Synergistic signals in the mechanism of antigen-induced exocytosis in 2H3 cells: evidence for an unidentified signal required for histamine release.

The aim of this study was to determine whether the increase in cytosolic free Ca2+ concentration ([Ca2+]i) in response to antigen (aggregated ovalbumin) on IgE-primed 2H3 cells was sufficient to account for exocytosis. When the [Ca2+]i responses to antigen and the Ca2+ ionophore A23187 were compared, A23187 was much less effective at releasing histamine at equivalent [Ca2+]i increases, and little or no stimulated histamine release occurred with A23187 concentrations that matched the [Ca2+]i response to antigen concentrations that stimulated maximal histamine release. The [Ca2+]i response to antigen is not, therefore, sufficient to account for exocytosis, although extracellular Ca2+ is necessary to initiate both the [Ca2+]i response and histamine release: the antigen must generate an additional, unidentified, signal that is required for exocytosis. To determine whether this signal was the activation of protein kinase C, the effects of the phorbol ester 12-0-tetradecanoyl phorbol 13-acetate (TPA) on the responses to antigen were examined. TPA blocked the antigen-induced [Ca2+]i response and the release of inositol phosphates but had little effect on histamine release and did not stimulate exocytosis by itself. The unidentified signal from the antigen is therefore distinct from the activation of protein kinase C and is generated independently of the [Ca2+]i response or the release of inositol phosphates. Taken together with other data that imply that there is very little activation of protein kinase C by antigen when the rate of histamine release is maximal, it is concluded that the normal exocytotic response to antigen requires the synergistic action of the [Ca2+]i signal together with an unidentified signal that is not mediated by protein kinase C.

Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression.

Vasopressin and corticotropin releasing factor (CRF) are both critical regulators of an animal's stress response and have been linked to anxiety and depression. As such, antagonists of the CRF1 and V1b receptor subtypes are being developed as potential treatments for affective disorders. The two most characterized V1b and CRF1 antagonists are SSR149415 and CP-154,526, respectively, and the present studies were designed to compare these two compounds in acute animal models of affective disorders. We employed five anxiety models: Separation-induced pup vocalizations (guinea pig and rat), elevated plus-maze (EPM), conditioned lick suppression (CLS), and marble burying (mouse); as well as three depression models: forced swim test (FST; mouse and rat) and tail suspension test (TST; mouse). SSR149415 (1-30 mg/kg) was active in the vocalization, EPM and CLS models, but inactive in marble burying. CP-154,526 (1-30 mg/kg) was active in vocalization models, but inactive in EPM, CLS, and marble burying. SSR149415 was inactive in all depression models; CP-154,526 was active in rat FST but inactive in mouse models. This work demonstrates the different profiles of V1b and CRF1 receptor antagonists and supports both approaches in the treatment of affective disorders.

Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan.

PURPOSE: To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) and topotecan in patients with epithelial ovarian carcinoma that recurred after or didn't respond to first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Patients with measurable and assessable disease were randomized to receive either PLD 50 mg/m(2) as a 1-hour infusion every 4 weeks or topotecan 1.5 mg/m(2)/d for 5 consecutive days every 3 weeks. Patients were stratified prospectively for platinum sensitivity and for the presence or absence of bulky disease. RESULTS: A total of 474 patients were treated (239 PLD and 235 topotecan). They comprised the intent-to-treat population. The overall progression-free survival rates were similar between the two arms (P =.095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively (P =.390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. Data analyzed in platinum-sensitive patients demonstrated a statistically significant benefit from PLD for progression-free survival (P =.037), with medians of 28.9 for PLD versus 23.3 weeks for topotecan. For overall survival, PLD was significantly superior to topotecan (P =.008), with a median of 108 weeks versus 71.1 weeks. The platinum-refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P =.455). Severe hematologic toxicity was more common with topotecan and was more likely to be associated with dosage modification, or growth factor or blood product utilization. CONCLUSION: The comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in this patient population.

Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.

RATIONALE: Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198. OBJECTIVES: The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally, neurological studies examined potential side effects of Ro64-6198 in the rat and mouse. RESULTS: Ro64-6198 (3-10 mg/kg) increased punished responding in a rat conditioned lick suppression test similarly to chlordiazepoxide (6 mg/kg). This effect of Ro64-6198 was attenuated by J-113397 (10 mg/kg), but not the mu opioid antagonist, naltrexone (3 mg/kg). In addition, Ro64-6198 (1-3 mg/kg) reduced isolation-induced vocalizations in rat and guinea pig pups. Ro64-6198 (3 mg/kg) increased the proportion of punished responding in a mouse Geller-Seifter test in wild-type (WT) but not ORL-1 KO mice, whereas diazepam (1-5.6 mg/kg) was effective in both genotypes. In rats, Ro64-6198 reduced locomotor activity (LMA) and body temperature and impaired rotarod, beam walking, and fixed-ratio (FR) performance at doses of 10-30 mg/kg, i.e., three to ten times higher than an anxiolytic dose. In WT mice, Ro64-6198 (3-10 mg/kg) reduced LMA and rotarod performance, body temperature, and FR responding, but these same measures were unaffected in ORL-1 KO mice. Haloperidol (0.3-3 mg/kg) reduced these measures to a similar extent in both genotypes. These studies confirm the potent, ORL-1 receptor-mediated, anxiolytic-like effects of Ro64-6198, extending the findings across three species. Ro64-6198 has target-based side effects, although the magnitude of these effects varies across species.

Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later.

OBJECTIVES: We evaluated recurrence and survival for 68 patients with malignant melanoma who participated in a 6-week structured psychiatric group intervention 5 to 6 years earlier, shortly after their diagnosis and initial surgical treatment. We also explored the role of several factors as possible predictors of outcome. DESIGN: This was a randomized controlled experimental study. The Cox proportion hazards regression model was used to quantify the relationship between treatment and the outcomes adjusted by the covariates (age, sex, Breslow depth, tumor site, baseline Profile of Mood States Total Mood Disturbance, baseline active-behavioral coping, baseline natural killer cell activity, and treatment [ie, group intervention]). The stepwise procedure was used for covariate selection. RESULTS: For control patients, there was a trend for recurrence (13/34) and a statistically significant greater rate of death (10/34) than for experimental patients (7/34 and 3/34, respectively). We found that being male and having a greater Breslow depth predicted greater recurrence and poorer survival. Analysis of multiple covariates found that only Breslow depth and treatment (ie, group intervention) were significant. Adjusting for Breslow depth, treatment effect remained significant. Finally, baseline affective distress and baseline coping were significant psychobehavioral predictors for recurrence and survival. Surprisingly, higher levels of baseline distress as well as baseline coping and enhancement of active-behavioral coping over time were predictive of lower rates of recurrence and death. CONCLUSION: Psychiatric interventions that enhance effective coping and reduce affective distress appear to have beneficial effects on survival but are not proposed as an alternative or independent treatment for cancer or any other illness or disease. However, the exact nature of this relationship warrants further investigation.

Growth and maturation of children with insulin-dependent diabetes mellitus.

The purpose of this paper is to define criteria used for classifying patients into varying degrees of diabetic control and to verify that children with diabetes maintained in higher degrees of metabolic control do not have delayed growth and maturation. Growth records of 252 children with insulin-dependent diabetes who have been under continuous observation in our clinic at three- to five-month intervals for at least three years and up to 16 years have been individually reviewed and analyzed. All children received two daily injections of a mixture of two parts of an intermediate to one part of regular insulin and were instructed to eat structured meals of high-quality selected foods. An over-all rating for diabetic control based primarily on the frequency and degree of glycosuria was made for the time period between clinic visits. The over-all diabetic control rating and the size of the subgroups were "good"--20 per cent, "fair to good"--64 per cent, and "fair"--16 per cent. All children maintained in "good" and "fair to good" control (84 per cent), grew and matured at a normal rate regardless of the age at onset or duration of diabetes. All children in lower degrees of control coming under care for greater than 24 months after diagnosis had accelerated growth during the early months after attaining a higher degree of control.

Blink rate in childhood schizophrenia spectrum disorder.

Spontaneous blink rate, a putative measure of dopamine function, was measured in schizophrenic, schizotypal, and normal children, aged 5.6-13.2 years during three different cognitive tasks. Unlike that of schizophrenic adults, the blink rate of the schizophrenic children who were not on neuroleptics was significantly lower than that of the normal children. There were no statistically significant differences, however, in the blink rates of the neuroleptic-treated schizophrenic children and the normal children. The schizophrenic and schizotypal children had similar spontaneous blink rates. Within each diagnostic group, the blink rate was lowest for listening, intermediate for conversation, and highest for verbal recall. These findings highlight the need to examine the relationship between age, blink rate, and dopamine function in childhood-onset schizophrenia spectrum disorder.

Blink rate in children with attention-deficit-hyperactivity disorder.

Spontaneous blink rate, a noninvasive measure of dopamine function, was coded in 28 children with attention-deficit-hyperactivity disorder (ADHD) and in 47 normal children during a listening, a conversation, and a verbal recall task. Unlike the normal children, the children with ADHD did not increase their blink rates significantly across these three tasks. The ADHD subjects were were not on stimulants had significantly lower blink rates than the normal children during verbal recall. The ADHD subjects on stimulants, however, had significantly higher blink rates than the normal subjects during the listening task. These preliminary findings are discussed in light of their potential implications for theories on neurotransmitter dysfunction and arousal in ADHD.

Event-related potential correlates of impaired attention in schizophrenic children.

Electrophysiological correlates of focused attention were studied in 13 schizophrenic and 19 age- and gender-matched children. Subjects performed a version of the Continuous Performance Task (CPT) in which a target was designated as any digit from 0 through 9 occurring on two successive stimulus presentations. Signal digits were surrounded by distractor digits which varied in position, value, and number. Event-related potentials (ERPs) elicited by each stimulus of a target pair were recorded from midline and homologous parietal, temporal, and occipital electrode placements. Schizophrenic children made significantly more errors of omission and commission than normal children. The amplitude and time course of the intertrial CNV was the same for both groups. There was a circumscribed amplitude asymmetry, left smaller than right, for the P1/N1 and P2 measures which was greater in normal than in schizophrenic children. The P3 component was significantly larger to the second stimulus of the target pair than to the first for both groups, and larger for the normal than the schizophrenic children to both stimuli.

Continuous-processing related ERPS in schizophrenic and normal children.

The continuous performance task (CPT) has proven to be sensitive to schizophrenic impairments. Multichannel event-related potential (ERP) data were recorded from schizophrenic and normal children during performance of easy and hard versions of the CPT. Schizophrenics produced fewer hits, more false alarms, and prolonged reaction times. Poor performance in schizophrenics was associated with four ERP abnormalities: (1) Schizophrenics did not exhibit the normal increase in amplitude of an early-onset, processing-related negativity from nontarget to target stimuli, suggesting a failure to appropriately allocate attentional resources to discriminative processing. (2) Although P3 amplitude to targets was not significantly smaller in schizophrenic children, the distribution of P3 amplitude between target and nontarget responses in the easy and hard versions of the CPT was abnormal, suggesting that schizophrenics differed in the strategic allocation of resources in later stages of CPT processing. (3) In all task conditions schizophrenics showed a parietal negative component with a latency of 400 msec seen in younger, but not older normal children, suggestive of maturational lag. (4) ERP data demonstrated absence of right-lateralized P1/N1 amplitude in schizophrenic children. Taken together these data indicate that at several stages of information processing, schizophrenics are deficient in the control and strategic allocation of processing resources.

Continuous-processing--related event-related potentials in children with attention deficit hyperactivity disorder.

Visual information processing in children with attention deficit hyperactivity disorder (ADHD) was studied using event-related potentials recorded during two versions of the Continuous Performance Task (CPT). ADHD children made more errors, and had longer reaction times than normal children on both the single- and dual-target CPT. Event-related potential waveforms were normal in the ADHD children with reference to early processing stages, i.e., contingent negative variation, P1-N1 laterality, and processing negativities, suggesting that ADHD children did not differ in their level of preparedness or their ability to mobilize resources for target identification and categorization. With respect to later processing, P3 amplitude was reduced in the ADHD group, whereas P3 latency was longer than normal. ADHD children had a diminished late frontal negative component, suggestive of reduced involvement in postdecisional processing.

Event-related potential correlates of linguistic information processing in schizophrenics.

Event-related potentials (ERPs) were recorded from adult schizophrenics and age- and education-matched normal controls during performance of an idiom recognition task involving judgments of the meaningfulness of idiomatic, literal, and nonsense phrases. Schizophrenics produced more errors and had prolonged reaction times while attempting to correctly differentiate meaningful from meaningless phrases. An ERP correlate of that deficit was a larger than normal N400 to idioms and literals, with no difference in N400 amplitude to nonsense phrases. This result was interpreted as evidence that the influence of the linguistic context provided by the first word of two-word idiomatic and literal phrases is reduced in schizophrenia. Schizophrenics also showed reduced amplitude P300.

Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis.

BACKGROUND: Children with primary nocturnal enuresis (PNE) wet the bed during all stages of sleep and irrespective of state of arousal, suggesting that during sleep, when voluntary, i.e., cortical control, is not available, the signal from the distended bladder is not registered in the subcortical centers inhibiting micturition. Deficient prepulse inhibition (PPI) of startle has been reported in PNE. This study evaluates the association of this PPI deficit in PNE with comorbidity with attention-deficit hyperactivity disorder (ADHD) and with intelligence. METHODS: Prepulse modulation of startle was studied in 96 boys with PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS: After adjustment for presence or absence of ADHD, lower or higher IQ, age, and unmodulated startle amplitude, there was a significant association between PNE and deficient PPI of startle following the 120-msec prepulse interval. Those enuretic boys who also were ADHD or had higher performance IQs (> or = 110) showed the greatest PPI deficit. CONCLUSIONS: A common deficiency of inhibitory signal processing in the brain stem may underlie both deficient PPI and the inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and intelligence suggests a possible genetic mediation of these effects.

Continuous-processing related ERPS in adult schizophrenia: continuity with childhood onset schizophrenia.

BACKGROUND: Previous work with schizophrenic children disclosed deficits on two continuous performance tests (CPTs) and ERP indices of reduced attentional resource allocation. METHODS: The two CPTs were administered to adult schizophrenics and matched control subjects. The simple CPT required only that the subject respond whenever the target digit was displayed. The complex version required a response whenever any digit was displayed on two successive trials. Event-related potentials (ERPs) were recorded during task performance. RESULTS: Schizophrenics had fewer hits on both CPT versions, showed a greater drop in performance from the simple to the complex CPT, and took longer to respond than controls. The processing negativity (Np) showed a greater amplitude increase from nontarget to target in normals than in schizophrenics, and the overlapping P2 component was more negative in normals. P3 latency was longer in schizophrenics, but P3 amplitude did not differ. CONCLUSIONS: Group performance and processing negativity effects replicated those from an earlier study of schizophrenic and normal children administered the same versions of the CPT, suggesting similar abnormalities in the allocation and modulation of information processing resources.

Behavioral characteristics of high- and low-IQ autistic children.

The authors are developing the Behavior Observation Scale to objectively differentiate autistic, normal, and mentally retarded children aged 30--60 months. They describe operational definitions and procedures and report data on the frequency of selected behaviors among 114 children. Prior studies have revealed that to assess the clinical significance of behaviors in autistic children, both frequency of occurrence per subject and the number of children exhibiting the behaviors must be considered concurrently. This study confirms the hypothesis that it is critical to consider the IQ of the child when assessing the clinical significance of individual behaviors and groups of behaviors.

Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report.

As part of an autopsy research project, the brains of four autistic subjects were examined and compared with those of three comparison subjects without CNS pathology and one with phenytoin toxicity. The cerebellum was selected for initial investigation because pathognomonic symptoms and neurophysiological measures suggest that pathology may exist in the cerebellar-vestibular axis in certain patients. Total Purkinje cell counts were significantly lower in the cerebellar hemisphere and vermis of each autistic subject than in the comparison subjects.

Natural human interferon-alpha administered orally as a treatment of bovine respiratory disease complex.

Natural human interferon-alpha (nHuIFN-alpha) from three sources was given orally to 368 calves experiencing a natural outbreak of bovine respiratory disease complex (BRDC). In one study, 200 calves were given one treatment daily for 3 days of placebo or 20, 200, or 2,000 IU of nHuIFN-alpha before shipment. Calves treated with 20 or 200 IU had a significant (p < 0.05) weight gain benefit for the first 21 days in the feedlot, if they had rectal temperatures <40 degrees C when treated with nHuIFN-alpha. In a second trial, 168 mixed-breed calves (five groups randomized to 31-36 calves/group) were treated with one dose of placebo or 200 or 400 IU of nHuIFN-alpha after shipment to the feedlot. Using this regimen, a dose of 200 IU per calf significantly (p < 0.08) decreased the number of sick calves per group and delayed development of BRDC. Results of these studies demonstrate that oral administration of nHuIFN-alpha, which may partially mimic the nasally secreted IFN response reported during BRDC, may be beneficial in cattle.

Carbamazepine as an anticonvulsant in children.

Forty-five children with major motor or psychomotor seizure disorders were treated with carbamazepine in place of sedative anticonvulsants (phenobarbital, primidone) because of chronic behavioral difficulties. A batter of measures believed to reflect attentional and perceptual abilities was administered initially and repeated 4 to 6 months later following the drug crossover. At the conclusion of the study, 37 of the 45 children were judged to be drug "successes"; that is, general alertness and attentiveness were improved, while seizures were adequately controlled. This study indicates that therapeutic regimens of carbamazepine are less likely to interfere with mental functions in children than are equivalent doses of sedative anticonvulsants.

Event-related potentials in high-functioning adult autistics: linguistic and nonlinguistic visual information processing tasks.

Event-related potentials (ERPs) were recorded from high-functioning adult autistics and age- and IQ-matched normal controls during performance of two non-linguistic information processing tasks, the Continuous Performance Task (CPT) and Span of Apprehension (SPAN), and an Idiom Recognition Task (IRT) involving idiomatic, literal and nonsense phrases. The autistics exhibited behavioral deficits only when attempting to identify idiomatic phrases. The ERP correlate of that deficit was greatly reduced N400 to idioms. In addition, autistics produced larger N1 amplitudes in all tasks, and larger P3s in the IRT and CPT.

Meta-analysis of the role of platinum compounds in advanced ovarian carcinoma. The Advanced Ovarian Cancer Trialists Group.

This paper presents a systematic overview or meta-analysis of 54 randomized clinical trials testing a variety of chemotherapeutic approaches in advanced ovarian carcinoma. Prolonged follow-up data are available for most patients and individual patient data were made available for all patients; analysis was made on the basis of "intention to treat." Our report concentrates on two comparisons: (1) platinum alone versus platinum in combination, which appears to show a long-term survival advantage for the combination (however, the platinum dose in the single-agent arm was relatively low); and (2) carboplatin versus cisplatin, which shows no obvious survival differences. It is striking that no single study to date has been large enough to detect the modest survival differences expected from current therapy. Consequently, a series of international studies have been initiated. The International Collaborative Ovarian Neoplasm (ICON) group will examine the role of adjuvant chemotherapy in early ovarian cancer (ICON 1) and will compare carboplatin with cisplatin, doxorubicin, and cyclophosphamide in more advanced disease (ICON 2).