Efficacy of taxol in the orpk mouse model of polycystic kidney disease

Studies on conscious Sprague-Dawley rats using intracerebral dialysis in live animals combined with high-performance liquid chromatography with electrochemical detection showed that administration of apomorphine into the nucleus accumbens decreased the levels of dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in the extracellular space of the dorsal striatum throughout the observation period and produced a transient reduction in the level of homovanillic acid in the dialysate from this structure. The studies demonstrated that reversible exclusion of the nucleus accumbens with procaine produced a transient increase in the levels of dopamine metabolites, without an increase in serotonin metabolites, in the extracellular space of the dorsal striatum. These results demonstrate that the nucleus accumbens affects dopamine metabolism in the striatum, this being mediated by the dopamine-reactive system in the nucleus accumbens.     

Renal expression of a transforming growth factor-alpha transgene accelerates the progression of inherited, slowly progressive polycystic kidney disease in the mouse

DNA ploidy measurement by flow (FCM) or image cytometry (ICM) of single cell suspensions of solid tumour has prognostic value, but it would be a definite advantage if the assessment could be done on histological sections. However, this is usually not possible by means of standard ICM, due to the capping of nuclei in thin sections, or overlap in thick sections. Three-dimensional (3D) microscopy by means of confocal laser scanning microscopy (CLSM) could solve this problem in theory but the results published so far are not very satisfactory. A new method has been developed in which the DNA content of haploid (human testis spermatozoa), diploid, tetraploid, octaploid (human and rat liver and human spermatogonia), and near-triploid (human breast cancer) nuclei stained with YOYO-1 iodide has been measured by a newly developed 3D image cytometry method (3DICM) in 20 microns thick histological sections. YOYO-1 iodide is a new highly sensitive, specific, stoichiometric, and stable fluorescent dye for DNA. DNA ploidy of a breast cancer which was near-triploid with FCM and ICM was also assessed with 3DICM in a tissue section adjacent to the section used for FCM and ICM and the results were compared. The integrated 3DICM fluorescence intensity showed good linearity (r = 0.99) with the real DNA content of all nuclei analysed. In human tissue, the coefficient of variation of 3DICM for haploid (n = 12), diploid (n = 63), triploid (n = 13), tetraploid (n = 12), and octaploid (n = 3) ploidy distributions was 5.1, 6.6, 4.2, 4.0, and 0.6 per cent, respectively (n = the number of nuclei). For the rat liver, the CV of the diploid (n = 21), tetraploid (n = 31), and octaploid (n = 3) peaks was 6.7, 4.8, and 1.6 per cent, respectively. Repeated "blind' measurements of nuclei with different DNA indices showed excellent reproducibility between different observers (r = 0.98). It is concluded that the 3DICM method used is accurate, reproducible, and clinically feasible in thick histological sections. This is especially important in small lesions, or if the results of DNA ploidy measurement of single cell suspensions (by FCM) or imprints (by ICM) are inadequate.     

Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2)

By use of differential display, we have isolated a new early auxin-responsive cDNA in Nicotiana tabacum. Nt-gh3 had 70% identity with the unique GH3 sequence isolated in soybean by Hagen et al. [Planta 162 (1984) 147-153] and is thus the first reported cDNA related to this gene until now. Nt-gh3 mRNA accumulates within a short time after auxin treatment, responds to very low concentrations of NAA (as little as 10[-9] M) and specifically to active auxins. Nt-gh3 mRNA is demonstrated to be one of the most relevant early molecular markers of primary auxin response.     

Seminal vesicle cysts in the patients with adult polycystic kidney disease

Hemifacial spasm features myoclonic-like, paroxysmal, unilateral muscle twitching, attributable to vascular compression at the facial pontine root entry zone. We present the case of an 85-year-old man who presented with idiopathic hemifacial spasm with onset 23 years before. For the last 5 years, he was successfully treated with botulinum toxin injections. However, occasional nitrate intake for precordial pain promptly triggered muscle twitching. Vasodilation may exacerbate not only cases of hemifacial spasm, but even of trigeminal neuralgia, both recognized as neurovascular compressive syndromes.     

Association between pancreatic cystadenocarcinoma, malignant liver cysts, and polycystic disease of the kidney

Polycystic kidney disease is an autosomal dominant disease that may be associated with cystic disease of the liver. In women, the cysts may develop early and be more troublesome than in men. Cystadenocarcinoma of the pancreas is uncommon, comprising 1% of primary pancreatic malignancies. This case report is the first to describe a familial association between polycystic kidney disease and cystadenocarcinoma of the pancreas and liver in the English medical literature. A patient with autosomal dominant polycystic kidney disease (ADPKD) and multiple hepatic cysts developed cystadenocarcinoma of the pancreas with multiple malignant liver cysts. The patient's mother, sister, and niece had ADPKD, and the patient's sister also died of pancreatic cystadenocarcinoma. We believe that the development of these two disease entities in which the primary pathology is cyst formation has a genetic association.     

Potassium citrate/citric acid intake improves renal function in rats with polycystic kidney disease

Polycystic kidney disease (PKD) has been shown to be exacerbated by acidosis or a low potassium intake, and there is evidence that administration of alkali might have a beneficial effect. This study determined whether ingestion of potassium citrate and citric acid would ameliorate PKD. Healthy normal and heterozygous littermate Han:SPRD rats with autosomal dominant PKD were provided with either tap water or 55 mM K3citrate/67 mM citric acid solution (KCitr) to drink starting at the age of 1 mo. Renal clearance measurements and histologic assessments were performed when the rats were 3 mo old. KCitr intake did not affect body weight or urine flow, but completely prevented the decline in GFR found in untreated rats with PKD. In rats that drank tap water, left kidney GFR averaged (in microliter/min per 100 g body wt) 503 +/- 78 (n = 9) in normal animals and 242 +/- 56 (n = 6) in rats with PKD. In rats that drank KCitr, GFR averaged 562 +/- 123 (n = 7) in normal animals and 534 +/- 103 (n = 7) in rats with PKD. Kidneys of rats with PKD were approximately double normal size. KCitr treatment did not affect kidney size, but led to fewer interstitial abnormalities and smaller cysts in cystic kidneys. KCitr ingestion led to a significantly lower (P < 0.001) plasma [K+] in rats with PKD (3.3 +/- 0.2 versus 4.1 +/- 0.2 mEq/L in rats on tap water). Chronic KCitr intake in the young heterozygous Han:SPRD rat with PKD yields a modest improvement of kidney histology and a dramatic improvement in GFR. The mechanism of action of KCitr and the long-term effects of this treatment on renal structure and function in PKD deserve further study.     

Segregation analysis of the testis-determining autosomal trait, Tda, that differs between the C57Bl/6J and DBA/2J mouse strains suggests a multigenic threshold model

The testis-determining autosomal trait (Tda) of the mouse was uncovered when the Y chromosome of the poschiavinus variety of Mus musculus domesticus was introduced into the C57BL/6J laboratory strain background. Testis development is normal in the F1 generation but, in the backcross and subsequent crosses to C57BL/6J females, XY individuals with the poschiavinus Y chromosome expressed bilateral ovaries or various combinations of an ovotestis with a contralateral ovary or testis or bilateral ovotestes and few had testes bilaterally. In other strain backgrounds, such as DBA/2J, XY individuals with the poschiavinus Y chromosome always expressed normal testes bilaterally. The first breeding analysis of this difference in the interaction of strain background with the poschiavinus Y chromosome suggested that the Tda trait was due to a single gene, but attempts to map it failed. We constructed two strains of C57BL/6J and DBA/2J that are consomic for the poschiavinus Y chromosome in order to conduct a segregation analysis of the Tda trait. In the C57BL/6J.Y-POS consomic strain, liability to express incomplete testis development is normally distributed and thresholds in development specify the probability of different classes of ovary, ovotestis, and testis combinations. Testis development is complete in the DBA/2J.Y-POS consomic strain. We demonstrated previously that the Tda trait of C57BL/6J is recessive to that of DBA/2J and the segregating first backcross generation of embryos rejected the single-gene model. We have extended our analysis to a F2 generation of embryos that also rejects a single-gene model. We also report a test mating analysis of the first backcross generation. It was initiated to provide an independent assessment of the single-gene model, but the analysis of the distribution of test mating results suggests that the difference in the Tda trait between C57BL/6J and DBA/2J may be due to a small number of loci, possibly four or five, and that the phenotypic effect between loci may be additive.     

Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of three genes: PKD1 on chromosome 16 accounts for approximately 85% of cases whereas PKD2 on chromosome 4 accounts for approximately 15%. Mutations in the PKD3 gene are rare. All patients present with similar clinical phenotypes, and the cardinal symptom is the formation of fluid-filled cysts in the kidneys. Previous work has provided data supporting the notion that cysts in ADPKD1 are focal in nature and form after loss of function of polycystin 1. This became evident by demonstrating that the normal PKD1 allele was inactivated somatically by loss of heterozygosity or by mutagenesis in a subset of renal or liver cysts examined. We show in this report, for the first time, multiple novel somatic mutations within the PKD2 gene of epithelial cells, in both kidneys of an ADPKD2 patient. From a total of 21 cysts examined, seven (33%) had the same C insertion within the inherited wild-type allele. In two other cysts, a nonsense mutation and a splice site AG deletion had occurred in a PKD2 allele that could not be identified as the inherited wild-type or mutant. We suggest that the autosomal dominant form of ADPKD2 occurs by a cellular recessive mechanism, supporting a two-hit model for cyst formation.     

New amino acid polymorphism, Ala/Val4058, in exon 45 of the polycystic kidney disease 1 gene: evolution of alleles

The PKD1 gene, which is responsible for the most common form of autosomal dominant polycystic kidney disease, has recently been cloned and sequenced. Many disease-causing mutations have been characterized in this gene, most of them resulting in premature protein termination. However, mutation analysis not routinely implemented for family investigations in a clinical setting, because of the large size and complexity of the gene. Instead, genetic linkage analysis using highly polymorphic CA dinucleotide repeats that map around the gene is still the method of choice. Recently, a few intragenic polymorphisms have been described that are also useful for linkage studies. Here, a new diallelic polymorphism is described for amino acid residue 4058, Ala/Val4058, with allelic frequencies of 0.88 and 0.12, respectively, and a heterozygosity of 0.23, in the Greek and Greek-Cypriot populations. Interestingly, this polymorphism and Ala4091-A/G, which has previously been described in Caucasians, were not detected in DNA from 44 Japanese samples tested. This is particularly important when allelic frequencies in a particular population are used for linkage analysis of families of different ethnic origin. Also, observation of the two polymorphisms together as haplotypes suggests that the Ala/Val4058 polymorphism occurred more recently than the establishment of the Ala4091-A/G polymorphism, and specifically on the G allele.     

DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning.

It has been proposed that DBA/2 and C57BL/6 mice perform differently on some learning and memory tasks because of functional differences in the hippocampal formation. To evaluate this hypothesis, DBA/2 and C57BL/6 male mice were tested on 2 forms of conditioned fear: contextual fear conditioning, which depends on the integrity of the hippocampal formation, and auditory cue conditioning, which does not. Both mouse strains displayed equivalent conditioning when the auditory cue was paired with shock, but DBA/2 mice showed significantly less conditioning to the context in which shock was experienced. These results are consistent with the hypothesis that the pattern of spared and impaired performance, which DBA/2 mice display on a variety of learning and memory tasks, is related to impaired hippocampal formation function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetics, haloperidol, and the Fos response in the basal ganglia: a comparison of the C57BL/6J and DBA/2J inbred mouse strains

The haloperidol-induced increase of Fos-like immunoreactive (Fos-li) neurons in the basal ganglia was compared in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. The D2 strain is 10-fold more sensitive than the B6 strain to haloperidol-induced catalepsy, a putative animal model of the extrapyramidal symptoms (EPS) seen after the administration of typical neuroleptics. In contrast, the strains are equally sensitive to the haloperidol facilitation of prepulse inhibition of the acoustic startle response, a measure of drug efficacy on the mesolimbic dopamine system. The haloperidol effects on Fos-li neurons were examined over the range of 0.1 to 6.0 mg/kg; the ED50s for haloperidol-induced catalepsy are 0.4 and 3.8 mg/kg in the D2 and B6 strains, respectively. In neither the core or shell of the nucleus accumbens nor the caudate-putamen (including the dorsolateral aspect) did the D2 strain show a greater Fos response compared to the B6 strain. In fact, in the dorsolateral caudate-putamen, the B6 strain showed a modest but significantly greater Fos response. However, at the output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra zona reticulata (SNr), the D2 strain consistently showed a greater Fos response. These data suggest that the EP and SNr may be important to understanding the difference in haloperidol-induced catalepsy between the D2 and B6 strains.     

Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice

PURPOSE: To characterize ocular abnormalities associated with iris atrophy in DBA/2J mice and to determine whether mice of this strain develop elevated intraocular pressure (IOP) and glaucoma. METHODS: Different approaches, including slit-lamp biomicroscopy, ophthalmoscopic examination, ultrasound backscatter microscopy, and histology were used to examine the eyes of DBA/2J mice ranging from 2 to 30 months old. IOP was measured in DBA/2J mice of different ages. RESULTS: DBA/2J mice were found to develop pigment dispersion, iris transillumination, iris atrophy, anterior synechias, and elevated IOP. IOP was elevated in most mice by the age of 9 months. These changes were followed by the death of retinal ganglion cells, optic nerve atrophy, and optic nerve cupping. The prevalence and severity of these lesions increased with age. Optic nerve atrophy and optic nerve cupping was present in the majority of mice by the age of 22 months. CONCLUSIONS: DBA/2J mice develop a progressive form of secondary angle-closure glaucoma that appears to be initiated by iris atrophy and the associated formation of synechias. This mouse strain represents a useful model to evaluate mechanisms of pressure-related ganglion cell death and optic nerve atrophy, and to evaluate strategies for neuroprotection.     

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat

Lactation in mammals is characterized by a marked hyperphagia and significantly elevated levels of prolactin (PRL). Several recent experiments in our laboratory have provided evidence for a causal relationship between PRL and hyperphagia. The present series of studies revealed that PRL injected intracerebroventricularly (i.c.v.) twice daily for ten days to free feeding virgin female rats produced a dose-dependent increase in food intake without disrupting vaginal cyclicity, that the hyperphagic effect of centrally administered PRL was not dependent on the presence of ovarian hormones, that it did not selectively potentiate feeding during the light or dark phase of the daily light cycle and that the latency of the feeding response to i.c.v. PRL administration was shorter in food restricted animals. Taken together, these results support the idea that PRL acts centrally to potentiate food intake.