs. A total of three cases of neoplasm have been reported. One case concerned a male patient of unknown age who experienced weight loss, insomnia, impatience and irritability soon after the start of betahistine therapy. An undiagnosed phaeochromocytoma was suspected. The remaining two cases were assessed as being unrelated to betahistine by the reporter. Finally, four deaths have been reported during the course of postmarketing surveillance for betahistine. The reporter assessed the causal relationship to betahistine in two as unrelated, in one as unlikely and the other as unassessable. In summary, clinical and postmarketing studies have revealed a good safety profile of betahistine that was confirmed by the safety surveillance data presented.     

In vivo fluorescence spectroscopy and imaging of human skin tumours

The feasibility of using in vivo autofluorescence for the diagnosis of skin cancer was evaluated. In vivo fluorescence measurements were performed on healthy human volunteers, and patients with different types of benign and malignant skin tumours. Fluorescence spectra as well as fluorescence images were acquired. The excitation-emission matrix of normal skin (n=3) showed a broad peak at the shortest excitation wavelength (365 nm) and at 440 nm fluorescence wavelength, smoothly decreasing towards longer excitation and fluorescence wavelengths. Non-melanoma skin tumours (n=31) and control skin excited with 375 nm showed a broad fluorescence band from 400 to 700 nm, peaking around 436 nm. No significant differences in measurements between tumours and the corresponding control sites were found. A large spatial variation in the fluorescence intensity was observed both in the tumours and in the control sites. Standard deviations found ranged from 0.15 to 1.5 times the mean fluorescence. Fluorescence images, excited with 375 nm and taken with an image intensified CCD camera, on eight malignant melanomas and eight benign pigmented lesions did not indicate any fluorescence intensity distribution specific to the malignancy of the lesion. Neither the shape of the fluorescence spectra, nor the spatial distribution of the fluorescence intensity showed any signature specific to the histopathological nature of the lesions investigated. Optical diagnostics of skin tumours using the autofluorescence does not seem to be feasible at the present time.