Precision computerised cognitive behavioural therapy (cCBT) for adolescents with depression: a pilot and feasibility randomised controlled trial protocol for SPARX-UK.

BACKGROUND: A serious game called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts), originally developed in New Zealand and incorporating cognitive behavioural therapy (CBT) principles, has been shown to help reduce symptoms of depression and anxiety in adolescents with mild to moderate depression in studies undertaken in Australasia. However, SPARX has never been trialled in the United Kingdom (UK), and there have been issues relating to low engagement when it has been used in a real-world context. AIMS: To conduct the first pilot and feasibility randomised controlled trial (RCT) in England to explore the use of SPARX in different settings. The trial will explore whether SPARX supported by an e-coach (assistant psychologists) improves adherence and engagement compared with self-directed (i.e. self-help) use. The trial results will be used to inform the optimal mode of delivery (SPARX supported vs. SPARX self-directed), to calculate an appropriate sample size for a full RCT, and to decide which setting is most suitable. METHODS: Following consultation with young people to ensure study suitability/appropriateness, a total of 120 adolescents (11-19 years) will be recruited for this three-arm study. Adolescents recruited for the study across England will be randomised to receive either SPARX with human support (from an e-coach), self-directed SPARX, or a waitlist control group. Assessments will be conducted online at baseline, week 4, and 8-10-week post-randomisation. The assessments will include measures which capture demographic, depression (Patient Health Questionnaire modified for adolescents [PHQ-A]) and anxiety (Revised Child Anxiety and Depression Scale [RCADS]) symptomatology, and health-related quality-of-life data (EQ-5D-Y and proxy version). Analyses will be primarily descriptive. Qualitative interviews will be undertaken with a proportion of the participants and clinical staff as part of a process evaluation, and the qualitative data gathered will be thematically analysed. Finally, feasibility data will be collected on recruitment details, overall study uptake and engagement with SPARX, participant retention, and youth-reported acceptability of the intervention. DISCUSSION: The findings will inform the design of a future definitive RCT of SPARX in the UK. If the subsequent definitive RCT demonstrates that SPARX is effective, then an online serious game utilising CBT principles ultimately has the potential to improve the provision of care within the UK's health services if delivered en masse. TRIAL REGISTRATION: ISRCTN: ISRCTN15124804. Registered on 16 January 2023, https://www.isrctn.com/ISRCTN15124804 .

Delivering solid treatments on shaky ground: Feasibility study of an online therapy for child anxiety in the aftermath of a natural disaster.

OBJECTIVE: To assess feasibility of online cognitive behaviour therapy (CBT) for children and adolescents with anxiety in the aftermath of a natural disaster. METHOD: 42 children and adolescents with clinical anxiety referred from primary care were invited to complete an internet CBT program (BRAVE-ONLINE). Outcome measures and assessment timelines were chosen to allow a comparison of the results with the program developers' randomised controlled trials. RESULTS: At 6-month post intervention, more than half (55%) of the 33 participants assessed, no longer met criteria for their primary anxiety disorder. The mean number of anxiety diagnoses dropped from 2.76 (SD = 0.85) at baseline to 1.06 (SD = 1.25) at follow-up (z = -4.51, p < .001). Participants' anxiety and mood symptoms reduced and health-related quality of life improved significantly by follow-up. Satisfaction ratings were moderate to high. On average, by 6-month follow-up, children and adolescents had completed 6 of 10 sessions and parents had completed 5/6 (child parent program) and 3/5 sessions (adolescent parent program). CONCLUSIONS: Following a natural disaster (the Canterbury earthquakes), children and adolescents showed clinically significant improvement in anxiety and mood when they used BRAVE-ONLINE. This approach was both feasible and acceptable to families and offered a solution when mental health services were under pressure.

2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients' and clinicians' values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.(AU)

US Preventative Services Task Force FRAX threshold has a low sensitivity to detect osteoporosis in women ages 50-64 years.

UNLABELLED: The US Preventative Services Task Force (USPSTF) recommends consideration for screening for osteoporosis in women under age 65 who have an estimated 10-year major osteoporotic fracture risk of 9.3 % or higher. We found that this threshold for osteoporosis screening in women ages 50-64 years old has a low sensitivity to detect osteoporosis. INTRODUCTION: The US Preventative Services Task Force (USPSTF) recommends consideration of dual-energy X-ray absorptiometry (DXA) in women under ages 50-64 with a major osteoporotic fracture (MOF) risk of 9.3 % or higher, as estimated by the fracture risk assessment tool (FRAX) tool. We assessed the performance of the 9.3 % MOF risk threshold for detecting osteoporosis and evaluated whether DXA indication appeared appropriate, based on USPSTF criteria and other risk factors, at our institution. METHODS: We performed a retrospective record review of women ages 50-64.5 years old to determine clinical factors and FRAX scores of women undergoing a DXA at our institution over a 6-month period after the USPSTF recommendations were released and evaluated the sensitivity and specificity of the 9.3 % MOF threshold to detect densitometric osteoporosis. Additionally, using the USPSTF criteria and several additional risk factors, we evaluated the extent of potentially inappropriate DXA use in women ages 50 to 64 years in a large primary care practice in an academic medical center. RESULTS: The analysis included 465 DXA tests. The overall sensitivity and specificity of a FRAX-calculated MOF risk ≥9.3 % was 37 and 74 %, respectively, for the detection of osteoporosis. The receiver operator characteristic curve (ROC) demonstrated an area under the curve of 0.58. Lowering the FRAX risk threshold to 5.5 % would increase the sensitivity of detecting osteoporosis in our population from 37 to 80 % while reducing the specificity from 74 to 27 %. Out of 465 DXAs, 371 (79.8 %) were classified as appropriately ordered per our pre-specified criteria. Of the 120 women with osteoporosis at the hip and/or spine based on T-score values of -2.5 or less, 14 DXAs (11.7 %) were classified as potentially inappropriate based on a FRAX-predicted MOF risk less than 9.3 % and lack of additional pre-specified risk factors. CONCLUSION: We found that the USPSTF-recommended MOF risk threshold of 9.3 % for osteoporosis screening in women ages 50-64 years old has a low sensitivity to detect osteoporosis.

A pilot study to examine the experiences and attitudes of women with breast cancer towards one versus two-step axillary surgery.

PURPOSE: To elicit the views, experiences and preferences of women with clinically node negative breast cancer towards intra-operative sentinel lymph node biopsy (SLNB) analysis. METHODS: Focus groups with 14 women with breast cancer from two UK centres; one group had undergone the standard practice of waiting two weeks for results of their axillary surgery, the other had experienced the intra-operative SLNB analysis. RESULTS: Women generally were unaware about their lymph nodes, what their function is and how they are removed. Preference was indicated for intra-operative sentinel lymph node biopsy (SLNB) analysis provided clear descriptions were given about the risk of experiencing false negative and false positive results. DISCUSSION: Adopting an intra-operative analysis technique of axillary nodes was viewed as an excellent option by women from both centres. The immediacy of knowing the results was seen as a great advantage for their physical and psychological well being and more cost effective.

Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents.

BACKGROUND: Depressive disorders are common in young people and are associated with significant negative impacts. Selective serotonin reuptake inhibitors (SSRIs) are often used, however, evidence of their effectiveness in children and adolescents is not clear. Furthermore, there have been warnings against their use in this population due to concerns about increased risk of suicidal ideation and behaviour. OBJECTIVES: To determine the efficacy and adverse outcomes, including definitive suicidal behaviour and suicidal ideation, of SSRIs compared to placebo in the treatment of depressive disorders in children and adolescents. SEARCH STRATEGY: We searched the CCDAN Trials Register, MEDLINE, PSYCHINFO and CENTRAL. Reference lists were checked, letters were sent to key researchers and internet databases searched. SELECTION CRITERIA: We included published and unpublished randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two or three review authors selected the trials, assessed the quality and extracted trial and outcome data. We used a fixed-effect meta-analysis. The relative risk was used to summarise dichotomous outcomes and the mean difference to summarise continuous measures. MAIN RESULTS: Twelve trials were eligible for inclusion, with ten providing usable data. At 8-12 weeks, there was evidence that children and adolescents 'responded' to treatment with SSRIs (RR 1.28, 95% CI 1.17 to 1.41). There was also evidence of an increased risk of suicidal ideation and behaviour for those prescribed SSRIs (RR 1.80, 95% CI 1.19 to 2.72). Fluoxetine was the only SSRI where there was consistent evidence from three trials that it was effective in reducing depression symptoms in both children and adolescents (CDRS-R treatment effect -5.63, 95% CI -7.38 to -3.88), and 'response' to treatment (RR 1.86, 95% CI 1.49 to 2.32). Where rates of adverse events were reported, this was higher for those prescribed SSRIs. AUTHORS' CONCLUSIONS: Caution is required to interpret the results. First, there were methodological issues, including high attrition, issues regarding measurement instruments and clinical usefulness of outcomes, often variously defined across trials. Second, patients seen in clinical practice are likely to be more unwell, and at greater risk of suicide, compared to those in the trials, and it is unclear how this group would respond to SSRIs. This needs to be considered, along with the evidence of an increased risk of suicide related outcomes in those treated with SSRIs. It is unclear what the effect of SSRIs is on suicide completion. While untreated depression is associated with the risk of completed suicide and impacts on functioning, it is unclear whether SSRIs would modify this risk in a clinically meaningful way.

Psychological and/or educational interventions for the prevention of depression in children and adolescents.

BACKGROUND: Depression is the fourth most important disease in the estimation of the burden of disease Murray 1996 and is a common problem with prevalence rates estimated to be as high as 8% in young people. Depression in young people is associated with poor academic performance, social dysfunction, substance abuse, suicide attempts, and completed suicide (NHMRC 1997). This has precipitated the development of programmes aimed at preventing the onset of depression. This review evaluates evidence for the effectiveness of these prevention programmes. OBJECTIVES: To determine whether psychological and/or educational interventions (both universal and targeted) are effective in reducing risk of depressive disorder by reducing depressive symptoms immediately after intervention or by preventing the onset of depressive disorder in children and adolescents over the next one to three years. SEARCH STRATEGY: The Cochrane Depression, Anxiety and Neurosis Group trials register (August 2002), MEDLINE (1966 to December Week 3 2002), EMBASE (1980 to January Week 2 2003), PsychInfo (1886 to January Week 2 2003) and ERIC (1985 to December 2002) were searched. In addition, conference abstracts, the reference lists of included studies, and other reviews were searched and experts in the field were contacted. SELECTION CRITERIA: Each identified study was assessed for possible inclusion by two independent reviewers based on the methods sections. The determinants for inclusion were that the trial include a psychological and/or educational prevention programme for young people aged 5 to 19 years-old, who did not meet DSM or ICD criteria for depression and/or did not fall into the clinical range on standardised, validated, and reliable rating scales of depression. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was assessed by two independent reviewers according to a list of pre-determined criteria, which were based on quality ratings devised by Moncrieff and colleagues (Moncrieff 2001). Outcome data was extracted and entered into Revman 4.2. Means and standard deviations for continuous outcomes and number of events for dichotomous outcomes were extracted where available. For trials where the required data were not reported or could not be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and described, but not included in the meta-analysis. Results were presented for each type of intervention: targeted or universal interventions; and educational or psychological interventions and if data were provided, by gender. Where possible data were combined in meta-analyses to give a treatment effect across all trials. Sensitivity analysis were conducted on studies rated as "adequate" or "high" quality, that is with a score over 22, based on the scale by Moncrieff et al (Moncrieff 2001). The presence of publication bias was assessed using funnel plots. MAIN RESULTS: Studies were divided into those that compared intervention with an active comparison or placebo (i.e. a control condition that resembles the intervention being investigated but which lacks the elements thought to be active in preventing depression) and those that used a "wait-list" or no intervention comparison group. Only two studies fell into the former category and neither showed effectiveness although one study was inadequately powered to show a difference and in the other the "placebo" contained active therapeutic elements, reducing the ability to demonstrate a difference from intervention. Psychological interventions were effective compared with non-intervention immediately after the programmes were delivered with a significant reduction in scores on depression rating scales for targeted (standardised mean difference (SMD) of -0.26 and a 95% confidence interval (CI) of -0.40 to -0.13 ) but not universal interventions (SMD -0.21, 95% CI -0.48, 0.06), with a significant effect maintained on pooling data (SMD -0.26, 95% CI -0.36, -0.15). While small effect sizes were reported, these were associated with a significant reduction in depressive episodes. The overall risk difference after intervention translates to "numbers needed to treat" (NNT) of 10. The most effective study is the targeted programme by Clarke (Clarke 2001) where the initial effect size of -0.46 is associated with an initial risk difference of -0.22 and NNT 5. There was no evidence of effectiveness for educational interventions. Reports of effectiveness for boys and girls were contradictory. The quality of many studies was poor, and only two studies made allocation concealment explicit. Sensitivity analysis of only high quality studies did not alter the results significantly. The only analysis in which there was significant statistical heterogeneity was the sub-group analysis by gender where there was variability in the response to different programmes for both girls and boys. For the most part funnel plots indicate findings are robust for short term effects with no publication bias evident. There are too few studies to comment on whether there is publication bias for studies reporting long-term (12-36 month) follow-up. REVIEWER'S CONCLUSIONS: Although there is insufficient evidence to warrant the introduction of depression prevention programmes currently, results to date indicate that further study would be worthwhile. There is a need to compare interventions with a placebo or some sort of active comparison so that study participants do not know whether they are in the intervention group or not, to investigate the impact of booster sessions to see if effectiveness immediately after intervention can be prolonged, ideally for a year or longer, and to consider practical implementation of prevention programmes when choosing target populations. Until now most studies have focussed on psychological interventions. The potential effectiveness of educational interventions has not been fully investigated. Given the gender differences in prevalence, and the change in these that occurs in adolescence with a disproportionate increase in prevalence rates for girls, it is likely that girls and boys will respond differently to interventions. Although differences have been reported in studies in this review the findings are contradictory and a more definitive delineation of gender specific responses to interventions would be helpful.

Rapid phenotypic change and diversification of a soil bacterium during 1000 generations of experimental evolution.

Evolutionary pathways open to even relatively simple organisms, such as bacteria, may lead to complex and unpredictable phenotypic changes, both adaptive and non-adaptive. The evolutionary pathways taken by 18 populations of Ralstonia strain TFD41 while they evolved in defined environments for 1000 generations were examined. Twelve populations evolved in liquid media, while six others evolved on agar surfaces. Phenotypic analyses of these derived populations identified some changes that were consistent across all populations and others that differed among them. The evolved populations all exhibited morphological changes in their cell envelopes, including reductions of the capsule in each population and reduced prostheca-like surface structures in most populations. Mean cell length increased in most populations (in one case by more than fourfold), although a few populations evolved shorter cells. Carbon utilization profiles were variable among the evolved populations, but two distinct patterns were correlated with genetic markers introduced at the outset of the experiment. Fatty acid methyl ester composition was less variable across populations, but distinct patterns were correlated with the two physical environments. All 18 populations evolved greatly increased sensitivity to bile salts, and all but one had increased adhesion to sand; both patterns consistent with changes in the outer envelope. This phenotypic diversity contrasts with the fairly uniform increases in competitive fitness observed in all populations. This diversity may represent a set of equally probable adaptive solutions to the selective environment; it may also arise from the chance fixation of non-adaptive mutations that hitchhiked with a more limited set of beneficial mutations.

Adolescents' perceptions of a health survey using multimedia computer-assisted self-administered interview.

OBJECTIVE: To ascertain young people's perceptions of an adolescent health survey when administered by multimedia computer assisted self-administered Interview (M-CASI) through analysis of (1) questionnaire item responses and (2) focus group interviews. SETTING: Auckland, New Zealand, 1999. STUDY TYPE: Pilot testing of a 488-item branching questionnaire delivered using a youth-oriented and user-friendly M-CASI interface in a variety of settings using both desktop and laptop computers. Post pilot focus groups of participants identifying their perceptions and experiences of the survey. SAMPLE: 110 school students aged 12 to 18 years. RESULTS: The mean number of questions answered by participants was 316 with the median time to completion being 48 minutes. On average 65% of the total number of questions were seen and of these 1.5% were deliberately not answered. A high level of acceptability and enjoyment of M-CASI was found in the analysis of focus group responses and agreed with the item responses relating to M-CASI within the questionnaire itself. Participants identified privacy and confidentiality as being particularly important for the honesty of their responses. The passive matrix screens of the computers were popular as they could only be viewed from in front. CONCLUSIONS: M-CASI is an acceptable instrument for the administration of a youth health survey. Laptop computers with passive matrix screens are able to enhance perceptions of privacy and confidentiality, which may improve honesty of responses. IMPLICATIONS: M-CASI is now feasible and offers advantages in health surveying.

Modulation of quantum yield of primary radical pair formation in photosystem II by site-directed mutagenesis affecting radical cations and anions.

Pigment-protein interactions play a significant role in determining the properties of photosynthetic complexes. Site-directed mutants of Synechocystis PCC 6803 have been prepared which modify the redox potential of the primary radical pair anion and cation. In one set of mutants, the environment of P680, the primary electron donor of Photosystem II, has been modified by altering the residue at D1-His198. It has been proposed that this residue is an axial ligand to the magnesium cation. In the other set, the D1-Gln130 residue, which is thought to interact with the C9-keto group of the pheophytin electron acceptor, has been changed. The effect of these mutations is to alter the free energy of the primary radical pair state, which causes a change in the equilibrium between excited singlet states and radical pair states. We show that the free energy of the primary radical pair can be increased or decreased by modifications at either the D1-His198 or the D1-Gln130 sites. This is demonstrated by using three independent measures of quantum yield and equilibrium constant, which exhibit a quantitative correlation. These data also indicate the presence of a fast nonradiative decay pathway that competes with primary charge separation. These results emphasize the sensitivity of the primary processes of PS II to small changes in the free energy of the primary radical pair.

Early intervention for schizophrenic disorders. Implementing optimal treatment strategies in routine clinical services. OTP Collaborative Group.

BACKGROUND: Early detection and intervention in schizophrenic disorders is an important challenge for psychiatry. METHOD: Review of literature on effective biomedical and psychosocial intervention strategies. RESULTS: Comprehensive programmes of drug and psychosocial interventions with adults who show early signs and symptoms of schizophrenic disorders may contribute to a lower incidence and prevalence of major episodes of schizophrenia. These programmes combine early detection of psychotic features by primary care services, with close liaison with mental health professionals. Long-term monitoring of signs of recurrence, with further intervention, appears essential to maintain these benefits. CONCLUSIONS: Field trials demonstrate that effective early treatment strategies can be routinely applied in clinical practice.

Comparison of primary charge separation in the photosystem II reaction center complex isolated from wild-type and D1-130 mutants of the cyanobacterium Synechocystis PCC 6803.

We compare primary charge separation in a photosystem II reaction center preparation isolated from a wild-type (WT) control strain of the cyanobacterium Synechocystis sp. PCC 6803 and from two site-directed mutants of Synechocystis in which residue 130 of the D1 polypeptide has been changed from a glutamine to either a glutamate (mutant D1-Gln130Glu), as in higher plant sequences, or a leucine residue (mutant D1-Gln130Leu). The D1-130 residue is thought to be close to the pheophytin electron acceptor. We show that, when P680 is photoselectively excited, the primary radical pair state P680+Ph- is formed with a time constant of 20-30 ps in the WT and both mutants; this time constant is very similar to that observed in Pisum sativum (a higher plant). We also show that a change in the residue at position D1-130 causes a shift in the peak of the pheophytin Qx-band. Nanosecond and picosecond transient absorption measurements indicate that the quantum yield of radical pair formation (phi RP), associated with the 20-30-ps component, is affected by the identify of the D1-130 residue. We find that, for the isolated photosystem II reaction center particle, phi RP higher plant > phi RP D1-Gln130Glu mutant > phi RP WT > phi RP D1-Gln130Leu mutant. Furthermore, the spectroscopic and quantum yield differences we observe between the WT Synechocystis and higher plant photosystem II, seem to be reversed by mutating the D1-130 ligand so that it is the same as in higher plants. This result is consistent with the previously observed natural regulation of quantum yield in Synechococcus PS II by particular changes in the D1 polypeptide amino acid sequence (Clark, A.K., Hurry, V. M., Gustafsson, P. and Oquist, G. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 11985-11989).

Psychiatric status of sexually abused children 12 months after disclosure of abuse.

OBJECTIVE: The assessment of psychiatric status of sexually abused children 12 months after the disclosure of recent sexual abuse. METHOD: Ninety-five children, aged from 4 through 16 years, were recruited to the study from a variety of agencies other than psychiatric units. Sixty-six (69.5%) were assessed for psychiatric diagnosis on DSM-III-R using data from parents, teachers, and children 12 months after disclosure of abuse. Abuse was extra- and intrafamilial. RESULTS: Overall 63.5% of the children warranted a diagnosis on Axis I. There was a wide range of diagnoses, with particularly high rates of oppositional defiant disorder (19.6%), post-traumatic stress disorder (18.2%), anxiety disorders (30.3%), depressive disorders (12.1%), and attention-deficit hyperactivity disorder (13.6%). Boys had a higher rate of diagnosis than girls. Abuse and social variables did not predict diagnoses but mothers' mental status rated on the General Health Questionnaire did. Subjects not located at follow-up were more often male and more likely to be socioeconomically disadvantaged. Thus the estimates of psychopathology here are likely to be conservative. CONCLUSIONS: This study highlights the need of sexually abused children for skilled long-term therapy tailored to individual presentation.

Methylphenidate and thioridazine in the treatment of intellectually subaverage children: effects on cognitive-motor performance.

Twenty-seven children (or smaller subgroups depending upon task difficulty and subject ability) with subaverage IQs took part in a double-blind, placebo-controlled, cross-over study of methylphenidate (0.4 mg/kg/day) and thioridazine (1.75 mg/kg/day). The children were tested for IQ performance, breadth of attention, and performance on a series of electronically controlled cognitive-motor tests. Methylphenidate improved accuracy on a memory task, reduced omission errors on an attentional task, and reduced seat movements on two tasks. Thioridazine failed to have any deleterious effects on IQ performance when subjects received reinforcers for correct answers. Thioridazine at the given dose did not adversely affect performance on any of the cognitive-motor performance tests. Methylphenidate appears likely to enhance sustained attention and motivation in appropriately selected children with mild developmental delays, whereas thioridazine at this modest dose does not appear to impair performance on most psychomotor tests.

Identification and characterisation in vitro of cells with a non-SCLC cell-like phenotype derived from a continuous SCLC cell line.

Two adherent sublines, H69V and H69VZ, have been isolated from the classic SCLC cell line NCI-H69. Significant morphological differences were observed between the parental and the derivative cell lines. While NCI-H69 grew as densely packed free floating cellular aggregates the derivative lines grew as a monolayer of epithelioid cells. The growth rates of both the derivative lines were faster than the parental line with doubling times closer to non-SCLC cell lines in the derivative lines. Both H69V and H69VZ either express very low levels or do not express neuroendocrine cell markers including L-dopa-decarboxylase (DDC), creatine kinase-BB isoenzyme (CK-BB), bombesin-like immunoreactivity (BLI), neuron specific enolase (NSE), and neurosecretory type dense core granules (DGCs), compared to the parental cell line. All the lines stained positive for epithelial markers such as CAM5.2. LDH isoenzyme and chromosome analyses confirmed the human origin of all the cell lines. Therefore, it appears that cell line NCI-H69 contains stem cell subpopulation capable of generating cells of both small and non-small cell like phenotypes.

Clinical effects of methylphenidate and thioridazine in intellectually subaverage children.

Thirty children with subaverage IQs and psychiatric diagnoses of attention deficit disorder and/or or conduct disorder took part in a double-blind study of placebo, methylphenidate, and thioridazine, which were given for 3 weeks each. The results showed a consistent and highly significant effect of methylphenidate in reducing teacher ratings of problem behavior. Parent ratings showed no behavioral effects for the group as a whole. An attentional model of stimulant drug response was used to divide subjects according to a cognitive maturity domain presumed to reflect selective attention. When divided according to breadth of attention, mental age, and IQ level, higher functioning subjects were found to show a generally favorable response to methylphenidate on both teacher and parent rating scales, whereas children of low functional level typically showed an adverse or indifferent response. The present data suggest that mental age and IQ may be important determinants of drug response; below a given level, there was a greatly reduced likelihood of responding positively. Clinical response to thioridazine was substantially less than the response to methylphenidate, with significant improvements confined to conduct and hyperactivity problems on teacher ratings.

Circumvention of pleiotropic drug resistance in subcutaneous tumours in vivo with verapamil and clomipramine.

The development of pleiotropic drug resistance (PDR) in vivo in solid tumour models suggests that a similar process may occur in the clinic. A subline of the Ridgway osteogenic sarcoma (ROS)--a murine subcutaneously-growing solid tumour--with moderate resistance (1.5 fold) to actinomycin D was selected by repeated suboptimal treatment with this drug in vivo. This subline (ROS/ADX/G2) showed cross-resistance to vincristine (3.5 fold) and etoposide (over 5.1 fold) but not to doxorubicin. The resistance could in all cases be partly or completely overcome by treatment with non-cytotoxic doses of verapamil or clomipramine. Resistance to actinomycin in this model was associated with lower (up to 3.2 fold) drug accumulation into tumours which could be increased (up to 2.8 fold) by treatment with 25 micrograms/g verapamil. These data support clinical trials of the use of membrane-active agents to overcome PDR.