Adapting cognitive behavioural therapy for adolescents with psychosis: insights from the Managing Adolescent first episode in psychosis study (MAPS).

Background: Onset of psychosis commonly occurs in adolescence, and long-term prognosis can be poor. There is growing evidence, largely from adult cohorts, that Cognitive Behavioural Therapy for Psychosis (CBTp) and Family Interventions (FI) can play a role in managing symptoms and difficulties associated with psychosis. However, adolescents have distinct developmental needs that likely impact their engagement and response to talking therapy. There is limited guidance on adapting CBTp to meet the clinical needs of under-eighteens experiencing psychosis. Method: This educational clinical practice article details learnings from therapists and supervisors working with young people (aged 14-18 years) with psychosis during the Managing Adolescent first-episode Psychosis: a feasibility Study (MAPS) randomised clinical treatment trial, supplemented by findings from nested qualitative interviews with young people receiving CBTp. Results: Suggested are given for tailoring CBTp assessment, formulation and interventions to meet the developmental and clinical needs of adolescents with psychosis. Developmentally appropriate techniques and resources described. Conclusions: Early indications from MAPS study indicate this developmentally tailored approach is an acceptable, safe and helpful treatment for young people with psychosis. Further research is needed to develop empirically grounded and evaluated CBTp for adolescents.

A psychological intervention for engaging dialogically with auditory hallucinations (Talking With Voices): A single-site, randomised controlled feasibility trial.

There is growing clinical interest in addressing relationship dynamics between service-users and their voices. The Talking With Voices (TwV) trial aimed to establish feasibility and acceptability of a novel dialogical intervention to reduce distress associated with voices amongst adults diagnosed with schizophrenia spectrum disorders. The single-site, single-blind (rater) randomised controlled trial recruited 50 participants who were allocated 1:1 to treatment as usual (TAU), or TAU plus up to 26 sessions of TwV therapy. Participants were assessed at baseline and again at end of treatment (six-months). The primary outcomes were quantitative and qualitative assessments of feasibility and acceptability. Secondary outcomes involved clinical measures, including targeted instruments for voice-hearing, dissociation, and emotional distress. The trial achieved 100 % of the target sample, 24 of whom were allocated to therapy and 26 to TAU. The trial had high retention (40/50 [80 %] participants at six-months) and high intervention adherence (21/24 [87.5 %] receiving ≥8 sessions). Signals of efficacy were shown in targeted measures of voice-hearing, dissociation, and perceptions of recovery. Analysis on the Positive and Negative Syndrome Scale indicated that there were no differences in means of general psychosis symptom scores in TwV compared to the control group. There were four serious adverse events in the therapy group and eight in TAU, none of which were related to study proceedings. The trial demonstrates the acceptability of the intervention and the feasibility of delivering it under controlled, randomised conditions. An adequately powered definitive trial is necessary to provide robust evidence regarding efficacy evaluation and cost-effectiveness. Trial registration: ISRCTN 45308981.

Stories From Children's Nurses in Flight: Exploring Experiences of Air Medical Transfers.

OBJECTIVE: Nurses are immersed in stories, and nurses who participate in flight transfers have stories to tell that may hold interest and offer insight for air medical professionals around the world. METHODS: Using a narrative inquiry methodology, 5 nurses working for a children's transport service in England were invited to tell stories from their experiences of air medical transfers. The aim of this article was to describe the meanings the nurses assigned to their experiences of flight transfers and to develop an interpretation of the narrative accounts, investigating the implications of the stories. RESULTS: This study provides a record of nurses' flight experiences within a predominately road-based children's transport service. The analysis considered the following topics: humor, parental presence on transport, and the joy and fear associated with the work. Implications for the training of nurses who fly were identified; it is recommended that the design of training should place the technical challenges of the work in the context of the emotional challenges. CONCLUSION: This article is a timely reflection on the social context of this new nursing experience for any situation around the world, which is seeing expansion of children's air medical transport provision.

A treatment protocol to guide the delivery of dialogical engagement with auditory hallucinations: Experience from the Talking With Voices pilot trial.

PURPOSE: To present a treatment protocol for delivering Talking With Voices, a novel intervention for people with psychosis that involves dialogical engagement with auditory hallucinations. METHOD: This paper presents a manualized approach to therapy employed in the Talking With Voices trial, a feasibility and acceptability randomized control trial of 50 adult participants. A rationale for following a treatment manual is provided, followed by the theoretical underpinnings of the intervention and its principles and values, including the main tenet that voices can often be understood as dissociated parts of the self which serve a protective function by indicating social-emotional vulnerabilities. The four therapy phases for improving the relationship between the voice-hearer and their voices are outlined: (1) engagement and psychoeducation, (2) creating a formulation, (3) dialoguing with voices, and (4) consolidating outcomes, including key milestones at each phase. Implementation issues are discussed, as well as recommendations for best practice and future research. RESULTS: The Talking With Voices treatment protocol indicates that it is feasible to manualize a dissociation-based approach to support service users who are distressed by hearing voices. CONCLUSION: For some individuals, it is possible to engage in productive dialogue with even extremely hostile or distressing voices. Developing coping strategies, creating a formulation, and ultimately establishing a dialogue with voices has the potential to improve the relationship between voice(s) and voice-hearer. Further research is now required to evaluate feasibility, acceptability, and efficacy. PRACTITIONER POINTS: It is feasible to integrate a dissociation model of voice-hearing within a psychological intervention for people with psychosis. Combining psychosocial education, formulation and direct dialogue can be used to facilitate a more peaceful relationship between clients and their voices. Practitioners trained in other therapeutic modalities can draw on existing transferrable skills to dialogue with their clients' voices. The input of those with lived experience of mental health difficulties has an important role in guiding treatment design and delivery.

"Flight Nurses," or "Nurses Who Fly"? An International Perspective on the Role of Flight Nurses.

OBJECTIVE: Discovering how transport nurses around the world are prepared and supported for a flight role may illuminate areas of best practice. This article reviews the flight nursing research, exploring what the international literature tells us about the role of flight nurses and discovering lessons from their experiences that may have particular relevance for the UK context. METHODS: The results of a literature search and thematic synthesis for flight nursing research are described. RESULTS: Thirteen research articles were obtained covering a broad range of countries. The scope of practice encompasses primary and secondary transport services and both civilian and military personnel. In an attempt to distill the role, work, and purpose of a flight nurse, a list of all the themes and categories that could be identified within the literature was assembled. These were inductively refined into 8 cluster themes, seeking to capture a broad description of the role of a nurse who flies. The definition of a "flight nurse" in the international context is debated. Thoughts related to training and education and, in particular, the nontechnical challenges of the role are discussed. CONCLUSION: This reflection provides insights that will influence the ongoing conversation around future air medical service development.

Dynamic sustained attention markers differentiate atypical development: The case of Williams syndrome and Down's syndrome.

Impaired sustained attention is considered an important factor in determining poor functional outcomes across multiple cognitive and behavioural disorders. Sustained attention is compromised for both children with Williams syndrome (WS) and Down's syndrome (DS), but specific difficulties remain poorly understood because of limitations in how sustained attention has been assessed thus far. In the current study, we compared the performance of typically developing children (N = 99), children with WS (N = 25), and children with DS (N = 18), on a Continuous Performance Task - a standard tool for measuring sustained attention. In contrast to previous studies, primarily focused on overall differences in mean performance, we estimated the extent to which performance changed over time on task, thus focusing directly on the sustained element of performance. Children with WS and children with DS performed more poorly overall compared to typically developing children. Importantly, measures specific to changes over time differentiated between children with the two syndromes. Children with WS showed a decrement in performance, whereas children with Down's syndrome demonstrated non-specific poor performance. In addition, our measure of change in performance predicted teacher-rated attention deficits symptoms across the full sample. An approach that captures dynamic changes in performance over assessments may be fruitful for investigating similarities and differences in sustained attention for other atypically developing populations.

Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study.

BACKGROUND: Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis. METHODS: We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197. FINDINGS: Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group). INTERPRETATION: A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis. FUNDING: National Institute for Health Research.

Let's Talk About Psychosis.

BACKGROUND: Research suggests that while patients wish to talk about positive psychotic symptoms, psychiatrists may be reluctant to do so in routine outpatient consultations. AIMS: To explore the content, context and impact of discussion of positive symptoms within psychiatric consultations. METHODS: Thematic analysis was applied to first discussions of positive symptoms, and overall impact assessed on the length of the consultation and the therapeutic relationship. RESULTS: Sixty-five of 143 consultations contained discussion of a positive psychotic symptom. Symptom discussion neither harmed the therapeutic relationship nor lengthened the consultation. Patients' disclosures strongly corresponded with psychological models of psychosis, emphasizing personal meaning and emotional impact. In contrast, psychiatrists focused on topographical characteristics, such as frequency and location. Strengths in psychiatric practice included using open questions, positive reinforcement and offering explanations tentatively. CONCLUSIONS: Findings support discussion of positive symptoms within outpatient consultations, to include necessary assessment of topography and risk alongside exploration of patients' subjective experience.

Ex vivo paracrine properties of cardiac tissue: Effects of chronic heart failure.

BACKGROUND: Cardiac regenerative responses are responsive to paracrine factors. We hypothesize that chronic heart failure (HF) in pediatric patients affects cardiac paracrine signaling relevant to resident c-kit(+)cluster of differentiation (CD)34- cardiac stem cells (CSCs). METHODS: Discarded atrial septum (huAS) and atrial appendages (huAA) from pediatric patients with HF (huAA-HF; n = 10) or without HF (n = 3) were explanted and suspension explant cultured in media. Conditioned media were screened for 120 human factors using unedited monoclonal antibody-based arrays. Significantly expressed (relative chemiluminescence >30 of 100) factors are reported (secretome). Emigrated cells were immunoselected for c-kit and enumerated as CSCs. RESULTS: After culture Day 7, CSCs emigrate from huAA but not huAS. The huAA secretome during CSC emigration included hepatocyte growth factor (HGF), epithelial cell-derived neutrophil attractant-78 (ENA-78)/chemokine (C-X-C motif) ligand (CXCL) 5, growth-regulated oncogene-α (GRO-α)/CXCL1, and macrophage migration inhibitory factor (MIF), candidate pro-migratory factors not present in the huAS secretome. Survival/proliferation of emigrated CSCs required coculture with cardiac tissue or tissue-conditioned media. Removal of huAA (Day 14) resulted in the loss of all emigrated CSCs (Day 28) and in decreased expression of 13 factors, including HGF, ENA-78/CXCL5, urokinase-type plasminogen activator receptor (uPAR)/CD87, and neutrophil-activating protein-2 (NAP-2)/CXCL7 candidate pro-survival factors. Secretomes of atrial appendages from HF patients have lower expression of 14 factors, including HGF, ENA-78/CXCL5, GRO-α/CXCL1, MIF, NAP-2/CXCL7, uPAR/CD87, and macrophage inflammatory protein-1α compared with AA from patients without HF. CONCLUSIONS: Suspension explant culturing models paracrine and innate CSC interactions in the heart. In pediatric patients, heart failure has an enduring effect on the ex vivo cardiac-derived secretome, with lower expression of candidate pro-migratory and pro-survival factors for CSCs.

Learning to read in Williams syndrome and Down syndrome: syndrome-specific precursors and developmental trajectories.

BACKGROUND: In typical development, early reading is underpinned by language skills, like vocabulary and phonological awareness (PA), as well as taught skills like letter knowledge. Less is understood about how early reading develops in children with neurodevelopmental disorders who display specific profiles of linguistic strengths and weaknesses, such as Down syndrome (DS) and Williams syndrome (WS). METHODS: Early reading, letter knowledge, rhyme matching, phoneme matching and receptive vocabulary were assessed in 26 children with DS and 26 children with WS between 4 and 8 years, as well as in two groups of typically developing (TD) children matched on nonverbal mental age (NVMA controls) or reading (RA controls). Reading was also measured 1 year later in DS, WS and RA controls to assess reading growth and its longitudinal predictors. RESULTS: Despite poor PA and vocabulary, children with DS displayed good reading and letter knowledge, compared with NVMA controls. Performance of children with WS was equivalent to RA controls and superior to NVMA controls on all tasks. Longitudinal delays emerged in reading in both DS and WS compared with RA controls. Vocabulary was a significant longitudinal predictor of reading growth for all children, but, for both children with DS and WS, and unlike RA controls, letter knowledge and PA were not. CONCLUSIONS: Children with DS and WS display atypical developmental patterns in the earliest stages of reading, further underlining the importance of cross-syndrome, longitudinal research, which tracks all levels of development in neurodevelopmental disorders. Identifying early syndrome-specific profiles of strengths and weaknesses underlying literacy development is critical for planning intervention programmes.

Heart cells with regenerative potential from pediatric patients with end stage heart failure: a translatable method to enrich and propagate.

Background. Human cardiac-derived progenitor cells (hCPCs) have shown promise in treating heart failure (HF) in adults. The purpose of this study was to describe derivation of hCPCs from pediatric patients with end-stage HF. Methods. At surgery, discarded right atrial tissues (hAA) were obtained from HF patients (n = 25; hAA-CHF). Minced tissues were suspended in complete (serum-containing) DMEM. Cells were selected for their tissue migration and expression of stem cell factor receptor (hc-kit). Characterization of hc-kit(positive) cells included immunohistochemical screening with a panel of monoclonal antibodies. Results. Cells, including phase-bright cells identified as hc-kit(positive), spontaneously emigrated from hAA-CHF in suspended explant cultures (SEC) after Day 7. When cocultured with tissue, emigrated hc-kit(positive) cells proliferated, first as loosely attached clones and later as multicellular clusters. At Day 21~5% of cells were hc-kit(positive). Between Days 14 and 28 hc-kit(positive) cells exhibited mesodermal commitment (GATA-4(positive) and NKX2.5(positive)); then after Day 28 cardiac lineages (flk-1(positive), smooth muscle actin(positive), troponin-I(positive), and myosin light chain(positive)). Conclusions. C-kit(positive) hCPCs can be derived from atrial tissue of pediatric patients with end-stage HF. SEC is a novel culture method for derivation of migratory hc-kit(positive) cells that favors clinical translation by reducing the need for exogenously added factors to expand hCPCs in vitro.

The multiple subfunctions of attention: differential developmental gateways to literacy and numeracy.

Attention is construed as multicomponential, but the roles of its distinct subfunctions in shaping the broader developing cognitive landscape are poorly understood. The current study assessed 3- to 6-year-olds (N=83) to: (a) trace developmental trajectories of attentional processes and their structure in early childhood and (b) measure the impact of distinct attention subfunctions on concurrent and longitudinal abilities related to literacy and numeracy. Distinct trajectories across attention measures revealed the emergence of 2 attentional factors, encompassing "executive" and "sustained-selective" processes. Executive attention predicted concurrent abilities across domains at Time 1, whereas sustained-selective attention predicted basic numeracy 1 year later. These concurrent and longitudinal constraints cast a broader light on the unfolding relations between domain-general and domain-specific processes over early childhood.

Neurocognitive development of attention across genetic syndromes: inspecting a disorder's dynamics through the lens of another.

Information on the neural circuits underpinning adult attention has been heavily informed by the impact of distinct brain lesions on attentional processes. In a similar fashion, the genetics, molecular, and systems neuroscience of attention can be informed by the impact of developmental disorders of known genetic origin on attentional processes. Here, we focus on three developmental disorders of known genetic origin (Williams syndrome, Down syndrome, and fragile X syndrome) to appraise key findings to date, new developments, and their implications for the neurocognitive development of attention. This growing body of knowledge suggests that attention should be understood as a multicomponential construct whose component processes follow distinct but dynamically interacting developmental trajectories. Further, attentional processes act as critical gateways to further processing, memory, and learning, and they are by converse influenced by other developing skills. In turn, these interactions at the cognitive level emphasize the need to study developing neural circuits involved in attentional control in terms of how their coordinated operations may be modified over time by neural disorders, rather than construing them as isolated cortical or subcortical "modules for attention."

Innovation in basic science: stem cells and their role in the treatment of paediatric cardiac failure--opportunities and challenges.

Heart failure is a leading cause of death worldwide. Current therapies only delay progression of the cardiac disease or replace the diseased heart with cardiac transplantation. Stem cells represent a recently discovered novel approach to the treatment of cardiac failure that may facilitate the replacement of diseased cardiac tissue and subsequently lead to improved cardiac function and cardiac regeneration. A stem cell is defined as a cell with the properties of being clonogenic, self-renewing, and multipotent. In response to intercellular signalling or environmental stimuli, stem cells differentiate into cells derived from any of the three primary germ layers: ectoderm, endoderm, and mesoderm, a powerful advantage for regenerative therapies. Meanwhile, a cardiac progenitor cell is a multipotent cell that can differentiate into cells of any of the cardiac lineages, including endothelial cells and cardiomyocytes. Stem cells can be classified into three categories: (1) adult stem cells, (2) embryonic stem cells, and (3) induced pluripotential cells. Adult stem cells have been identified in numerous organs and tissues in adults, including bone-marrow, skeletal muscle, adipose tissue, and, as was recently discovered, the heart. Embryonic stem cells are derived from the inner cell mass of the blastocyst stage of the developing embryo. Finally through transcriptional reprogramming, somatic cells, such as fibroblasts, can be converted into induced pluripotential cells that resemble embryonic stem cells. Four classes of stem cells that may lead to cardiac regeneration are: (1) Embryonic stem cells, (2) Bone Marrow derived stem cells, (3) Skeletal myoblasts, and (4) Cardiac stem cells and cardiac progenitor cells. Embryonic stem cells are problematic because of several reasons: (1) the formation of teratomas, (2) potential immunologic cellular rejection, (3) low efficiency of their differentiation into cardiomyocytes, typically 1% in culture, and (4) ethical and political issues. As of now, bone marrow derived stem cells have not been proven to differentiate reproducibly and reliably into cardiomyocytes. Skeletal myoblasts have created in vivo myotubes but have not electrically integrated with the myocardium. Cardiac stem cells and cardiac progenitor cells represent one of the most promising types of cellular therapy for children with cardiac failure.

Prospective and positive mental imagery deficits in dysphoria.

We know less about positive mental imagery than we do about negative mental imagery in depression. This study examined the relationship between depressed mood and the subjective experience of emotion in imagined events; specifically, prospective imagery, and imagery in response to emotionally ambiguous stimuli. One hundred and twenty-six undergraduates completed measures of depression, imagery vividness for future events, and a homograph interpretation task in which they generated images and subsequently rated image pleasantness and vividness. As predicted, compared to low dysphoria, high dysphoria was associated with poorer ability to vividly imagine positive (but not negative) future events. These findings were augmented by the observation that high dysphorics provided lower pleasantness ratings of images generated in response to homographs they interpreted as positive. We suggest that an imbalance in the inability to vividly imagine positive but not negative future events may curtail the ability of high dysphorics to be optimistic. High dysphoric individuals are further disadvantaged: even when they interpret ambiguity positively, the resulting images they generate are associated with less positive affect. Therapeutic strategies that address both such positive-specific imagery biases hold promise for depression treatment innovation.

Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts.

BACKGROUND: Hypophosphatasia (HPP) is a rare, heritable, metabolic bone disease due to deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. The infantile form features severe rickets often causing death in the first year of life from respiratory complications. There is no established medical treatment. In 1997, an 8-month-old girl with worsening and life-threatening infantile HPP improved considerably after marrow cell transplantation. OBJECTIVE: Our aim was to better understand and to advance these encouraging transplantation results. DESIGN: In 1999, based on emerging mouse transplantation models involving implanted donor bone fragments as well as osteoblast-like cells cultured from bone, we treated a 9-month-old girl suffering a similar course of infantile HPP. RESULTS: Four months later, radiographs demonstrated improved skeletal mineralization. Twenty months later, PCR analysis of adherent cells cultured from recipient bone suggested the presence of small amounts of paternal (donor) DNA despite the absence of hematopoietic engraftment. This patient, now 8 yr old (7 yr after transplantation), is active and growing, and has the clinical phenotype of the more mild, childhood form of HPP. CONCLUSIONS: Cumulative experience suggests that, after immune tolerance, donor bone fragments and marrow may provide precursor cells for distribution and engraftment in the skeletal microenvironment in HPP patients to form tissue-nonspecific isoenzyme of alkaline phosphatase-replete osteoblasts that can improve mineralization.

Stem cells for repair of the heart.

PURPOSE OF REVIEW: Stem cell therapy for treatment of cardiac disease has shown therapeutic potential. RECENT FINDINGS: A number of stem and progenitor populations have been identified for potential use in cardiac repair. Each possesses a unique potency that justifies consideration for use. Autologous, unfractionated bone marrow cells or skeletal myoblasts were used in early clinical trails to evaluate reparative effects on recent or record infarcts. In each case, evidence of limited improvement in cardiac function was obtained. Myoblast grafts were unexpectedly correlated with arrhythmias, thereby identifying a safety issue. The small number of patients and the lack of randomized control groups preclude conclusions regarding efficacy. Randomized controlled, intermediate-sized, double-blind clinical trials must be undertaken to this end. SUMMARY: Cellular therapy may be useful in the treatment of cardiac disease in adults. Appropriate adaptations to meet unique requirements for treatment of pediatric cardiovascular disease may be required. Bone marrow and skeletal myoblasts do not promote true tissue regeneration in spite of observed functional improvement. Trials using cells possessing true potential for (trans)differentiation may elucidate the potential and value of this therapy as a reparative modality. Development of optimal strategies for targeted delivery consistent with pathobiology is of exception clinical relevance.

Nonmyeloablative bone marrow transplantation of BXSB lupus mice using fully matched allogeneic donor cells from green fluorescent protein transgenic mice.

Male BXSB mice, a mouse model of systemic lupus erythematosus, were given bone marrow transplants (BMT) at 20 wk of age using MHC-matched donor cells and nonmyeloablative conditioning (550 cGy irradiation). Transplanted mice and irradiation controls were followed for a period of 20 wk. Mice transgenic for green fluorescent protein were used as donors to allow tracking of donor cells and a determination of chimerism. Radiation controls had reduced renal pathology at 10 wk posttransplant, but not at 20 wk compared with untreated mice, while nonmyeloablative BMT mice had significantly reduced pathology at both time intervals. The monocytosis characteristic of older BXSB mice was also reduced by BMT, but the treatment did not prevent production of Ab to dsDNA. A stable chimerism of 24-40% donor CD45-positive cells was achieved in spleen and bone marrow, and there was no evidence of clinical graft vs host disease. Donor cells were detected in most recipient organs, notably the thymus and renal glomeruli. The results suggest that complete depletion of mature lymphocytes or of progenitor stem cells is not required to control lupus nephritis in BXSB mice.

Effects of angiotensin-converting enzyme inhibitor on delayed-onset doxorubicin-induced cardiotoxicity.

Childhood survivors of cancer who are treated with anthacycline chemotherapy, such as doxorubicin (DOX), can develop late-onset cardiomyopathy years after chemotherapy. The mechanism(s) for progression of anthracycline cardiotoxicity to late cardiomyopathy is unknown. Because angiotensin II has been implicated in the progression of other cardiomyopathies, this investigation was undertaken to determine whether treatment with an angiotensinconverting enzyme (ACE) inhibitor, lisinopril, reduces the time-dependent effects of doxorubicin on cardiac gene expression and myocellular apoptosis. A single dose of saline (control) or doxorubicin (DOX treated; 2 mg/kg iv) was administered to rabbits. Control and DOX-treated groups were also subgrouped to receive lisinopril and designated as lisinopril or DOX + lisinopril, respectively (1 mg/kg/d oral), for 10 wk. Histopathology, as determined at the light and ultrastructural level, was consistent with a reduced number of cardiomyocytes relative to interstitial cells in the left ventricle (LV) of the DOX-treated group compared with control and DOX + lisinopril groups. Gene expression of the pro-atrial naturetic peptide (ANP), quantified by steady-state messenger ribonucleic acid (mRNA) levels with reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blotting, increased approx 12-fold (n = 10; p < 0.05) in the LV of DOX-treated groups compared to control and DOX + lisinopril groups. Increased ANP mRNA expression following doxorubicin dosing was localized predominantly in ventricular myocytes by in situ hybridization. Deoxyribonucleic acid (DNA) fragmentation, determined by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling), was increased in both DOX-treated and DOX + lisinopril groups compared to the control group. Lisinopril prevented both late-onset increased ventricular ANP expression and subsequent DOX-induced myocyte loss. The authors speculate that these protective effects of lisinopril are related to reduced ANP expression and myocyte loss, the latter possibly mediated by effects on myocellular apoptosis.

Mixed bone marrow or mixed stem cell transplantation for prevention or treatment of lupus-like diseases in mice.

Scientific analyses fortified by interpretations of immunodeficiency diseases as 'experiments of nature' have revealed the specific immune systems to be comprised of T cells subserving cell-mediated immunities plus B cells and plasma cells which produce and secrete antibodies. These two separate cellular systems regularly interact with each other to produce a coordinated defense which permits mammals to live within a sea of microorganisms that threaten the integrity and the survival of individuals. We have shown that bone marrow transplantation (BMT) can be used as a form of cellular engineering to construct or reconstruct the immune systems and cure otherwise fatal severe combined immunodeficiency. When severe aplastic anemia complicated the first BMT which was performed to cure a fatal severe combined immunodeficiency, a second BMT cured for the first time a complicating severe aplastic anemia. Subsequently, BMT has been used effectively to treat some 75 otherwise fatal diseases such as resistant leukemias, lymphomas, inborn errors of metabolism, and genetic anomalies of the hematopoietic development such as sickle cell anemia, thalassemia, congenital neutropenias, and many other diseases. More recently, we have employed BMT in mice both to cure and cause autoimmunities, and, together, these experiments showed that autoimmunities actually reside in the hematopoietic stem cells. We have also found that mixed BMT or mixed hematopoietic stem cell transplantation (HSCT) can be used to prevent and cure the most complex autoimmunities such as those occurring in BXSB mice and in (NZW x BXSB)F1 W/BF1 mice. Untreated, the former develop fulminating lethal glomerulonephritis plus numerous humoral autoimmunities. Mice of the (W/B)F1 strain develop autoimmune thrombocytopenic purpura, coronary vascular disease with myocardial infarction, glomerulonephritis, and numerous autoantibodies. All of these abnormalities are prevented or cured by mixed syngeneic (autoimmune) plus allogeneic (normal healthy) BMT or mixed peripheral blood HSCT. Thus, the most complex autoimmune diseases can be prevented or cured in experimental animals by mixed syngeneic plus allogeneic BMT or HSCT which produce stable mixed chimerism as a form of cellular engineering.