Loss of heterozygosity for distal markers on 22q in human gliomas.

Loss of constitutional heterozygosity as determined through the analysis of restriction-fragment-length polymorphism (RFLP) on tumoral and constitutional DNA has proven to be helpful to delimit the location of tumor-suppressor genes in the human genome. In malignant gliomas this approach indicates that chromosomes 9p, 10, 17p, and 22 may contain genes of this category involved in its origin and/or progression. Regarding chromosome 22, the data so far provided by molecular studies confirmed those previously reported by cytogenetic studies, suggesting the existence of a sub-group of malignant gliomas characterized by monosomy of this chromosome. However, the precise location of the putative glioma suppressor gene on chromosome 22 remains ambiguous. We have performed a combined cytogenetic and RFLP study on a series of 31 gliomas, looking for structural abnormalities of this chromosome. In 3 instances, terminal deletions of the long arm of chromosome 22 were observed by both methodologies, suggesting that the band q13 region distal to the D22S80 marker might be the critical domain non-randomly involved in tumor suppression of gliomas.     

No increase in carcinogen-DNA adducts in the lungs of monkeys exposed chronically to marijuana smoke.

Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.     

Acute effects of chlorpromazine in a monkey operant behavioral test battery.

The effects of acute chlorpromazine treatment were assessed using a complex operant test battery (OTB) containing five tasks thought to depend upon processes associated with short-term memory and attention [delayed-matching-to-sample (DMTS)], color and position discrimination [conditioned position responding (CPR)], motivation [progressive ratio (PR)], time perception [temporal response differentiation (TRD)], and learning [incremental repeated acquisition (IRA)]. Adult male rhesus monkeys were tested 15 min after IV injection of saline or chlorpromazine (0.010, 0.030, 0.100, or 0.175 mg/kg). Behavioral endpoints measured included percent task completed, response rate or latency, and response accuracy. The order of task sensitivity to disruption by chlorpromazine was TRD = PR = IRA = DMTS = CPR in which sensitivity was defined as a significant alteration in any aspect of task performance. Chlorpromazine slowed response rates in all tasks except TRD but did decrease accuracy in that task. These effects were similar to those noted in previous studies of acute chlorpromazine treatment. Specific motoric effects suggested decreased task initiation at doses that left general motor ability intact. This finding is similar to that noted in parkinsonism caused by chronic chlorpromazine treatment.     

Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity.

We compared and contrasted the mechanism of action for the cysteine knot protein subfamily, Wise and Sost (Sclerostin). Our data suggest that functional interactions between Sost or Wise and LRP5/LRP6 have the potential to regulate bone deposition by modulating the Wnt pathway. INTRODUCTION: The human disease sclerosteosis exhibits an increase in bone mass thought to be caused by hyperactive osteoblasts. Sclerostin, SOST, the gene affected in this disease, has been postulated to exert its activity by functioning as a BMP antagonist. However, recent evidence indicates that SOST is highly related to Wise, which can also modulate the Wnt pathway by binding to LRP5 and LRP6. MATERIALS AND METHODS: For this study, we used cell culture to test the BMP and Wnt activity function of both Wise and Sost. In addition, we used Xenopus in vivo Wnt assays along with Xenopus in vitro Wnt assays to support our cell culture results. Epitope tagged cell supernatants containing either Sost or soluble mutant or wildtype LRP5/LRP6 were used for immunoprecipitation. Sost immunoprecipitation results were confirmed in vivo using cell culture. Finally, to support our in vitro data, we co-localized Sost, Wise, LRP5, and LRP6 in mouse long bone sections. Results: In this study, we report in vitro and in vivo evidence to show that Sost physically interacts with Lrp5 and Lrp6 and inhibits the canonical Wnt signaling pathway. Furthermore, using in vitro and in vivo assays, we showed that a variant of LRP5 (LRP5(G171V)) known to cause the human high bone mass (HBM) trait and a homologous change in LRP6 (LRP6(G158V)) abolished protein interactions with Sost. We used variants of Sost amino acids to further identify the contact points between Sost and LRP6. In Xenopus and mammalian cell culture assays, we showed that SOST is able to attenuate Wnt signaling and that this attenuation can be rescued by the addition of alpha-Sost antibodies or by the introduction of single amino acid substitution that alter its binding to LRP6. Sost differs from Wise in that it is unable to stimulate Wnt signaling. Using immunohistochemistry, we found that Sost and Wise are co-localized to osteoblasts, along with LRP5 and LRP6. CONCLUSIONS: Our data suggest that functional interactions between Sost or Wise and LRPs have the potential to regulate bone deposition by modulating Wnt signaling.     

Acute effects of d-amphetamine in a monkey operant behavioral test battery

The acute effects of d-amphetamine were assessed using a battery of complex food-reinforced operant tasks that included responding in delayed matching-to-sample (DMTS, n = 6), conditioned position responding (CPR, n = 7), progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 4), and incremental repeated acquisition (IRA, n = 9) tasks. Performance in these tasks is thought to depend upon specific brain functions such as short-term memory and attention (DMTS), color and position discrimination (CPR), motivation to work for food (PR), time perception (TRD), and learning (IRA). d-Amphetamine sulfate (0.01-1.0 mg/kg IV), given 15-min pression produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses of 0.3 and 1.0 mg/kg for TRD and at 1.0 mg/kg for CPR when compared to saline injections. Accuracy was not consistently affected in the DMTS or IRA tasks. Response rates decreased or response latencies increased significantly at doses of 0.3 and 1.0 mg/kg in the PR and DMTS tasks. A dose of 0.1 mg/kg for the IRA and TRD tasks, 0.3 mg/kg for DMTS and 1.0 mg/kg for the CPR tasks significantly decreased percent task completed. Thus, the relative sensitivities of these tasks for detecting d-amphetamine behavioral effects were IRA = TRD greater than PR = DMTS greater than CPR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Syringomyelia and Arnold Chiari in scoliosis initially classified as idiopathic: Experience with 25 patients

The authors analysed the clinical and radiological findings and the surgical management of 25 patients admitted for scoliosis classified as idiopathic at first presentation, but in fact associated with spinal cord and/or brain stem anomalies. Twenty patients had syringomyelia, 19 had Chiari malformation. Scoliosis was the only presenting symptom when all these patients were referred to the orthopaedic surgeon. On examination, five patients had normal neurological findings, while the others showed very mild neurological deficits. The diagnosis of syringomyelia and Chiari malformation was established by MRI, which is the best form of neuroradiological examination for discovering spinal abnormalities. Neurosurgical treatment is strongly recommended as the first step in the management of “pseudo” idiopathic scoliosis.