Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.

Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 microg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.     

Inhibition of the allograft response by donor specific blood transfusion: association with reduced local TH1 cytokines and nitric oxide but enhanced prostaglandin E2 production

BACKGROUND: Donor-specific blood transfusion (DST) may improve allograft survival in human and animal models, but the mechanisms for this graft protective effect are incompletely understood. The sponge matrix allograft model was used to determine if DST induces regulatory factors within the allograft. METHODS: C57BL/6 (H-2b) recipients received donor-specific (DBA/2J, H-2d) or syngeneic (C57BL/6) blood 7 days before sponge matrix allograft (DBA/2J) implantation. Fourteen days postgrafting, the sponge infiltrating cells (SIC) were examined for cytotoxic T cell (CTL) and natural killer (NK) activity, and sponge exudate fluid (SEF) was assessed for nitric oxide (.N=O) and prostaglandin E2 (PGE2) content. Interleukin- (IL) 2, IL-4, IL-10, and interferon-gamma (IFN-gamma) production by SIC was also determined. Recipient splenocytes were simultaneously assessed for anti-donor cytotoxic and proliferative responses and .N=O production. RESULTS: SIC from mice receiving syngeneic transfusions (ST) acquired both CTL and NK activity postgrafting, with maximal activity by day 14. DST suppressed both CTL and NK activity throughout the postgrafting period. Limiting dilution analysis (LDA) of SIC to determine precursor and native CTL frequency showed significantly lower responder cell frequency after DST compared with ST. SEF .N=O levels and SIC production of IL-2 and IFN-gamma in grafted DST mice were significantly lower than in grafted mice receiving ST. No significant amounts of IL-4 and very low levels of IL-10 were produced by SIC from grafted mice after either ST or DST. Conversely, PGE2 content of sponge fluid and serum from DST mice was higher than in mice receiving ST. Antigen stimulated splenocyte proliferation and CTL development assessed by LDA were also inhibited by DST. CONCLUSIONS: Reduction in local TH1 cytokines, absence of detectable TH2 cytokines, with enhanced PGE2 and depressed .N=O were observed in the local graft environment after DST. These data support the hypothesis that DST induces donor-specific intragraft suppressor factors, accompanied by reduced local and systemic immune activation.     

Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

PURPOSE: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. EXPERIMENTAL DESIGN: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. RESULTS: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. CONCLUSIONS: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.     

Plasma fibronectin levels in meningococcal disease

Fibronectin (a glycoprotein which modulates inflammation) may decrease mortality in systemic infection. Children with meningococcal disease (MCD) may have low fibronectin levels. We aimed to compare plasma fibronectin levels in children with MCD and controls, correlate fibronectin levels with interleukin-6 (IL-6), shock and death, and assess fibronectin as an aid to early diagnosis in MCD. Samples were taken on admission from 99 children with MCD and 49 controls. Plasma fibronectin was measured using a turbidimetric immunoassay. Plasma fibronectin was significantly lower in MCD compared to controls (57 μg/ml vs 105 μg/ml; P < 0.005). Children who died had significantly lower levels than survivors (29 μg/ml vs 62 μg/ml; P = 0.01). Fibronectin levels were negatively correlated with IL-6 levels. Fibronectin was a poor predictor of MCD. Conclusion Plasma fibronectin levels are decreased in children with MCD, especially in shock and death. This decrease is associated with high IL-6 levels. Fibronectin could be a novel therapy in severe MCD. Received: 6 June 1996 / Accepted: 16 October 1996     

Prolonged effects of repeated social defeat stress on mRNA expression and function of mu-opioid receptors in the ventral tegmental area of rats.

Social defeat stress alters the activity of mesocorticolimbic dopamine projections from the ventral tegmental area (VTA), a process that has been implicated in the development of sensitization and drug-seeking behavior. We showed previously that acute brief social defeat stress increased short-term expression of mu-opioid receptor mRNA in the VTA. The present study assessed the presence and functional significance of mu-opioid receptor mRNA expression 1 week after the last episode of social defeat stress. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat, and subsequent exposures behind a protective screen once a day for 5 days. Regional mu-receptor mRNA levels were assessed by in situ hybridization histochemistry, and the amount of mRNA labeling was measured in the VTA and the substantia nigra (SN). Expression of mu-opioid receptor mRNA was significantly higher in defeated rats relative to handled control animals in the VTA, but not in the SN. In an additional group of rats, bilateral local intra-VTA injection of the selective mu-opioid receptor agonist DAMGO (1.0 microg per side) was performed 7-10 days after the last defeat stress or handling control procedure. Baseline motor activity did not differ between control and stressed rats. Intra-VTA DAMGO significantly increased locomotor activity in stressed rats compared to handled control rats. These results suggest that repeated social stress upregulates VTA mu-opioid receptors and can produce locomotor activation via stimulation of these receptors. This locomotor effect is probably the consequence of enhanced disinhibition of mesolimbic dopamine neurons.     

A comparison study of different PCR assays in measuring circulating plasma epstein-barr virus DNA levels in patients with nasopharyngeal carcinoma.

PURPOSE: To compare the performance of three PCR assays in measuring circulating Epstein-Barr virus (EBV). DNA levels in nasopharyngeal carcinoma patients and to confirm its prognostic significance. EXPERIMENTAL DESIGN: Plasma from 58 newly diagnosed nasopharyngeal carcinoma patients were collected before, during, and every 3 to 6 months after radiotherapy. EBV DNA levels were determined by real-time quantitative PCR using primer/probe sets for polymerase-1 (Pol-1), latent membrane protein 2 (Lmp2), and BamHI-W. Pretreatment levels from the three assays were correlated with each other and serial measurements from the Pol-1 assay were correlated with clinical variables. RESULTS: Pol-1 was more accurate than BamHI-W in predicting EBV DNA concentrations in cell lines. Of the three assays, BamHI-W yielded the highest concentrations followed by Pol-1 in plasmas (n = 23). The correlation coefficient was 0.99 (P < 0.0001) for Pol-1 and Lmp2, 0.66 (P < 0.0001) for Pol-1 and BamHI-W, and 0.55 (P < 0.0001) for BamHI-W and Lmp2. Elevated pretreatment DNA levels as detected by Pol-1 were correlated with advanced nodal stage (P = 0.04) and overall stage (P = 0.028). There was no correlation between pretreatment EBV DNA levels and freedom-from-relapse or overall survival; however, there was a significant correlation between posttreatment levels and these variables. The 2-year freedom-from-relapse and overall survival rates were 92% and 94% for patients with undetectable, and 37% and 55% for those with detectable, posttreatment levels (P < 0.0001 and P < 0.002). CONCLUSIONS: The three PCR assays yielded similar results in detecting EBV DNA in plasmas. The Pol-1-detected posttreatment EBV DNA level was the strongest predictor for treatment outcomes.     

Dental age estimation of Omani children using Demirjian's method

Dental age plays a significant role in forensic dentistry, orthodontics and paediatric dentistry, as well as in general diagnosis and treatment planning. Different methods have been developed to determine dental age. One of the most commonly used methods is Demirjian’s method, which was developed in 1973 from research on a large number of French-Canadian children. It is based on the degree of tooth mineralisation by examining the radiological appearance of the lower mandibular left quadrant. The purpose of this study was to assess the dental age of Omani children using Demirjian's method and evaluate the applicability of the method in dental age estimation for Omani children. The sample consisted of 485 digital panoramic radiographs of children (264 males, 221 females) aged between 4.6?years and 16.5?years, and obtained from the records of the Military Dental Centre in Oman. The data were analysed using SPSS. Paired t-tests, intraclass correlation coefficients (ICC) and difference-against-mean plots were used to compare the dental age calculated by Demirjian's method with chronological age. A single examiner scored the radiographs, and intra-observer reliability was evaluated using Cronbach's alpha on data from rescoring one out of every 20 radiographs. For boys, the mean difference between chronological age and dental age for all age groups was 0.10 (95% CI ?0.03 to 0.24). For girls, the mean difference between chronological age and dental age for all age groups was 0.05 (95% CI ?0.11 to 0.22). Difference-against-mean plots showed no evidence of differential bias by age. For boys, the ICC was 0.896 (95% CI 0.869–0.917); for girls, it was 0.886 (95% CI 0.854–0.911). Difference-against-mean plots for boys (Fig. 1) and girls (Fig. 2) showed some evidence of differential bias by age. In conclusion, the extent of the observed differences was sufficient for doubt to be cast upon the utility of Demirjian’s method for Oman, particularly when it is considered that the method’s most likely application would be in age determination for minors in the workforce.     

Videotapes and multiple interviews: The effects on the child witness

Because of perceived disadvantages of multiple interviews, it has been proposed that the evidence‐in‐chief of child witnesses be given via a videotape made at their first and only interview. However, the child may still be required to face cross‐examination in court having presented their evidence on only one previous occasion. These changes overlook the potential benefits multiple interviews can have on memory for events, particularly given the delays faced by most courts. This paper deals with memory researth which is relevant to this debate, with a particular focus on the phenomenon of reminiscence (remembering previously unrecallable information). The implications of this research forgathering and presenting evidence are discussed.