Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.

Lesions of the frontal cortex, hippocampus, and intralaminar thalamic nuclei have distinct effects on remembering in rats.

Lesions of the intralaminar thalamic nuclei (ILn), the medial wall (MW) area of prefrontal cortex, and the hippocampus were compared and found to have distinct effects on delayed matching-to-sample (DMS) and delayed non-matching-to-sample (DNMS) tasks based on different types of stimulus cues. Hippocampal lesions impaired DNMS trained in a radial arm maze but had little effect on DMS trained with retractable levers or olfactory DNMS. MW lesions affected the DMS task but had limited effects on olfactory DNMS and radial arm maze DNMS. ILn lesions resulted in a more generalized pattern of impairment for radial maze tasks and (in previous studies) for the DMS and olfactory DNMS tasks. Only the hippocampal lesion was associated with a delay-dependent impairment. It is argued that ILn lesions disrupt remembering through their effects on the recurrent, feedback pathways that link functionally related areas of the basal ganglia and cortex.

The effects of frontal cortical lesions on remembering depend on the procedural demands of tasks performed in the radial arm maze.

We trained 24 rats to perform an eight-arm radial maze task and then assigned them with a matching procedure to one of three treatments: sham surgery or lesions of the projection areas of the mediodorsal thalamic nucleus (MDn) in the medial wall (MW) or in both the MW and rhinal sulcal (RS) areas of frontal cortex. After recovery we trained the rats to perform six tasks, beginning with the standard eight-arm task, followed by two versions of a four forced choice procedure, and then three versions of a two-choice delayed-nonmatching-to-sample (DNMTS) task. The two lesion groups performed comparably on all tasks, showing that impairments were not exacerbated by extension of the MW lesion to include all cortical areas innervated by MDn. As in previous studies, frontal animals performed the radial maze task poorly immediately after surgery but improved with subsequent training. Controlling the order of the arm entries by opening the first four gates in a random sequence had little effect on performance, although frontal animals were impaired when lengthy delays (5 or 15 min) were imposed after the last of the four forced entries. Frontal animals were not impaired on two-choice DNMTS when the arms used for training were selected at random from the eight alternatives on a trial by trial basis, even when visual cues were eliminated by darkening the room and covering the maze. Frontal animals were significantly impaired when the selection of sample and choice arms was limited to the same two alternatives on every trial. This finding may explain the reported sensitivity of DNMTS to the effects of frontal lesions when training is carried out in operant chambers.

Effects of reversible inactivation of thalamo-striatal circuitry on delayed matching trained with retractable levers.

The intralaminar thalamic nuclei are characterized by their prominent projections to striatum. Lesions of the intralaminar nuclei have been found to impair delayed matching trained with retractable levers. Comparable impairments have been observed for rats with lesions of the olfactory tubercle, involving ventral areas of striatum and pallidum. We conducted two experiments to test the functional dependence of thalamic and striatal lesions on the delayed matching task. In experiment 1, we determined the effects of inactivating the intralaminar nuclei with bilateral lidocaine infusions. In experiment 2, we compared the effects of unilateral thalamic inactivations in rats with unilateral olfactory tubercle lesions. We trained rats to perform the delayed matching task to criterion and then implanted dual cannulas aimed at the bilaterally symmetrical areas in the intralaminar nuclei. Rats in experiment 2 were also given a unilateral olfactory tubercle lesion. The results of experiment 1 showed dose-dependent impairments for bilateral infusions that were qualitatively similar, although of lesser severity than delayed matching impairments observed in previous studies for rats with lesions involving extensive areas of the intralaminar nuclei. A comparable impairment was observed in experiment 2 when thalamus was inactivated on the side opposite the olfactory tubercle lesion. Performances were significantly worse when thalamus was inactivated on the contra-lesion than on the ipsi-lesion side of the brain. These results are discussed in terms of the role of ventral striatum and related thalamic nuclei in memory.

A comparison of the effects of hippocampal or prefrontal cortical lesions on three versions of delayed non-matching-to-sample based on positional or spatial cues.

We trained rats to perform one of three versions of delayed non-matching-to-sample (DNMS): DNMS between two retractable levers in an enclosed operant chamber; varying-choice DNMS between two arms selected at random on every trial in an uncovered eight-arm radial arm maze; or recurring-choice DNMS between the same two arms on every trial in a covered radial maze (N=33/task). Rats with medial prefrontal cortical lesions showed delay-independent impairments on the retractable lever and recurring-choice tasks, but performed varying-choice DNMS normally. Rats with hippocampal lesions exhibited delay-independent impairments of the retractable lever task and delay-dependent impairments of both radial maze tasks. When rats trained initially to perform recurring choice DNMS were switched to varying choice DNMS, the impairments of both the prefrontal and hippocampal groups were reduced, although hippocampal animals remained significantly impaired. When rats trained initially to perform varying choice DNMS were switched to recurring choice DNMS, the impairment of the hippocampal group was exacerbated while the prefrontal group remained unimpaired. Thus training the prefrontal group to perform the varying choice task first seemed to protect from impairment when these rats were subsequently trained to perform recurring choice DNMS. This protection provides evidence against the possibility that factors related to proactive interference or to temporal discrimination can account for the effects of prefrontal lesions on delayed conditional discriminations involving two response alternatives in fixed locations.

Safety evaluation of Protaminobacter rubrum: intravenous pathogenicity and toxigenicity study in rabbits and mice.

The iv pathogenicity and toxigenicity of Protaminobacter rubrum was studied in New Zealand White rabbits and CF1 BR mice. Following a probe study, nine groups of six rabbits each were injected iv with; 1 ml of viable-cell suspension (VCS) at concentrations of 2.23 x 10(8), 10(6), 10(4) and 10(2) organisms/ml; the cell-free supernatant (CFS; in which the test organism had been cultured to a concentration of approximately 3 x 10(10) cells/ml) at dilutions of 1:100, 1:10,000 and 1:1,000,000 in phosphate buffered saline (PBS); uninoculated culture medium; or uninoculated PBS. Rabbits were observed daily for 14 days and body weights were recorded on days 0, 7 and 14. Body temperatures were recorded in two rabbits per group until 18 hr after dosing. On day 14, each rabbit was killed. Blood samples, sections of liver and spleen, and any tissues presenting lesions possibly indicating an infection were excised and cultured for P. rubrum. Deaths occurred in the probe study following 1 ml iv injection of VCS at a concentration of 2.5 x 10(10) organisms/ml or of undiluted CFS in which P. rubrum had been grown to a concentration of approximately 2.5 x 10(10) organisms/ml. Blood and tissue samples obtained less than 24 hr after treatment from rabbits in the VCS group tested positive for P. rubrum, which would be expected after iv administration of such a high concentration of cells. No deaths occurred, no adverse effects on body-weight gain were seen, and in no instance was P. rubrum recovered from blood or tissue cultures in the definitive study. Overt signs of infection or toxinosis were limited to transient reduced activity in the highest two VCS concentration groups, and the highest CFS group. Modestly elevated body temperatures were also recorded for rabbits that received the highest two concentrations of either VCS or CFS. A similar 14-day study was carried out in mice. Four groups of 20 Crl: COBS CF1 BR mice received a single iv injection of 0.1 ml of VCS (2.5 x 10(10) organisms/ml), CFS in which the test organism was cultured to approximately 2.5 x 10(10) cells/ml, uninoculated culture medium or uninoculated PBS. The mice were observed daily and body weights were recorded on days 0, 7 and 14. On day 14, each mouse was killed and blood samples as well as liver and spleen sections were obtained and cultured. In this study no deaths occurred, and signs of infection or toxinosis were limited to reduced activity and ptosis for all mice in the VCS and CFS groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Metastatic myxopapillary ependymoma: report of a case with fine-needle aspiration findings.

A case of recurrent and metastasizing myxopapillary ependymoma of the sacral region in a 35-yr-old man is reported. Fifteen years after the original diagnosis, he presented with an abdominal mass, subcutaneous nodules in the previous surgical excision line, and bilateral inguinal lymph node enlargement. FNA cytology of the inguinal lymph nodes showed a poorly cohesive, highly cellular smear pattern exhibiting papillary formations and rosette-like structures composed of slim columnar cells having cytoplasmic processes without evidence of atypia. Histologic and ultrastructural findings confirmed the diagnosis. Chromosomal analysis was also done.

Benign fibrous histiocytoma of the foot: a literature review and case report.

A rare case of benign fibrous histiocytoma involving the foot of a sixty-three-year-old white man is presented, with a review of the literature. The histopathologic appearance of benign fibrous histiocytoma, differential diagnosis, and surgical management are discussed. Fibrous histiocytomas are characteristically nonencapsulated tumors composed of a mixture of fibroblastic and histiocytic cells arranged in a storiform or cartwheel pattern.

A review of the toxicology profile of rioprostil.

The toxicity of rioprostil was extensively investigated. Studies in rodents, dogs and monkeys indicate a low order of acute toxicity. Oral subchronic and chronic toxicity studies in rats and dogs produce effects that would be expected based on the pharmacological activity of the compound. In reproduction studies with rioprostil, male and female fertility is unaffected in rats at doses up to 2.0 mg/kg/day and there is no evidence of embryotoxicity, fetotoxicity, or teratogenicity in rats at doses up to 1.7 mg/kg/day. In rabbits a maternally toxic dose (1.5 mg/kg) also increases resorptions, reduces fetal weight, and increases the incidence of malformations. Evaluation of 24-month carcinogenicity studies in mice and rats at oral doses up to 2.0 and 1.5 mg/kg/day, respectively, are in progress. Mutagenicity studies are negative.

Treatment of Parkinson's disease and restless legs syndrome with cabergoline, a long-acting dopamine agonist.

Dopamine agonists have diverse chemical and physical properties that can directly stimulate the dopamine receptors, unlike levodopa which undergoes presynaptic breakdown to dopamine before dopaminergic effects in Parkinson's disease (PD). Cabergoline, a dopamine agonist effective given once daily, is being used as treatment for PD. In theory, therapy with cabergoline provides striatal intrasynaptic dopamine replacement of PD in a physiological manner because of its long half-life and the resultant sustained rather than pulsatile dopaminergic stimulation. Several placebo-controlled trials using cabergoline as adjunctive therapy in PD have shown that cabergoline significantly reduces 'off' time, improves motor function and reduces levodopa requirement. Cabergoline has also been used as monotherapy in PD and has been shown to be as effective as other dopamine agonists in improving motor function and to be superior to levodopa in reducing dyskinesias over a five-year period. Work from our group and others have also demonstrated the efficacy of cabergoline in PD patients with nocturnal disabilities and those with restless legs syndrome (RLS). More recently we have reported that cabergoline is a well-tolerated dopamine agonist in both young and elderly patients and has an acceptable side-effect profile.

Spontaneous lesions in the sternums of growing rats.

Pathologic examination of sternums from young growing rats revealed a number of skeletal lesions involving both cartilage and bone elements. Degeneration or aseptic necrosis of the intersternebral cartilage was a frequent finding in most rats that were examined either at 130 or 180 days of age. Thickening of the sternal cortices and trabeculae containing prominent cement lines were less frequently occurring lesions in these sternums. These changes were absent in rats of 70 days of age. The etiology of the lesions is not understood, although several factors may be incriminated.

Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.

The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

An unusual case of generalized ceroid-lipofuscinosis in a cynomolgus monkey.

Histologic, histochemical, and electron microscopic studies of generalized ceroid-lipofuscinosis in a cynomolgus monkey are presented. Histologically, a wide variety of tissue cells contained numerous bright eosinophilic intracytoplasmic granules that varied in size from 0.5 micron to 4.0 microns in diameter. Histochemically, the granules gave a weakly positive reaction with periodic acid-Schiff and for lipids. They were weakly acid fast and capable of emitting autofluorescence. Ultrastructurally, the granules were single unit membrane-bound, and contained dense osmiophilic material with frequent concentric or fingerprint-type lamellar formation. The granules were different than hemofuscin, iron, and bilirubin. Tinctorially the granules were unique--they were bright red with hematoxylin and eosin and, thus, differed from typical age-related lipofuscin pigment.