Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis.

BACKGROUND AND AIMS: There is a significant relationship between inheritance of high transforming growth factor (TGF)-beta1 and angiotensinogen-producing genotypes and the development of progressive hepatic fibrosis in patients with chronic hepatitis C. In cardiac and renal fibrosis, TGF-beta1 production may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The aim of the present study was to determine the effects of the angiotensin-converting enzyme inhibitor, captopril, on the progression of hepatic fibrosis in the rat bile duct ligation model. METHODS: Rats were treated with captopril (100 mg. kg(-1). day(-1)) commencing 1 or 2 weeks after bile duct ligation. Animals with bile duct ligation only and sham-operated animals served as controls. Four weeks after bile duct ligation, indices of fibrosis were assessed. RESULTS: Captopril treatment significantly reduced hepatic hydroxyproline levels, mean fibrosis score, steady state messenger RNA levels of TGF-beta1 and procollagen alpha1(I), and matrix metalloproteinase 2 and 9 activity. CONCLUSIONS: Captopril significantly attenuates the progression of hepatic fibrosis in the rat bile duct ligation model, and its effectiveness should be studied in human chronic liver diseases associated with progressive fibrosis.

DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls.

The DRD4 dopamine receptor is thus far unique among neurotransmitter receptors in having a highly polymorphic gene structure that has been reported to produce altered receptor functioning. These allelic variations are caused by a 48-bp segment in exon III of the coding region which may be repeated from 2-10 times. Varying the numbers of repeated segments changes the length, structure, and, possibly, the functional efficiency of the receptor, which makes this gene an intriguing candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. Thus far, these DRD4 alleles have been investigated for association with schizophrenia, bipolar disorder, Parkinson's disease, and chronic alcoholism, and all have been largely negative for a direct association. We evaluated the DRD4 genotype in 226 Finish adult males, 113 of whom were alcoholics, many of the early onset type with features of impulsivity and antisocial traits. Genotype frequencies were compared to 113 Finnish controls who were free of alcohol abuse, substance abuse, and major mental illness. In 70 alcoholics and 20 controls, we measured CSF homovanillic acid (HVA), the major metabolite of dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). No association was found between a particular DRD4 dopamine receptor allele and alcoholism. CSF concentrations of the monoamine metabolites showed no significant difference among the DRD4 genotypes. This study of the DRD4 dopamine receptor in alcoholics is the first to be conducted in a clinically and ethnically homogeneous population and to relate the DRD4 genotype to CSF monoamine concentrations. The results indicate that there is no association of the DRD4 receptor with alcoholism.

Swallowing dysfunction in nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis causes renal failure in most patients at approximately 10 years of age. This can be prevented or retarded by cystine-depleting therapy with oral cysteamine. Many patients who do not receive adequate cysteamine therapy undergo renal transplantation, but the accumulation of cystine continues in other organs, resulting in various clinical abnormalities. We report age-related swallowing dysfunction in patients with nephropathic cystinosis. METHODS: We studied 43 patients with cystinosis (24 who had received a renal transplant and 19 who had not), 3 to 31 years of age. Oral motor function was assessed by a cranial-nerve oral sensorimotor examination, and an oral motor index was calculated for each patient. The oral phase of swallowing was assessed by ultrasonography, and the pharyngeal and esophageal phases were evaluated by videofluoroscopy. RESULTS: Approximately half the patients were slow eaters. Oral motor dysfunction, reflected by a higher oral motor index, increased with age. Speech, oral structure and anatomy, and tongue and lip strength were particularly affected. Seven of nine patients 21 to 31 years old had abnormalities in all three phases of swallowing; the deficits were variable in younger patients. In 28 patients with cystinosis, the mean (+/- SD) duration of oropharyngeal swallowing for a dry swallow (3.06 +/- 1.06 seconds) was longer than in 14 normal subjects (1.89 +/- 0.57 seconds; P less than 0.001). This prolongation reflected impairment of the initiation phase of swallowing. CONCLUSIONS: Swallowing dysfunction is a late complication of nephropathic cystinosis, probably related to muscular dysfunction. Changes in the consistency of foods, swallowing exercises, and long-term cysteamine therapy should be considered for patients with cystinosis who have difficulty in swallowing.

Electrophoretic examination of proteinuria in Lowe's syndrome and other causes of renal tubular Fanconi syndrome.

Urine samples from 26 patients with five different causes of renal tubular Fanconi syndrome were examined by zone electrophoresis on agarose gel and immunofixation. The tubular disorders associated with Lowe's syndrome, cystinosis, and idiopathic Fanconi syndrome exhibited urine protein electrophoretic characteristics that differentiated them from normal and from each other. In particular, Lowe's syndrome urine exhibited four discrete bands in the gamma globulin zone. Electrophoresis of urinary proteins may be useful in distinguishing among the different metabolic disorders causing renal tubular Fanconi syndrome.

Carrier-mediated transport of monoiodotyrosine out of thyroid cell lysosomes.

Monoiodotyrosine (MIT) crosses the lysosomal membrane of rat FRTL-5 thyroid cells by a carrier-mediated process. In egress studies, MIT lost from inside lysosomes was quantitatively recovered outside lysosomes as MIT, indicating that the compound was transported intact across the lysosomal membrane. In uptake studies, [125I]MIT entry required intact lysosomes and exhibited saturation kinetics. The apparent Km for MIT was approximately 1.5 microM and the Vmax was approximately 0.24 pmol/unit hexosaminidase/min. Countertransport of MIT was demonstrated, with an initial velocity of [125I]MIT uptake which reached a maximum at high intralysosomal MIT loading. Nonradioactive MIT and diiodotyrosine competed to approximately equivalent extents with [125I]MIT for uptake in countertransport experiments. The existence of a lysosomal MIT carrier in thyroid cells may explain how this product of thyroglobulin catabolism is transported to the cytosol for iodine salvage and reutilization.