Methodological approaches to situational analysis in global mental health: a scoping review.

Global inequity in access to and availability of essential mental health services is well recognized. The mental health treatment gap is approximately 50% in all countries, with up to 90% of people in the lowest-income countries lacking access to required mental health services. Increased investment in global mental health (GMH) has increased innovation in mental health service delivery in LMICs. Situational analyses in areas where mental health services and systems are poorly developed and resourced are essential when planning for research and implementation, however, little guidance is available to inform methodological approaches to conducting these types of studies. This scoping review provides an analysis of methodological approaches to situational analysis in GMH, including an assessment of the extent to which situational analyses include equity in study designs. It is intended as a resource that identifies current gaps and areas for future development in GMH. Formative research, including situational analysis, is an essential first step in conducting robust implementation research, an essential area of study in GMH that will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in low- and middle-income countries (LMICs). While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions.

Self-Stigma in Relatives of people with Mental Illness scale: development and validation.

BACKGROUND: Serious mental illness (SMI) is profoundly stigmatised, such that there is even an impact on relatives of people with SMI. Aims To develop and validate a scale to comprehensively measure self-stigma among first-degree relatives of individuals with SMI. METHOD: We conducted group interviews focusing on self-stigma with first-degree relatives (n = 20) of people with SMI, from which 74 representative quotations were reframed as Likert-type items. Cognitive interviews with relatives (n = 11) identified 30 items for the Self-Stigma in Relatives of people with Mental Illness (SSRMI) scale. Relatives (n = 195) completed the scale twice, a month apart, together with four external correlate scales. RESULTS: The 30-item SSRMI was reliable, with scores stable over time. Its single-factor structure allowed generation of a 10-item version. Construct validity of 30- and 10-item versions was supported by expected relationships with external correlates. CONCLUSIONS: Both versions of the SSRMI scale are valid and reliable instruments appropriate for use in clinical and research contexts. Declaration of interest None.

Quality of life in bipolar disorder: towards a dynamic understanding.

BACKGROUND: Although quality of life (QoL) is receiving increasing attention in bipolar disorder (BD) research and practice, little is known about its naturalistic trajectory. The dual aims of this study were to prospectively investigate: (a) the trajectory of QoL under guideline-driven treatment and (b) the dynamic relationship between mood symptoms and QoL. METHODS: In total, 362 patients with BD receiving guideline-driven treatment were prospectively followed at 3-month intervals for up to 5 years. Mental (Mental Component Score - MCS) and physical (Physical Component Score - PCS) QoL were measured using the self-report SF-36. Clinician-rated symptom data were recorded for mania and depression. Multilevel modelling was used to analyse MCS and PCS over time, QoL trajectories predicted by time-lagged symptoms, and symptom trajectories predicted by time-lagged QoL. RESULTS: MCS exhibited a positive trajectory, while PCS worsened over time. Investigation of temporal relationships between QoL and symptoms suggested bidirectional effects: earlier depressive symptoms were negatively associated with mental QoL, and earlier manic symptoms were negatively associated with physical QoL. Importantly, earlier MCS and PCS were both negatively associated with downstream symptoms of mania and depression. CONCLUSIONS: The present investigation illustrates real-world outcomes for QoL under guideline-driven BD treatment: improvements in mental QoL and decrements in physical QoL were observed. The data permitted investigation of dynamic interactions between QoL and symptoms, generating novel evidence for bidirectional effects and encouraging further research into this important interplay. Investigation of relevant time-varying covariates (e.g. medications) was beyond scope. Future research should investigate possible determinants of QoL and the interplay between symptoms and wellbeing/satisfaction-centric measures of QoL.

Psychometric properties of the well-being index (WHO-5) spanish version in a sample of euthymic patients with bipolar disorder.

BACKGROUND: The concept of well-being which focuses on positive emotions has received increased research attention. However, a consensus definition of this term is lacking. The Well-Being Index scale (WHO-5) is a generic, self-report scale that contains five Likert-type items to evaluate psychological well-being. This construct may provide a relevant outcome in bipolar disorder (BD) research and care beyond the rating of mood symptoms. Thus, in the current study, the psychometric properties of the WHO-5 Spanish version were assessed in a sample of euthymic patients with BD. METHODS: Patients with BD- I and BD-II and healthy controls completed the Well-Being Index (WHO-5) together with an assessment of depressive (Hamilton Depression Rating Scale-17; HAM-D) and manic symptoms (Young Mania Rating Scale; YMRS); and a measure of psychosocial functioning (Functioning Assessment Short Test; FAST). Internal consistency reliability was measured through Cronbach's alpha. Test-retest reliability was calculated comparing the WHO-5 total score at baseline and after 10 days of the first administration. To assess the structure of the scale, a principal component analysis (PCA) was carried out. Correlations between the WHO-5, HAM-D, YMRS and FAST were calculated. Finally, a t-test for independent samples was applied to compare the WHO-5 total score in the patient and control groups. RESULTS: A total of 104 patients with BD and 40 healthy controls were included in this study. A Chronbach's alpha of 0.83 indicated acceptable internal consistency. A paired sample t-test revealed no significant differences between WHO-5 total score at baseline and at follow-up (tn = - 0.72; df = 15; p = 0.48). The PCA provided a single factor solution that accounted for 59.74% of the variation in WHO-5. Test-retest reliability was high (r = 0.83; p < 0.001). Moderate negative correlations were observed between the WHO-5 total score, the FAST (r = - 0.46.; p < 0.001) and the HAM-D (r = - 0.68; p < 0.001), but not with the YMRS (r = - 0.07; p = 0.42). Finally, significant differences were found when comparing the WHO-5 total score between patient and healthy controls (t = 5.1; df = 147; p < 0.001). LIMITATIONS: some limitations include the lack of a comparator scale to test for validity construct and the small sample size in the test-retest reliability CONCLUSIONS: The WHO-5 shows an acceptable reliability index and measures a unitary construct in a Spanish population of euthymic patients with BD.

Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations.

BACKGROUND: Thoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype-phenotype correlations within families of the patients with TAAD. METHODS: 51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan-Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery. RESULTS AND DISCUSSION: In 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35-46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45-57, p = 0.0083). This effect was also found when the 'genotype-positive' group was restricted to probands with 'likely causative' variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27-47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group). CONCLUSIONS: This study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.

Response to chemotherapy estimates by FDG PET is an important prognostic factor in patients with Ewing sarcoma

Background. Response to chemotherapy is a prognostic factor in patients with Ewing sarcoma (ES); the role of FDG PET to predict response in these patients has not been thoroughly investigated. We evaluated the diagnostic accuracy and the potential of FDG PET to predict response to chemotherapy (CHT). Materials and methods. e analyzed data of 50 patients with ES (median age 12.6 years). All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had 18F-FDG PET/CT at diagnosis and after induction CHT, prior to local control. We compared response assessed by histopathology with FDG PET using standard uptake values (SUVs). Results. Median SUV at diagnosis (SUV I) was 5 (range 1.2-17), and median SUV after neoadjuvant chemotherapy (SUV II) was 1.8 (range 0-8.4). Median SUV II/I ratio was 0.3 (range 0-1). SUV at diagnosis was significantly lower in patients with good histological response than in patients with poor histological response (median 3.8 vs. 7.2, p 0.02). We found a significant correlation between SUV II and outcome; the positive predictive value of an SUV II ≤ 2.5 for favorable response was 84.21 %, and the median SUV II was significantly higher in patients with disease progression (2.3 vs. 1.6, p = 0.04). In multivariate analysis, necrosis and SUV II were significant predictors of outcome. Conclusions. 18F-FDG PET demonstrates high diagnostic accuracy for response to initial chemotherapy in patients with ES and it correlates with outcome. The role of FDG PET in predicting response and outcome should be further investigated (AU)

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Response to chemotherapy estimates by FDG PET is an important prognostic factor in patients with Ewing sarcoma.

BACKGROUND: Response to chemotherapy is a prognostic factor in patients with Ewing sarcoma (ES); the role of FDG PET to predict response in these patients has not been thoroughly investigated. We evaluated the diagnostic accuracy and the potential of FDG PET to predict response to chemotherapy (CHT). MATERIALS AND METHODS: We analyzed data of 50 patients with ES (median age 12.6 years). All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had (18)F-FDG PET/CT at diagnosis and after induction CHT, prior to local control. We compared response assessed by histopathology with FDG PET using standard uptake values (SUVs). RESULTS: Median SUV at diagnosis (SUV I) was 5 (range 1.2-17), and median SUV after neoadjuvant chemotherapy (SUV II) was 1.8 (range 0-8.4). Median SUV II/I ratio was 0.3 (range 0-1). SUV at diagnosis was significantly lower in patients with good histological response than in patients with poor histological response (median 3.8 vs. 7.2, p 0.02). We found a significant correlation between SUV II and outcome; the positive predictive value of an SUV II ≤ 2.5 for favorable response was 84.21 %, and the median SUV II was significantly higher in patients with disease progression (2.3 vs. 1.6, p = 0.04). In multivariate analysis, necrosis and SUV II were significant predictors of outcome. CONCLUSIONS: (18)F-FDG PET demonstrates high diagnostic accuracy for response to initial chemotherapy in patients with ES and it correlates with outcome. The role of FDG PET in predicting response and outcome should be further investigated.

Anthropometric and physiological characteristics of Melanesian futsal players: a first approach to talent identification in Oceania.

This study assessed the anthropometric and physiological characteristics of elite Melanesian futsal players in order to determine the best performance predictors. Physiological parameters of performance were measured in 14 Melanesian (MEL-G, 24.4±4.4 yrs) and 8 Caucasian (NMEL-G, 22.9±4.9) elite futsal players, using tests of jump-and-reach (CMJ), agility (T-Test), repeated sprint ability (RSA), RSA with change-of-direction (RSA-COD), sprints with 5 m, 10 m, 15 m, and 30 m lap times, and aerobic fitness with the 30-15 intermittent fitness test (30-15 IFT). The anthropometric data revealed significantly lower height for MEL-G compared with NMEL-G: 1.73±0.05 and 1.80±0.08 m, respectively; P = 0.05. The CMJ was significantly higher for MEL-G than NMEL-G: 50.4±5.9 and 45.2±4.3 cm, respectively; P = 0.05. T-Test times were significantly lower for MEL-G than NMEL-G: 10.47±0.58 and 11.01±0.64 seconds, respectively; P = 0.05. MEL-G height was significantly related to CMJ (r = 0.706, P = 0.01), CMJpeakP (r = 0.709, P = 0.01) and T-Test (r = 0.589, P = 0.02). No significant between-group differences were observed for sprint tests or 30-15 IFT, including heart rate and estimated VO2max. Between groups, the percentage decrement (%Dec) in RSA-COD was significantly lower in MEL-G than NMEL-G (P = 0.05), although no significant difference was noted between RSA and RSA-COD. Within groups, no significant difference was observed between %Dec in RSA or RSA-COD; P = 0.697. This study presents specific anthropometric (significantly lower height) and physiological (significantly greater agility) reference values in Melanesians, which, taken together, might help coaches and physical fitness trainers to optimize elite futsal training and talent identification in Oceania.

Online mindfulness-based intervention for late-stage bipolar disorder: pilot evidence for feasibility and effectiveness.

OBJECTIVES: People in the late stage of bipolar disorder (BD) experience elevated relapse rates and poorer quality of life (QoL) compared with those in the early stages. Existing psychological interventions also appear less effective in this group. To address this need, we developed a new online mindfulness-based intervention targeting quality of life (QoL) in late stage BD. Here, we report on an open pilot trial of ORBIT (online, recovery-focused, bipolar individual therapy). METHODS: Inclusion criteria were: self-reported primary diagnosis of BD, six or more episodes of BD, under the care of a medical practitioner, access to the internet, proficient in English, 18-65 years of age. Primary outcome was change (baseline - post-treatment) on the Brief QoL.BD (Michalak and Murray, 2010). Secondary outcomes were depression, anxiety, and stress measured on the DASS scales (Lovibond and Lovibond, 1993). RESULTS: Twenty-six people consented to participate (Age M=46.6 years, SD=12.9, and 75% female). Ten participants were lost to follow-up (38.5% attrition). Statistically significant improvement in QoL was found for the completers, t(15)=2.88, 95% CI:.89-5.98, p=.011, (Cohen׳s dz=.72, partial η(2)=.36), and the intent-to-treat sample t(25)=2.65, 95% CI:.47-3.76, (Cohen׳s dz=.52; partial η(2)=.22). A non-significant trend towards improvement was found on the DASS anxiety scale (p=.06) in both completer and intent-to-treat samples, but change on depression and stress did not approach significance. LIMITATIONS: This was an open trial with no comparison group, so measured improvements may not be due to specific elements of the intervention. Structured diagnostic assessments were not conducted, and interpretation of effectiveness was limited by substantial attrition. CONCLUSION: Online delivery of mindfulness-based psychological therapy for late stage BD appears feasible and effective, and ORBIT warrants full development. Modifications suggested by the pilot study include increasing the 3 weeks duration of the intervention, adding cautions about the impact of extended meditations, and addition of coaching support/monitoring to optimise engagement.

Asenapine treatment and health-related quality of life in patients experiencing bipolar I disorder with mixed episodes: post-hoc analyses of pivotal trials.

OBJECTIVE: To evaluate the baseline impact of episode type (manic vs. mixed), defined using DSM-IV-TR criteria, in bipolar I disorder (BD-I) on health-related quality of life (HRQoL), and to investigate the differential effect of asenapine vs. placebo and olanzapine on HRQoL in BD-I patients with mixed episodes. METHODS: In two identically designed 3 week, randomized, double-blind, flexible-dose, placebo- and olanzapine-controlled trials of asenapine, HRQoL was assessed using the 36-item Short-Form Health Survey (SF-36v2) administered at baseline and endpoint. In addition to evaluating the impact of clinical presentation (manic vs. mixed episodes) on baseline HRQoL, the impact of treatment intervention on HRQoL was assessed via analysis of covariance models at study endpoint, with center and treatment-by-diagnosis interaction as fixed effect and baseline score as covariates. RESULTS: A total of 960 BD-I patients (asenapine: 372; olanzapine: 391; placebo: 197) were included in the two studies. The observed burden of disease on HRQoL was substantial compared to general US population norms, particularly in patients experiencing mixed episodes. The greatest impairments were observed in the mental domains of HRQoL (Mental Component Summary scores: mixed = 31.9; manic = 42.8). For patients with mixed episodes, when compared to olanzapine, asenapine treatment was associated with improvements noted in every domain, which did not reach statistical significance except for Vitality (asenapine = 55.0, olanzapine = 51.3; p = 0.014) and Role-Emotional (asenapine = 44.8, olanzapine = 40.3; p = 0.020). Compared to placebo patients with mixed episodes, asenapine treatment provided significant improvements (p < 0.05) in Bodily Pain (asenapine = 50.9, placebo = 45.9), Social Functioning (asenapine = 44.1, placebo = 39.6) and Mental Health (asenapine = 46.6, placebo = 42.7) by Week 3; by comparison, olanzapine treatment did not lead to significant improvements in any domain of HRQoL compared to placebo. CONCLUSIONS: Post-hoc analyses of two trials showed that BD-I patients with mixed episodes reported considerable impairments in HRQoL compared to patients with manic episodes. At 3 weeks, in patients with mixed episodes, asenapine was shown to lead to significant improvements in HRQoL compared to olanzapine and placebo. Results from these post-hoc analyses should be confirmed in prospective studies. TRIAL REGISTRATION: NCT00159744, NCT00159796.

Effect of aerobic exercise on insulin, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in overweight and obese postmenopausal women.

AIM: The purpose of presented study was to verify the influence of aerobic physical activity program on the serum insulin, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) concentrations in overweight and obese postmenopausal women. METHODS: Somatic parameters and serum concentrations of insulin, IGF-1 and IGFBP-3 were measured in 21 overweight and obese women, before and after 8-week cycloergometer physical workout and 16 age-matched, controls. Age of all studied women ranged from 54 to 78 years. RESULTS: The comparative analysis of biochemical indices measured before and after the training program showed that the systematic exercise cause the significant decrease in insulin (P<0.05) and IGF-1 concentrations (P<0.05). There were no differences in these parameters in controls over the studied period. The level of IGFBP-3 was not significantly changed in both investigated groups. In women participating in the training program the positive correlation (P<0.05) between changes in IGF-1 levels (Δ) and changes in insulin concentrations (Δ) within two terms of the study were found. The magnitude of changes (Δ) in insulin and IGF-1 levels over the study period correlated with their concentrations measured before the training program (P<0.01). CONCLUSION: Results of the present study indicate that regular aerobic physical activity decreases serum insulin and IGF-1 levels in postmenopausal women. The magnitude of insulin and IGF-1 concentration changes depend on their initial levels. Changes of IGF-1 levels are associated with insulin concentration modifications.

Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis.

Evasion of apoptosis contributes importantly to c-Myc-induced tumorigenesis. The BH3-only Bcl-2 family members Puma and Noxa are critical pro-apoptotic transcriptional targets of p53, a major mediator of Myc-induced apoptosis and suppressor of Myc-induced tumorigenesis. Hence, we have explored the impact of their individual or combined loss on myc-driven lymphomagenesis. Notably, Puma deficiency both increased B-lineage cells and accelerated the development of B lymphoma, accompanied by leukaemia, but not of pre-B lymphoma. Noxa deficiency alone also increased B-lineage cells but did not accelerate lymphomagenesis. However, its deficiency combined with loss of one puma allele produced more rapid onset of both pre-B and B lymphomas than did loss of a single puma allele alone. Nevertheless, the acceleration evoked by loss of both genes was not as marked as that caused by p53 heterozygosity. These results show that Puma imposes a significant, and Noxa a minor barrier to c-Myc-driven lymphomagenesis. They also indicate that additional BH3-only proteins probably also drive Myc-induced apoptosis and that non-apoptotic functions of p53 may contribute substantially to its tumour suppressor role.

In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute.

The ability of p53 to induce apoptosis in cells with damaged DNA is thought to contribute greatly to its tumour suppressor function. P53 has been proposed to induce apoptosis via numerous transcriptional targets or even by direct cytoplasmic action. Two transcriptional targets shown to mediate its apoptotic role in several cell types encode Noxa and Puma, BH3-only members of the Bcl-2 family. To test if their functions in p53-dependent apoptosis overlap, we generated mice lacking both. These mice develop normally and no tumours have yet arisen. In embryonic fibroblasts, the absence of both Noxa and Puma prevented induction of apoptosis by etoposide. Moreover, following whole body gamma-irradiation, the loss of both proteins protected thymocytes better than loss of Puma alone. Indeed, their combined deficiency protected thymocytes as strongly as loss of p53 itself. These results indicate that, at least in fibroblasts and thymocytes, p53-induced apoptosis proceeds principally via Noxa and Puma, with Puma having the predominant role in diverse cell types. The absence of tumours in the mice suggests that tumour suppression by p53 requires functions in addition to induction of apoptosis.

Ischemic epigenetics and the transplanted kidney.

The primary purpose of this investigation was to study oxidative demethylation of DNA following ischemia/reperfusion injury (I/RI) that putatively influences posttransplant gene expression in transplanted kidneys. Our hypothesis was that as a result of I/RI, oxidative damage, which is inherent in solid organ transplantation, may lead to aberrant demethylation of cytosine-guanine (CpG) sites within gene promoter regions of DNA. The methylated CpG sites normally contribute to the binding of proteins that render DNA inaccessible to transcription factors. Therefore, conversion of methylated cytosines to nonmethylated cytosines by oxidative damage in postischemic organs might facilitate enhanced gene expression in donor organs by exposing the demethylated CpG site in a gene promoter to DNA-binding proteins that enhance gene transcription. In this study, we investigated the demethylation of a specific CpG within the IFNgamma response element resident in the promoter region of the C3 gene in the rat kidney. In response to 24 hours of cold ischemia and a subsequent 2 hours of reperfusion in an isolated ex-vivo circuit, we observed a significant change in the ratio of methylated to unmethylated cytosines at this site. Epigenetic modifications to donor DNA have not been previously investigated, but our own data suggests that they have the potential to modify gene expression posttransplantation. Since epigenetic modification may become stable and heritable upon mitosis, such changes to the donor organ DNA may persist with enormous implications for transplant outcomes.

Generation of transgenic rabbits by the novel technique of chimeric somatic cell cloning.

A novel technique of chimeric somatic cell cloning was applied to produce a transgenic rabbit (NT20). Karyoplasts of transgenic adult skin fibroblasts with Tg(Wap-GH1) gene construct as a marker were microsurgically transferred into one, previously enucleated, blastomere of 2-cell non-transgenic embryos, while the second one remained intact. The reconstructed embryos either were cultured in vitro up to the blastocyst stage (Experiment I) or were transferred into recipient-females immediately after the cloning procedure (Experiment II). In Experiment I, 25/102 (24.5%) embryos formed blastocysts from whole embryos and 46/102 (44.12%) embryos developed to the blastocyst stage from single non-operated blastomeres, while the reconstructed blastomeres were damaged and degenerated. Thirteen (12.7%) embryos did not exceed 3- to 4-cell stages and 18 (17.7%) embryos were inhibited at the initial 2-cell stage. Out of 14 blastocysts which were subjected to molecular analysis, the transgene was detected in the cells of 4 blastocysts. In Experiment II, 163/217 (75.0%) embryos were transferred into 9 pseudopregnant recipient-rabbits (an average of 18 embryos per recipient). Four recipient-females (44.4%) became pregnant and delivered a total of 24 (14.7%) pups. Molecular analysis confirmed that two pups (1.2%), one live and one stillborn, showed a positive transgene signal. Live transgenic rabbit NT20 appeared healthy and anatomically as well as physiologically normal. The results of our experiments showed that transgenic adult skin fibroblast cell nuclei, which have been introduced into the cytoplasmic microenvironment of single enucleated blastomeres from 2-cell stage rabbit embryos, are able to direct the development of chimeric embryos not only to the blastocyst stage but also up to term.

Subversion of the Bcl-2 life/death switch in cancer development and therapy.

The Bcl-2 protein family, which largely determines commitment to apoptosis, has central roles in tumorigenesis and chemoresistance. Its three factions of interacting proteins include the BH3-only proteins (e.g., Bim, Puma, Bad, Noxa), which transduce diverse cytotoxic signals to the mammalian pro-survival proteins (Bcl-2, Bcl-x(L), Bcl-w, Mcl-1, A-1), whereas Bax and Bak, when freed from pro-survival constraint, provoke the mitochondrial permeabilization that triggers apoptosis. We have discovered unexpected specificity in their interactions. Only Bim and Puma, which mediate multiple cytotoxic signals, engage all the pro-survival proteins. Noxa and Bad instead bind subsets and cooperate in killing, indicating that apoptosis requires neutralization of different pro-survival subsets. Furthermore, Mcl-1 and Bcl-x(L), but not Bcl-2, directly sequester Bak in healthy cells, and Bak is freed only when BH3-only proteins neutralize both its guards. BH3-only proteins such as Bim are tumor suppressors and mediate many of the cytotoxic signals from anticancer agents. Hence, compounds mimicking them may prove valuable for therapy. Indeed, the recently described ABT-737 is a promising "BH3 mimetic" of Bad. We find that, like Bad, ABT-737 kills cells efficiently only if Mcl-1 is absent or down-regulated. Thus, manipulation of apoptosis by targeting the Bcl-2 family has exciting potential for cancer treatment.

Stroke volume and systolic time intervals: beat-to-beat comparison between echocardiography and ambulatory impedance cardiography in supine and tilted positions.

The aim of the study was to compare stroke volume (SV), ejection time (ET) and pre-ejection period (PEP) measurements obtained using a central haemodynamics ambulatory monitoring device based on impedance cardiography (ICG), in supine and tilted positions (60 degrees), with pulsed Doppler echocardiography as a non-invasive reference method. The Holter-type ICG device was used for off-line, beat-to-beat, automatic determination of SV, ET and PEP. ICG data were compared with those obtained simultaneously using pulsed Doppler echocardiography in the ascending aorta from a suprasternal projection, 1 min before and 10 min after tilting. The tests were performed in 13 young, healthy subjects (six men and seven women, aged 23-33 years). Linear regression between the measured values obtained for all subjects was described by the following formulas: SVicg= 13.9 + 0.813 x SVecho (r = 0.857, SEE = 9.03, n = 496), ETicg = 16.8 + 0.987 x ETecho (r = 0.841, SEE=21.3, n = 496), PEPicg= 22.8 + 0.890 x PEPecho (r = 0.727, SEE = 14.6, n = 496). The data showed that ambulatory impedance cardiography gives useful absolute values of SV and systolic time intervals measured in supine and tilted positions.

Susceptibility of oral bacteria to Melaleuca alternifolia (tea tree) oil in vitro.

The in vitro activity of Melaleuca alternifolia (tea tree) oil against 161 isolates of oral bacteria from 15 genera was determined. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) ranged from 0.003 to 2.0% (v/v). MIC90 values were 1.0% (v/v) for Actinomyces spp., Lactobacillus spp., Streptococcus mitis and Streptococcus sanguis, and 0.1% (v/v) for Prevotella spp. Isolates of Porphyromonas, Prevotella and Veillonella had the lowest MICs and MBCs, and isolates of Streptococcus, Fusobacterium and Lactobacillus had the highest. Time kill studies with Streptococcus mutans and Lactobacillus rhamnosus showed that treatment with > or = 0.5% tea tree oil caused decreases in viability of >3 log colony forming units/ml after only 30 s, and viable organisms were not detected after 5 min. These studies indicate that a range of oral bacteria are susceptible to tea tree oil, suggesting that tea tree oil may be of use in oral healthcare products and in the maintenance of oral hygiene.

FISH mapping of two putative keratin gene clusters on cat (Felis catus) chromosomes.

Genes encoding keratins are evolutionary highly conserved and clustered in two linkage groups in mammalian genomes. Canine keratin 9 (K-9) and keratin 2e (K-2) cosmid-derived gene probes were used to localize the acidic and basic-neutral keratin gene clusters to cat chromosomes E1q12 and B4q15, respectively. The status of the physical map of the cat genome is discussed.