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.

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.

Improving access to diagnostics: an evaluation of a satellite laboratory service in the emergency department.

OBJECTIVES: To measure the impact of a satellite laboratory upon laboratory result turnaround times and clinical decision making times. DESIGN: A prospective cohort study, the intervention group had blood tests sent Monday to Friday 12 noon to 8 pm and the control group had blood tests sent outside these hours. The data were collected over a six week period before the laboratory was opened, and a subsequent six week period. SETTING: An urban teaching hospital emergency department. PARTICIPANTS: 1065 patients requiring blood tests. MAIN OUTCOME MEASURE: Time from the blood sample being sent to the laboratory to the results being available on the clinician's computer. RESULTS: The time to haematology (blood count) results in the intervention group decreased by 47.2 minutes (95% CI 38.3 to 56.1, p<0.001) after the laboratory was opened. The corresponding control group times were unchanged (0.6 minutes; -13.8 to 15.0, p = 0.94). Similar sized differences were also seen for haemostasis (d-dimer) testing 66.1 (41.8 to 90.4) minutes compared with -14.2 (-47.1 to 18.7) and chemistry 41.3 (30.3 to 52.2) compared with -4.2 (-17.4 to 8.9) testing. Decisions to discharge patients were significantly faster (28.2 minutes, 13.5 to 42.8, p<0.0001) in the intervention group after the laboratory was opened (controls; -2.6 minutes -27.0 to 21.7). No change was seen with decisions to admit patients. There was a trend for earlier laboratory results modifying intravenous drug or fluids orders, or both (p = 0.06) CONCLUSION: A comprehensive satellite laboratory service is an important adjunct to improve the timeliness of care in the emergency department.

Detection of cis-trans isomers of a synthetic peptide fragment of erythropoietin.

The synthesis of the protected fragment t-butoxycarbonyl-alanine-isoleucine-serine(benzyl)-proline (Pro)-Pro-OH derived from the hormone erythropoietin is described. The analysis of the peptide by high-pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC) yields apparently inconsistent results. Although HPLC consistently indicates the presence of only one component, TLC reveals a number of distinct species. Because satisfactory amino acid analysis and fast atom bombardment-mass spectrometry results are obtained, we think it possible that the distinct components arise from the cis-trans isomerization of the peptide bonds to the prolyl residues. An analysis using capillary electrophoresis under basic conditions identifies four components in the final product. Also, under similar conditions proton nuclear magnetic resonance spectroscopy is able to confirm the presence of cis and trans isomers. The results from this study demonstrate the usefulness of each of the four techniques in identifying the isomerism of the standard amino acid-Pro bond with respect to the peptide's ionic state.

Medial temporal lobe in childhood-onset schizophrenia.

The majority of anatomic and neuroimaging studies in adult-onset schizophrenia demonstrate decreased volumes of the medial temporal lobe when compared with findings in normal individuals. The goal of this study was to investigate the hypothesis that subjects with childhood-onset schizophrenia would show decreased volumes of the medial temporal lobe when compared to normal children. Thirteen children meeting DSM-III-R criteria for schizophrenia (mean age 14.2+/-3.8 years) and 20 normal children (mean age 12.0+/-2.8 years) were investigated. MRI scans were performed on a 1.5-T GE Signa MR scanner using a coronal plane SPGR at 1.4-mm slice thickness. Volumes were assessed by manually tracing bilateral hippocampus, amygdala and temporal lobes. After adjustment for age and total brain volume, the amygdala was significantly larger in the schizophrenics than in the control subjects, and this volume increase was more pronounced on the left side. Hippocampus volumes did not differ significantly across groups. There was a nearly significant left-greater-than-right asymmetry of the amygdala in the schizophrenic group but not in the normal group. A nearly significant right-greater-than-left asymmetry was found in the anterior hippocampus for both schizophrenic and control groups. These findings are consistent with previous reports of at least initial sparing of temporal lobe regions in childhood-onset schizophrenia.

Measures of psychopathology in children with complex partial seizures and primary generalized epilepsy with absence.

OBJECTIVE: This investigation examined psychopathology in 48 children with complex partial seizures (CPS), 39 children with primary generalized epilepsy with absence (PGE), and 59 nonepileptic children, aged 5 to 16 years, by comparing the Child Behavior Checklist (CBCL) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). METHOD: The CBCL was completed by parents and the K-SADS was administered to both parent and child. RESULTS: The CBCL identified psychopathology in 26% and the K-SADS in 51% of the CPS and PGE patients (kappa = 0.32). The CPS and PGE groups had significantly higher mean CBCL scores, as well as higher rates of psychiatric diagnoses and symptoms of psychopathology, compared with the nonepileptic group. However, the CPS and PGE groups did not differ in these measures. Within each patient group, Full Scale IQ, but not seizure control, was associated with these measures of psychopathology. CONCLUSION: These findings suggest that the K-SADS identifies more children with psychopathology than the CBCL in children with CPS and PGE.

Thought disorder in attention-deficit hyperactivity disorder.

OBJECTIVE: This study compared thought disorder and associated cognitive variables in attention-deficit hyperactivity disorder (ADHD) and schizophrenia. METHOD: Speech samples of 115 ADHD, 88 schizophrenic, and 190 normal children, aged 8 to 15 years, were coded for thought disorder. A structured psychiatric interview, the WISC-R, the Continuous Performance Test, and the Span of Apprehension task were administered to each child. RESULTS: The ADHD and schizophrenic groups had thought disorder compared with the normal children. However, the subjects with ADHD had a narrower range of less severe thought disorder than did the schizophrenic subjects. The younger children with ADHD and schizophrenia had significantly more thought disorder than did the older children with these diagnoses. IQ, attention, and working memory were associated with thought disorder in the ADHD but not the schizophrenic group. CONCLUSIONS: Thought disorder in childhood is not specific to schizophrenia and reflects impaired development of children's communication skills.

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.

Identification of the region of non-Abeta component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity.

The non-beta-amyloid (Abeta) component of Alzheimer's disease amyloid (NAC) and its precursor alpha-synuclein have been linked to amyloidogenesis in several neurodegenerative diseases. NAC and alpha-synuclein both form beta-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic. We recently established that a peptide comprising residues 3-18 of NAC retains these properties. To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC. Toxicity was measured by the ability of fresh and aged peptides to inhibit the reduction of the redox dye 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) by rat pheochromocytoma PC12 cells and human neuroblastoma SHSY-5Y cells. On immediate dissolution, or after ageing, the fragments NAC(8-18) and NAC(8-16) are toxic, whereas NAC(12-18), NAC(9-16) and NAC(8-15) are not. Circular dichroism indicates that none of the peptides displays beta-sheet structure; rather all remain random coil throughout 24 h. However, in acetonitrile, an organic solvent known to induce beta sheet, fragments NAC(8-18) and NAC(8-16) both form beta-sheet structure. Only NAC(8-18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. These findings indicate that residues 8-16 of NAC, equivalent to residues 68-76 in alpha-synuclein, comprise the region crucial for toxicity.

Conversational repair in pediatric epilepsy.

This study examined if children with complex partial seizures disorder (CPS) and primary generalized epilepsy with absence (PGE) were impaired in the use of self-initiated repair during a conversation compared to normal children. Transcriptions of speech samples of 92 CPS, 51 PGE, and 65 normal children, ages 5-16 years, were coded for self-initiated repair according to Evans (1985). The WISC-R, a structured psychiatric interview, and seizure-related information were obtained for each child. We found impaired use of repair in both the CPS and PGE groups compared to the normal subjects. The CPS patients, particularly those with a temporal lobe focus, overused self-initiated corrections of referents and syntax compared to the PGE and normal subjects. The CPS and PGE patients with frontal lobe involvement underused fillers compared to the normal children. These findings provide additional evidence that both CPS and PGE impact the ongoing development of children's communication skills.

Parents' and adolescents' perceptions of helpful and nonhelpful support for adolescents' assumption of diabetes management responsibility.

The study identified parents' and adolescents' perceptions of helpful and nonhelpful support, specific to adolescents' assumption of responsibility for diabetes management. Sixteen pairs of parents and adolescents with type 1 diabetes (11-18 years of age) were interviewed. The interviews were audiotaped and transcribed verbatim. Data were analyzed for manifest content according to social support dimensions identified by Barrera and Ainlay (1983). Inter-rater agreement between primary investigator and doctorally prepared diabetes nurse and educator was 100%. Both parents and adolescents describe directive guidance and tangible assistance as helpful and nonhelpful, depending on degree of directness and perceived need for help. Nurses can encourage parents to use subtle guidance and adolescents to communicate their needs.

Health-compromising behavior and diabetes mismanagement among adolescents and young adults with diabetes.

PURPOSE: This study examined the relationship between health-compromising behavior, age, gender, and diabetes mismanagement. METHODS: A total of 107 adolescents and young adults, 12 to 24 years old, with type 1 diabetes were asked to complete a health-compromising behavior scale and a diabetes mismanagement scale. RESULTS: Based upon participants' responses, the study population was divided into 2 different groups: those involved in health-compromising behavior and those not involved in such behavior. A multiple regression analysis was performed using age, gender, and health-compromising behavior as predictor variables and diabetes mismanagement as the outcome variable. Variables that accounted for significant variance in diabetes mismanagement were being female and being involved in health-compromising behavior. CONCLUSIONS: Adolescents and young adults with diabetes appear to be either involved or not involved in health-compromising behavior. Being female and being involved in health-compromising behavior were associated with diabetes mismanagement.

Development and validation of the Parental Intrusiveness Rating Scale among bulimic and comparison women.

OBJECTIVE: Based on hypotheses generated during clinical interviews with 80 women with a lifetime history of bulimia nervosa (BN), we designed an instrument for assessing the extent to which women with BN report parental intrusiveness and breakdown of appropriate role boundaries during their adolescent development. METHOD: Through an iterative process of item generation and scale administration, the Parental Intrusiveness Rating Scale (PIRS), consisting of 20 maternal items and 20 paternal items, was developed. Maternal subscales include Invasion of Privacy, Jealousy and Competition, and Overconcern with the Daughter's Eating, Weight, and Shape. Paternal subscales include Invasion of Privacy, Seductiveness, and Overconcern with the Daughter's Eating, Weight, and Shape. We validated the instrument using a subset of the above BN and comparison women (ns = 55 and 33, respectively), as well as an independent sample of women with BN and college comparison subjects (ns = 31 and 540, respectively). RESULTS: Parental intrusiveness scores were significantly positively correlated with disturbed relationships in the family of origin of our initial cohort. Reliability analyses, both test-retest and item-scale correlations, revealed adequate to strong statistical associations in the combined sample. CONCLUSION: The PIRS promises to enrich our understanding of problematic parental behaviors among women who develop BN and allows us to broaden the conceptualization of familial risk factors for this disorder.

Prepulse inhibition of startle, intelligence and familial primary nocturnal enuresis.

UNLABELLED: Previous studies have shown a significant reduction of prepulse inhibition of startle in boys with primary nocturnal enuresis. Those enuretic boys who had higher IQs showed less prepulse inhibition. This study evaluates the association of prepulse inhibition and IQ in primary nocturnal enuresis in respect to family history of primary nocturnal enuresis. Prepulse inhibition of startle was studied in 83 boys with primary nocturnal enuresis and 57 non-enuretic boys using an interval of 120 ms between the onset of a 75 dB 1000 Hz tone and a 104 dB noise burst. Of the boys with primary nocturnal enuresis, 56 had a family history of primary nocturnal enuresis and 27 had no family history (no first-degree relative). Of the 57 non-enuretic boys, 42 also had no family history (no first-degree relative) of primary nocturnal enuresis, while 15 did have a positive family history. Associations between prepulse inhibition and IQ scores were compared among these four groups. Strong and significant associations between prepulse inhibition deficit and higher IQ scores in the enuretic group with familial primary nocturnal enuresis were unique in comparison to the other groups. CONCLUSIONS: The strong heritabilities of primary nocturnal enuresis, intelligence and prepulse inhibition suggest genetic mediation of the association of prepulse inhibition with intelligence in familial primary nocturnal enuresis.

A devastating ocular pathogen: beta-streptococcus Group G.

PURPOSE: To report the clinical findings, treatment, and outcomes of four cases of beta-streptococcus Group G (BHS-G) ocular infection. METHODS: The medical and microbiologic records of four cases of BHS-G ocular infection were retrospectively reviewed. RESULTS: Two cases of BHS-G endophthalmitis and two cases of BHS-G keratitis were recorded. Three patients developed fulminant infection within 12 hours of the onset of symptoms. One patient's history was incomplete. One patient developed endophthalmitis from a contaminated donor button; another following cataract surgery. One developed keratitis in a keratoplasty suture tract; and another patient developed a corneal abscess after being struck with a tree branch. The patient with the contaminated donor button developed overwhelming endophthalmitis resulting in no light perception vision, severe pain, and evisceration. The postoperative cataract patient developed a purulent endophthalmitis and is still hypotonus with light perception vision. The second keratitis patient developed a significant suture abscess with marked stromal loss but eventually healed. The traumatic keratitis patient developed a large ulcer with hypopyon and descemetocele but was lost to follow-up. CONCLUSIONS: This is the first report of a series of BHS-G ocular infections. The ocular infections were characterized by rapid onset, extreme inflammation, and--despite in vitro antibiotic sensitivity--a poor or sluggish response to antibiotic therapy.

Thought disorder in childhood schizophrenia: replication and update of concept.

OBJECTIVES: To examine whether measures of thought disorder differentiated schizophrenic from normal children and to examine the relationship of these measures with developmental and cognitive factors. METHOD: The speech samples of 88 schizophrenic and 190 normal children, aged 9 to 13 years, were coded with the Kiddie Formal Thought Disorder Rating Scale and Halliday and Hassan's analysis of cohesion. RESULTS: Above and beyond differences in mental age, gender, and neuroleptic status, the patients had significantly more formal thought disorder (FTD) and cohesive deficits than the normal children matched by mental age. The younger schizophrenic and normal children had significantly more thought disorder than the older children with these diagnoses. Combined FTD and cohesion scores correctly identified 76% of schizophrenic and 88% of normal children with little variability across mental age. The thought disorder measures generated 2 independent components: FTD and cohesion. CONCLUSIONS: Thought disorder measures that include both FTD and cohesion provide a quantitative diagnostic tool of childhood-onset schizophrenia.

Childhood schizophrenia: responsiveness to questions during conversation.

OBJECTIVES: This study characterized further the communicative deficits associated with childhood-onset schizophrenia. It examined the use of speech functions that involve responses to Yes/No and Wh- questions in children with schizophrenia and normal children during conversation. It also ascertained the relationship of these speech functions with cognition and thought disorder. METHOD: Speech function variables, formal thought disorder, and cohesion were coded in 32 schizophrenic and 34 normal children, aged 5.6 to 12.4 years, from speech samples elicited with the Story Game. RESULTS: The schizophrenic children were significantly more impaired in the use of speech functions than the normal children. Other than the association of a subset of the speech functions with distractibility and loose associations, the speech function measures were unrelated to cognitive and thought disorder measures. CONCLUSIONS: Speech function analysis detects communication deficits not captured by thought disorder measures in children with schizophrenia.

Toxicity of non-abeta component of Alzheimer's disease amyloid, and N-terminal fragments thereof, correlates to formation of beta-sheet structure and fibrils.

The non-Abeta component of Alzheimer's disease amyloid (NAC) and its precursor alpha-synuclein have been linked to amyloidogenesis in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Previously we have shown that NAC forms beta-sheet structures and fibrils [El-Agnaf, O.M.A., Bodles, A.M., Guthrie, D.J.S., Harriott, P. & Irvine, G.B. (1998) Eur. J. Biochem. 258, 157-163]. As a measure of their neurotoxic potential we have examined the ability of fresh and aged NAC and fragments thereof to inhibit the reduction of the redox dye 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide by rat pheochromocytoma PC12 cells. Micromolar concentrations of NAC and fragments thereof display varying degrees of toxicity. On immediate dissolution and after an incubation period for 3 days at 37 degrees C the full-length peptide and fragments NAC(3-18) and NAC(1-18) scrambled sequence [NAC(1-18 s)] were toxic, whereas fragments NAC(1-13) and NAC(6-14) were not. CD indicates that NAC(3-18) and NAC(1-18 s) exhibit beta-sheet secondary structure in aqueous solution, whereas NAC(1-13) and NAC(6-14) do not. NAC(3-18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days measured by an HPLC assay, and forms fibrils, as determined by electron microscopy. However, although some fibrils were detected for NAC(1-18 s) it does not come out of solution to a significant degree. Fragments NAC(1-13) and NAC(6-14) form few fibrils and remain in solution. These findings indicate that the ability of the central region of NAC to form beta-sheet secondary structures is important for determining the toxicity of the peptide. This contrasts with what has been reported previously for most Abeta peptides as their toxicity appears to require the peptide to have formed fibrillary aggregates as well as displaying beta-sheet. These results suggest that an intermediate, which exhibits beta-sheet structure, may be responsible for the toxic properties of NAC and provides further evidence for the role of NAC in the pathogenesis of AD, PD and DLB.

Parents' perceived benefits and barriers of adolescents' diabetes self-management: part 2.

Knowledge is limited about parents' decision making regarding adolescents' assumption of diabetes management. This study's purpose was to identify parents' perceived benefits and barriers about this process. We interviewed 17 parents of adolescents with type I diabetes. Questions were adapted from Janis and Mann's (1977) decisional balance sheet. Interviews were audiotaped and transcribed verbatim. Descriptive expressions were identified and categories inductively generated. Inter-rater agreement was initially 85% and was 100% after discussion of disagreements. Parents' perceived benefits for themselves were relief from burden and knowledge and confidence and/or pride in adolescents' abilities. Their perceived benefits for their sons and daughters were also twofold: knowledge and/or confidence in abilities and freedom, independence, and/or control. Parents perceived barriers for themselves were loss of control, authority, and supervision, dealing with consequences. and expression of lack of barriers. Their perceived barriers for their sons and daughters were burden of responsibility and also lack of barriers. Understanding parents' perceived benefits and barriers would be beneficial to health care professionals when working with parents, because decision making related to the transfer of diabetes management to their adolescent sons and daughters is crucial to the success of its management.