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Hyperlipoproteinaemia resulting from thyroid suppression and long-term ingestion of a high cholesterol diet caused prolonged lipaemia retinalis in 6 rhesus monkeys. No atherosclerotic deposits or other ophthalmoscopically visible changes of the retinal vasculature were detectable. In 2 animals histopathological examination revealed segmental atrophy and gliosis of the optic nerves bearing a resemblance to chronic ischaemic optic neuropathy. One monkey developed ophthalmoscopically visible temporal pallor of the optic discs. Emboli of fat laden cells in blood vessels of the brain in one of these 2 monkeys, and in a penicillated splenic artery in the other animal, were associated with signs of systemic embolic occlusion, suggesting a similar course in the development of optic nerve damage. [ABSTRACT FROM PUBLISHER]

Rats killed 24 hours after a single injection of 30–100 mg/kg Isoproterenol (N-iso-propyl noradrenaline), show focal myocardial necrosis. Animals previously immunized against homologous (rat) heart homogenate showed a marked increase in severity and extent of the lesions. Immunization against rabbit heart caused a lesser degree of enhancement; rat kidney, rabbit serum and kidney and saline-adjuvant emulsion as antigens, gave results similar to the controls. There was no correlation between the level of circulating anti-heart antibodies, as measured by passive haemagglutination, and the severity of the myocardial necrosis. Within each treatment group, however, animals with higher titres tended to show greater myocardial damage. It is suggested that circulating anti-heart antibodies, normally non-toxic in vivo, become cytopathogenic after the myofibre cell barrier is broken down by Isoproterenol. [ABSTRACT FROM AUTHOR]

Two patients with gout and amyloidosis are reported. In contrast with other forms of chronic arthritis gout is apparently not associated with an increased incidence of amyloidosis. The possible reasons for this exception are discussed. [ABSTRACT FROM AUTHOR]

We previously described the development of nonproteinuric diabetic nephropathy (NPDN) in the Cohen diabetic rat (CDs), a model that simulates Type 2 diabetes in humans. Using linkage analysis in an F2 cross, we currently set out to investigate the mechanisms underlying NPDN. We crossbred between CDs and SBN/y, a nondiabetic rat strain, generated F1 and F2 progenies, fed them diabetogenic diet that elicits diabetes and NPDN in CDs but not in SBN/y, and determined metabolic and renal phenotypes. Over 5 mo, ∼75% of F2 developed a diabetic phenotype. In parallel, a nephropathy developed in F2, with glomerular filtration rate (GFR) declining in ∼25% and, unexpectedly, significant proteinuria appearing in ∼75%. We scanned the F2 genome with microsatellite markers and used linkage analysis to identify quantitative trait loci (QTLs). We detected diabetes-related QTLs on RNO4 and 13. We also detected two QTLs for the decline in GFR on RNO4 and 13 and another QTL for proteinuria on RNO13. The metabolic and renal-related QTLs overlapped. These results suggest that the mechanisms underlying the nephropathy in F2 are related to genes that map to RNO4 and 13, as well as a common genetic background for the development of diabetes and the renal disease. Our findings further indicate that proteinuria is inhibited in parental diabetic CDs, thus accounting for the nonproteinuric phenotype, but "unmasked" in diabetic F2 whose genome has been modified. Identifying the nature of the factor inhibiting proteinuria in diabetic CDs but not in F2 may provide a clue to treatment and prevention of proteinuria in diabetes.

Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a central role in the activation of several transient receptor potential (TRP) channels. The role of PIP2 on temperature gating of thermoTRP channels has not been explored in detail, and the process of temperature activation is largely unexplained. In this work, we have exchanged different segments of the C-terminal region between cold-sensitive (TRPM8) and heat-sensitive (TRPV1) channels, trying to understand the role of the segment in PIP2 and temperature activation. A chimera in which the proximal part of the C-terminal of TRPV1 replaces an equivalent section of TRPM8 C-terminal is activated by PIP2 and confers the phenotype of heat activation. PIP2, but not temperature sensitivity, disappears when positively charged residues contained in the exchanged region are neutralized. Shortening the exchanged segment to a length of 11 aa produces voltage-dependent and temperature-insensitive channels. Our findings suggest the existence of different activation domains for temperature, PIP2, and voltage. We provide an interpretation for channel-PIP2 interaction using a full-atom molecular model of TRPV1 and PIP2 docking analysis.

Temperature transduction in mammals is possible because of the presence of a set of temperature-dependent transient receptor potential (TRP) channels in dorsal root ganglia neurons and skin cells. Six thermo-TRP channels, all characterized by their unusually high temperature sensitivity (Q10 > 10), have been cloned: TRPV1-4 are heat activated, whereas TRPM8 and TRPA1 are activated by cold. Because of the lack of structural information, the molecular basis for regulation by temperature remains unknown. In this study, we assessed the role of the C-terminal domain of thermo-TRPs and its involvement in thermal activation by using chimeras between the heat receptor TRPV1 and the cold receptor TRPM8, in which the entire C-terminal domain was switched. Here, we demonstrate that the C-terminal domain is modular and confers the channel phenotype regarding temperature sensitivity, channel gating kinetics, and PIP2 (phosphatidylinositol-4,5-bisphophate) modulation. Thus, thermo-TRP channels contain an interchangeable specific region, different from the voltage sensor, which allows them to sense temperature stimuli.

The Cohen diabetic rat is an experimental model reminiscent of human type 2 diabetes. The aim of this study was to characterize the development of end-organ damage in this model. Cohen diabetic sensitive (CDs) and Cohen diabetic resistant (CDr) rats were fed regular diet or a diabetogenic diet. Glucose tolerance, renal function, and renal and retinal histology were studied at set intervals. CDs fed diabetogenic diet were the only strain that expressed the diabetic metabolic phenotype. In this strain, urinary protein excretion did not increase with the development of diabetes, but plasma urea and creatinine levels increased and creatinine clearance decreased. Light microscopy revealed in CDs enlarged glomeruli with increased mesangial matrix and thickening of the glomerular capillary wall; electron microscopy demonstrated thickened basement membrane and mesangial abundance. There was increased staining for type IV collagen in glomeruli and interstitium of CDs. The retinas of diabetic CDs demonstrated pathology consistent with nonproliferative diabetic retinopathy. The histological findings in the kidneys, the absence of proteinuria, the impairment in glomerular filtration, and the development of retinopathy in CDs are consistent with diabetes-associated nephropathy that is similar to a nonalbuminuric type of nephropathy associated with type 2 diabetes in humans.

In voltage-dependent channels, positive charges contained within the S4 domain are the voltage-sensing elements. The "voltage-sensor paddle" gating mechanism proposed for the KvAP K+ channel has been the subject of intense discussion regarding its general applicability to the family of voltage-gated channels. In this model, the voltage sensor composed of the S3b and the S4 segment shuttles across the lipid bilayer during channel activation. Guided by this mechanism, we assessed here the accessibility of residues in the S3 segment of the Shaker K+ channel by using cysteine-scanning mutagenesis. Mutants expressed robust K+ currents in Xenopus oocytes and reacted with methanethiosulfonate ethyltrimethylammonium in both closed and open conformations of the channel. Because Shaker has a long S3-S4 linker segment, we generated a deletion mutant with only three residues to emulate the KvAP structure. In this short linker mutant, all of the tested residues in the S3b were accessible to methanethiosulfonate ethyltrimethylammonium in both closed and open conformations. Because the S3b moves together with the S4 domain in the paddle model, we tested the effects of deleting two negative charges or adding a positive charge to this region of the channel. We found that altering the S3b net charge does not modify the total gating charge involved in channel activation. We conclude that the S3b segment is always exposed to the external milieu of the Shaker K+ channel. Our results are incompatible with any model involving a large membrane displacement of segment S3b.

Background: The diagnosis of infective endocarditis is usually made on the basis of clinical and laboratory criteria and may be confirmed by histologic examination or culture of excised valves. We tried to determine the incidence and significance of inflammatory changes in valves excised during operations for reasons other than infective endocarditis., Methods: The charts and histopathology of all patients undergoing valve replacement during a 10-year period (1993-2002) were reviewed. A total of 868 patients underwent a total of 970 valve replacements during this period, of whom 11 patients (1.3%) were for endocarditis, with the remaining 857 (98.7%) for other indications. All excised valves were cultured and examined histologically for the presence of inflammatory infiltrates, vegetations, and microorganisms., Results: In 8 of 857 patients (0.9%), the histologic examination unexpectedly demonstrated an infiltrate suggestive of endocarditis. Blood and valve cultures, and serologic tests for Mycoplasma, Chlamydia, Legionella, Q fever, Brucella, Rickettsiae, VDRL, and Bartonella were negative in all but 1 patient, who was found to have Q fever. All received a prolonged course of antibiotics. Six patients had an uneventful recovery; 1 had intramyocardial abscesses and expired during cardiac reoperation; and 1 had recurrent fever and dehiscence of the aortic and mitral valve prostheses and after two cardiac reoperations remains in severe heart failure., Conclusions: The presence of an unexpected inflammatory infiltrate in heart valves excised for reasons other than endocarditis may occur in 0.9% of such operations; these infiltrates could indicate presence of endocarditis. A microbial origin should be sought, and patients should receive empiric antibiotic treatment for endocarditis.

Osteoporosis is well documented in type I diabetes, but its occurrence is controversial in type II diabetes. Microangiopathy is a major complication of type I and type II diabetes. We studied bone and microvascular changes in the Cohen diabetic rat, a unique nonobese model of noninsulin-dependent diabetes mellitus. The aim of this study was to find whether there is a temporal correlation between the onset of these two complications. The diabetic rats were divided into three groups (A, B, and C) according to duration of diabetes (2 months, 3 months, and 7 to 8 months, respectively). Trabecular bone area was assessed by computerized image analysis and microangiopathy by means of renal function tests, histologic examination of the kidneys, and ultrastructural measurement of the width of capillary basement membranes. Bone density of the distal femur and vertebra was significantly reduced in the diabetic rats relative to the control rats in all three groups (Group A femur: 11.5 +/- 1.6% versus 21.8 +/- 3.0%, p < 0.02; Group A vertebra: 15.9 +/- 1.6% versus 28.5 +/- 2.0%, p < 0.02; Group C femur: 7.9 +/- 1.1% versus 29.6 +/- 3.5%, p < 0.001; Group C vertebra: 11.4 +/- 0.7% versus 37.1 +/- 1.9%, p < 0.002). Renal function tests were normal in the Group A diabetic rats and there was marked albuminuria in the Group C diabetic rats. Histologic changes in the kidneys were seen only in the Group C diabetic rats. Five of 15 Group C diabetic rats showed no albuminuria or histologic evidence of kidney damage. The bone density in this subgroup was reduced relative to controls to the same degree as that of the rats with renal damage. There was no evidence of capillary basement membrane thickening in the Group A diabetic rats. Our findings indicate that in the Cohen diabetic rat, osteoporosis precedes the onset of microangiopathy. Microangiopathy probably does not play an important role in the pathogenesis of osteoporosis in this animal model.

In search of an experimental model that would simulate the association between proteinuria and salt sensitivity in humans, we studied protein excretion in the Sabra rat model of salt susceptibility. Monthly measurements of urinary protein excretion in animals fed standard rat chow revealed that normotensive salt-sensitive SBH/y developed proteinuria that averaged 65 +/- 7 mg/day (n = 10) at 9 mo, whereas proteinuria in normotensive salt-resistant SBN/y was 39 +/- 4 mg/day (n = 10) (P < 0.01). Histopathological evaluation revealed focal and segmental glomerulosclerosis (FSGS) lesions grade 2 in SBH/y and normal histology in SBN/y. To amplify the differences between the strains, uninephrectomy was performed. At 9 mo, proteinuria in SBH/y with one kidney (SBH/y-1K) was 195 +/- 12 mg/day (n = 10) and in SBN/y was 128 +/- 10 mg/day (n = 10) (P < 0.001); histopathology revealed FSGS grade 3 in SBH/y-1K and grade 1-2 in SBN/y-1K. To determine the effect of salt loading, animals were provided with 8% NaCl in chow, causing hypertension in SBH/y but not in SBN/y. Proteinuria markedly increased in both SBH/y with two kidneys (SBH/y-2K) and SBH/y-1K, but not in SBN/y; histopathology revealed FSGS grade 1-2 in SBH/y-2K, grade 2 in SBH/y-1K, no lesions in SBN/y-2K, and grade 0-1 in SBN/y-1K. We concluded that the SBH/y strain is more susceptible to develop proteinuria and glomerulosclerosis than SBN/y. In search for the genetic basis of this phenomenon, we investigated the role of candidate proteinuric gene loci. Consomic strains were constructed by introgressing chromosome 1 (which harbors the rf-1 and rf-2 proteinuric loci) or chromosome 17 (which harbors rf-5) from SBH/y onto the SBN/y genomic background. The resulting consomic strains developed marked proteinuria that was severalfold higher than in SBN/y-1K; histopathological evaluation, however, revealed FSGS lesions grade 1-2, similar to those found in SBN/y-1K and less severe than in SBH/y-1K. These results suggest a functional role of gene systems located on chromosomes 1 and 17 in inducing proteinuria in the salt-susceptible Sabra rat strain. These genetic loci do not appear to harbor major genes for glomerulosclerosis.

We undertook the present study to examine the effect of the angiotensin-converting enzyme inhibitor enalapril, the angiotensin II antagonist losartan, and calcium antagonist verapamil on systolic pressure and spontaneous blood glucose levels in rats from the Cohen-Rosenthal diabetic hypertensive strain. Genetic hypertension and diabetes developed in this strain after crossbreeding of Cohen diabetic and spontaneously hypertensive rats. The new rat strain was fed their usual copper-poor sucrose diet, which is essential for the development of this model, and for 4 weeks received either enalapril, losartan, or verapamil. Systolic pressure was reduced significantly compared with controls in all treated groups. Chronic treatment with enalapril or verapamil, but not with losartan, succeeded in lowering spontaneous blood glucose, indicating improved diabetic control. Data suggest that angiotensin-converting enzyme inhibition by enalapril, but not angiotensin II antagonism by losartan, can improve glucose metabolism in addition to its hypotensive effect in a genetic diabetic hypertensive rat strain. This confirms that the drop in glucose with converting enzyme inhibition is highly dependent on bradykinin accumulation. Data further suggest that calcium channel blockade by verapamil can also improve glucose metabolism. The question remains whether the reduction in glucose by verapamil was a result of inhibition of glucogenesis.

Intraocular malignant mesenchymal tumors are very rare, and only a few case reports of such primary and metastatic tumors have been reported. We report a case of a malignant mesenchymoma involving the entire uveal tract. A 21-year-old woman presented with a tumor on the whole iris of the right eye, which caused intractable glaucoma. Upon enucleation of the eye, a very anaplastic tumor was found to occupy the whole uveal tract; its features were compatible with a tumor of mesenchymal origin, including rhabdomyosarcomatous and liposarcomatous characteristics. Choroidal osteoma was a coincidental finding. The histologic findings of the tumor were of two types of malignant mesenchymal tumors, and therefore the diagnosis of malignant mesenchymoma was made. This is to our knowledge the first tumor of its kind to be reported intraocularly.

The chromatographic behaviour of E.coli tRNA(Val) (1), Val-tRNA(Val) (1) and Phe-tRNA(Val) (1) was studied on BD-cellulose columns. At pH 4.0 and 4 degrees C the elution position of Phe-tRNA(Val) (1) was not affected by the presence of absence of Mg(2+), whereas Val-tRNA(Val) (1) was slightly retarded when Mg(2+) was ommited. It is postulated that the amino acid and its nature influence the structure that the aminoacyl-tRNA assumes. Under suitable conditions the heteroaminoacylated Phe-tRNA(Val) (1) eluted significantly later than other tRNAs. This fact showed that heterologous mischarging can be a useful step in tRNA purification methods.

Apparent deficiency of alpha-galactosidase A was observed in a 51-year-old, clinically healthy male, with no clinical symptoms of Fabry disease, and without excess urinary excretion of ceramide trihexoside. The deficiency, which was similar to that found in Fabry disease patients, could be demonstrated using both synthetic and natural substrates. This pseudodeficiency was transmitted in his family by classical X-linked inheritance. His wife showed enzyme activity in the normal range, two daughters were heterozygotes for this mutation as demonstrated by hair root assay, and three sons showed normal alpha-galactosidase activity. Kinetic studies in cultured skin fibroblasts indicated a five-fold increase in the apparent Km and a greater heat stability of the residual alpha-galactosidase activity when compared to controls. These data indicate that the residual enzyme activity in this mutation behaves similarly to that observed in Fabry disease patients but does not cause any clinical abnormalities.

Red cells of newborn calves contain 105-110 mmole K(+) and 1-5 mmole Na(+) per liter of cells. As the animals age the K(+) content decreases to a value of 25-30 mmole/liter of cells after about 60 days. At approximately the same time, the sodium content reaches a value of 60-70 mmole/liter. The time required for half change (t((1/2))) is 35-37 days for both Na(+) and K(+). The activity of (Na + K)-adenosine triphosphatase (ATPase) and the influx of K(42) and Rb(86) into the red cells are high at birth and are reduced to 5 and 15% of their original values, respectively, in mature animals. t((1/2)) for both is of the order of 30-35 days. The membrane Mg-ATPase activity is also high at birth and is reduced with a t((1/2)) of 28-32 days to a final value of about 20% of its activity at birth. Separation of red cells according to their age showed that, in animals at the age of transition, newly formed red cells contain a higher K/Na ratio and a higher active transport capacity than older red cells of the same animal. It is suggested that the changes observed are a reflection of the average age of the red cell population as the animal grows.