Further delineation of the executive deficit in males with fragile-X syndrome

This paper presents a detailed analysis of one aspect of performance by young males with fragile-X syndrome (FMR-1 full mutation) who were assessed on a computerised visual search task as part of a larger study examining aspects of attention [Neuropsychologia 38 (2000) 1261]. They were matched on chronological and mental age to 25 boys with Down's syndrome (trisomy 21) and on mental age to 50 mainstream school boys (controls). The controls were further divided into those matched on "poor attention" to the fragile-X boys and a "good" attention group, as rated by the comprehensive teacher rating scale (ACTeRS) questionnaire. Both fragile-X and Down's syndrome boys made significantly more repeated responses on targets (but a lower proportion of errors based on confusion of shape) than the two control groups and these differences were stronger in the fragile-X group. In the single target condition, search was for a single type of target throughout. In the dual target condition, participants were required to alternate between two different targets. Fragile-X boys showed significantly greater inability than Down's syndrome and normal boys to switch attention between targets and both learning-disabled groups were inferior to the control groups. Thus, both learning-disabled groups displayed a weakness in inhibiting repetition and in switching attention from one type of target to another and the impairments were more acute in fragile-X boys. The results provide further support for an attention deficit in this population at higher levels of attention control/executive functioning that involve switching visual attention and inhibiting repetitious behaviour.     

Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats.

PURPOSE: NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile. Experimental Design: Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion. In step 2, the NSC 655649 dose was divided into three consecutive daily doses. Plasma and urine were sampled to assess the pharmacokinetic and excretory characteristics of NSC 655649. A total of 12 patients were enrolled at the MTD for the purpose of gender equity. RESULTS: Forty-three patients were treated with NSC 655649 for a total of 108 cycles in step 1, and 26 patients were treated for a total of 41 cycles in step 2. The MTD for both steps 1 and 2 was determined to be 572 mg/m(2). Myelosuppression was the dose-limiting toxicity. Local venous irritation was generally grade 1-2 in severity but could only be adequately prevented by administration of study drug through central i.v. access. One patient with adenocarcinoma of unknown primary experienced a partial response on step 1. Four patients experienced stable disease of >100 days duration. CONCLUSIONS: NSC 655649 may be safely given at an MTD of 572 mg/m(2) in both single-dose and multiple-dose formats. Optimally, this drug should be administered through central i.v. access.     

A phase Ib/II trial of granulocyte-macrophage-colony stimulating factor and interleukin-2 for renal cell carcinoma patients with pulmonary metastases: a case of fatal central nervous system thrombosis

BACKGROUND: Interleukin-2 (IL-2) and granulocyte-macrophage-colony stimulating factor (GM-CSF) are cytokines with nonoverlapping pleiotropic effects. In a prior Phase Ib study, this combination of agents exhibited antitumor effects in the lungs of four of eight patients with renal cell carcinoma and pulmonary metastases. We conducted this Phase Ib/II trial to determine the response rate of renal cell carcinoma patients with pulmonary metastases treated with continuous infusion IL-2 plus GM-CSF. METHODS: Patients with renal cell carcinoma and pulmonary metastases were treated with 1.5, 2.25, or 4.5 x 10(6) IU/m(2)/day 96-hour continuous infusion IL-2 on Days 1-4, 8-11, and 15-18, and 1.25, 2.25, or 2.5 microg/kg/day GM-CSF on Days 8-19. RESULTS: Sixteen patients were treated per protocol, 14 of whom could be evaluated for disease progression. None of these 14 patients had >50% shrinkage of either total tumor burden or pulmonary metastasis. One patient developed Grade 5 neurotoxicity. Autopsy revealed acute multifocal cerebral venous thrombosis as well as acute subdural and subarachnoid hemorrhage. CONCLUSIONS: The combination of IL-2 and GM-CSF may be associated with marked morbidity and, as in one case in this study, mortality. No significant antitumor activity was appreciated. Thus, the combination of IL-2 and GM-CSF, when administered at this dose and according to this schedule, does not appear to be active in renal cell carcinoma and is associated with significant toxicities. Further studies using this combination of agents should only be undertaken with extreme caution and particular attention to neurotoxicity.     

Effects of suramin on the proliferation of primary epithelial cell cultures derived from normal,benign hyperplastic and cancerous human prostates

Primary epithelial cultures (PECs) derived from normal, benign hyperplastic (BPH), and cancerous human prostate tissue were treated with increasing doses of suramin, and assayed for cell proliferation over a period of days. The suramin IC₅₀ (inhibitory concentration 50%) value was 0.5 to 1.0 × 10^?4 M whereas doses between 2.5 × 10^?4 and 5 × 10^?4 M resulted in total growth inhibition. This inhibition was reversible by exchange with suramin-free medium up to day 6. Concentrations ? 5 × 10^?4 M resulted in increased cytotoxicity as exposure time increased. No differential response to suramin could be demonstrated among the prostate PECs derived from different tissues. The established cell lines, PC-3 and DU 145, grown in serum containing medium exhibited IC₅₀s comparable to the PECs grown in serum free medium. EGF, bFGF, α, or β ECGF at the concentrations tested did not reverse suramin inhibition. Increasing concentrations of bovine pituitary extract (BPE) increased cell growth in both the treated and the control cells. However, the percent growth inhibition by suramin at each concentration of BPE remained constant. Flow cytometry examination of cells treated for 7 days with suramin (0–10^?3 M) failed to detect any significant cell cycle alterations compared to control. At high concentrations of suramin (? 10^?4 M), large numbers of viable and dead cells were detectable in the medium. The increase in unattached viable cells was most prevalent (80%) in cultures treated with suramin at the time of plating, but also occurred with cells (25–30%) plated hours prior to the addition of suramin. Treatment for several days with low concentrations of suramin (10^?7 to 10^?5 M) transiently enhanced cell growth compared to Controls. © 1993 Wiley-Liss. Inc.     

Characterization of colonic transit of nondisintegrating tablets in healthy subjects

The transit of pharmaceutical dosage forms through the colon has been shown to be highly variable. The amount of fiber in the diet is known to alter gastrointestinal transit; however, the dietary intake of the subjects in previous studies was not adequately controlled. Using the technique of gamma scintigraphy, we have therefore characterized the variability in the colonic transit of nondisintegrating tablets, by strictly controlling the dietary fiber intake of the subjects. Eight healthy male subjects followed a diet containing 25g dietary fiber per day, for six days prior to dosing. Each subject received five 6-mm nondisintegrating tablets on three consecutive days. Mouth-to-anus transit times exhibited a high degree of variability. Regional differences in colonic transit were evident. Tablet stasis appeared to occur mainly in the ascending colon and hepatic flexure. Despite the diets of the volunteers being identical, colonic transit was still observed to be highly variable, which suggests that this variability is intrinsic.     

A parametric analysis of olanzapine-induced weight gain in female rats

RATIONALE: Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear. OBJECTIVE: The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings. METHODS: Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration. RESULTS: Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg). CONCLUSIONS: These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.     

An electrophysiological investigation of factors facilitating strategic recollection

Episodic memory is thought to be mediated by executive processes that facilitate the retrieval of task-relevant information at the expense of irrelevant information. The exclusion task [A process dissociation framework: Separating automatic from intentional uses of memory. Journal of Memory and Language, 30, 513-541, 1991] can be used to explore these processes. In this task, studied items from one source ("targets") are endorsed on one response key, whereas new and studied items from another source ("nontargets") are rejected on another key. Herron and Rugg [Strategic influences on recollection in the exclusion task: Electrophysiological evidence. Psychonomic Bulletin and Review, 10, 703-710, 2003] reported that nontargets elicited the ERP correlate of recollection (the "left parietal old/new effect") when target accuracy was low, but not when it was high. Their explanation for this was that participants only focused exclusively on the recollection of target information when the likelihood of target recollection was high, as under these conditions this strategy is one that that will give rise to accurate task performance. The fact, however, that targets were encoded in different tasks in the high- and low-accuracy groups means that the results can also be explained in terms of the encoding operations performed at study rather than in terms of target accuracy. This study was designed to distinguish between these competing accounts. All targets were encoded elaboratively. Target accuracy was reduced in one condition with a 40-min study-test interval. Nontargets elicited no left parietal effect in either condition, suggesting that target-specific strategic retrieval is facilitated by certain classes of encoding operations rather than simply high target accuracy per se.     

Extracranial internal carotid artery aneurysm presenting as symptomatic hypoglossal and glossopharyngeal nerve paralysis

Aneurysms of the extracranial portion of the internal carotid artery are rare, particularly in young patients. They usually develop following trauma, or secondary to infection involving the parapharyngeal space that extends to the vessel wall. This is a case of an internal carotid artery aneurysm presenting acutely following chiropractic neck manipulation with hypoglossal and glossopharyngeal nerve palsy. The imaging findings and subsequent operative management are described.