Submarine landslide megablocks show half of Anak Krakatau island failed on December 22nd, 2018.

As demonstrated at Anak Krakatau on December 22nd, 2018, tsunamis generated by volcanic flank collapse are incompletely understood and can be devastating. Here, we present the first high-resolution characterisation of both subaerial and submarine components of the collapse. Combined Synthetic Aperture Radar data and aerial photographs reveal an extensive subaerial failure that bounds pre-event deformation and volcanic products. To the southwest of the volcano, bathymetric and seismic reflection data reveal a blocky landslide deposit (0.214 ± 0.036 km3) emplaced over 1.5 km into the adjacent basin. Our findings are consistent with en-masse lateral collapse with a volume ≥0.175 km3, resolving several ambiguities in previous reconstructions. Post-collapse eruptions produced an additional ~0.3 km3 of tephra, burying the scar and landslide deposit. The event provides a model for lateral collapse scenarios at other arc-volcanic islands showing that rapid island growth can lead to large-scale failure and that even faster rebuilding can obscure pre-existing collapse.

Alterations in blood microbiota after colonic cancer surgery.

BACKGROUND: Mechanisms contributing to the perioperative stress response remain poorly understood. This study investigated changes in the amount of bacterial DNA in blood and the diversity of blood microbiota in the perioperative period in patients undergoing minimally invasive surgery for colonic cancer in an enhanced recovery after surgery setting. METHODS: DNA encoding the bacterial 16S ribosomal RNA gene (16S rDNA) in whole blood obtained the day before surgery, and on postoperative day (POD) 1 and POD 10-14 was amplified and quantified by PCR before sequencing for taxonomic assignment. Richness, evenness and similarity measures were calculated to compare microbiota between days. Differences in relative abundance were analysed using the linear discriminant analysis effect size (LEfSe) algorithm. RESULTS: Thirty patients were included between January and July 2016. The concentration of bacterial 16S rDNA in blood increased between the day before surgery and POD 1 (P = 0.025). Bacterial richness was lower on POD 10-14 than on the day before surgery and POD 1 (both P < 0·001). LEfSe analysis comparing the day before surgery and POD 10-14 identified changes in the abundance of several bacteria, including Fusobacterium nucleatum, which was relatively enriched on POD 10-14. CONCLUSION: These findings suggest that the blood of patients with colonic cancer harbours bacterial 16S rDNA, which increases in concentration after surgery.

ANTECEDENTES: Los mecanismos que contribuyen a la respuesta al estrés perioperatorio siguen siendo poco conocidos. Este estudio investigó los cambios en la cantidad de ADN bacteriano en la sangre y la diversidad de la microbiota sanguínea en el período perioperatorio en pacientes sometidos a cirugía mínimamente invasiva por cáncer de colon en el contexto de un programe de recuperación mejorada después de la cirugía. MÉTODOS: El ADN que codifica el gen de ARN ribosómico (rNDA) 16S bacteriano en sangre completa obtenido el día antes de la cirugía, el día 1 del postoperatorio y el día 10-14 del postoperatorio se amplificó y cuantificó mediante qPCR antes de la secuenciación para la asignación taxonómica. Se calcularon medidas de riqueza, uniformidad y similitud para comparar la microbiota entre los diferentes días. Las diferencias en la abundancia relativa se analizaron mediante un algoritmo de análisis discriminante lineal de tamaño de efecto (linear discriminant analysis effect size, LEfSe). RESULTADOS: De enero a julio de 2016 se incluyeron 30 pacientes. La concentración de 16S rNDA bacteriano en sangre aumentó desde el día antes de la operación al día 1 del postoperatorio. La riqueza bacteriana disminuyó en el día 10-14 del postoperatorio en comparación con el preoperatorio y el día 1 del postoperatorio. La comparación del preoperatorio y del día 10-14 postoperatorio por LEfSe identificó cambios en la abundancia de varias bacterias, incluida Fusobacterium nucleatum que mostró un enriquecimiento relativo el día 10-14 del postoperatorio. CONCLUSIÓN: Estos hallazgos sugieren que la sangre de los pacientes con cáncer de colon alberga 16S rNDA bacteriano cuya concentración aumenta tras la cirugía.

Associations between blood cultures after surgery for colorectal cancer and long-term oncological outcomes.

BACKGROUND: Systemic inflammation following curative surgery for colorectal cancer may be associated with increased risk of recurrence. [Correction added on 29 November 2019, after first online publication: text amended for accuracy.] This study investigated whether a clinically suspected infection, for which blood cultures were sent within 30 days after surgery for colorectal cancer, was associated with long-term oncological outcomes. METHODS: This register-based national cohort study included all Danish residents undergoing surgery with curative intent for colorectal cancer between January 2003 and December 2013. Patients who developed recurrence or died within 180 days after surgery were not included. Associations between blood cultures taken within 30 days after primary surgery and overall survival, disease-free survival and recurrence-free survival were analysed using Cox regression models adjusted for relevant clinical confounders, including demographic data, cancer stage, co-morbidity, blood transfusion, postoperative complications and adjuvant chemotherapy. RESULTS: The study included 21 349 patients, of whom 3390 (15·9 per cent) had blood cultures taken within 30 days after surgery. Median follow-up was 5·6 years. Patients who had blood cultures taken had an increased risk of all-cause mortality (hazard ratio (HR) 1·27, 95 per cent c.i. 1·20 to 1·35; P < 0·001), poorer disease-free survival (HR 1·22, 1·16 to 1·29; P < 0·001) and higher risk of recurrence (HR 1·15, 1·07 to 1·23; P < 0·001) than patients who did not have blood cultures taken. CONCLUSION: A clinically suspected infection requiring blood cultures within 30 days of surgery for colorectal cancer was associated with poorer oncological outcomes.

ANTECEDENTES: La inflamación sistémica en el cáncer colorrectal puede asociarse con un aumento del riesgo de recidiva. En este estudio se investigó si la sospecha clínica de infección, en la que se obtuvieron cultivos de sangre periférica durante los primeros 30 días de la cirugía por cáncer colorrectal, se asociaba con los resultados oncológicos a largo plazo. MÉTODOS: Se trata de un estudio de cohortes de un registro de una base de datos nacional, que incluyía todos los sujetos residentes en Dinamarca sometidos a cirugía por cáncer colorrectal con intención curativa desde enero de 2003 a diciembre de 2013. Los pacientes con recidiva o que fallecieron durante los primeros 180 días después de la cirugía fueron excluidos. Se estimaron las asociaciones entre los cultivos de sangre periférica efectuados en los primeros 30 días tras la cirugía primaria y la supervivencia global, supervivencia libre de enfermedad y supervivencia libre de recidiva mediante modelos de regresión de Cox, ajustados por variables clínicas confusoras relevantes (incluyendo datos demográficos, estadio del cáncer, comorbilidad, transfusión de sangre, complicaciones postoperatorias y quimioterapia adyuvante). RESULTADOS: El estudio incluyó 21.349 pacientes, de los cuales en 3.390 (16%) se habían obtenido cultivos de sangre periférica durante los primeros 30 días tras la cirugía. La mediana de seguimiento fue de 5,6 años. Los pacientes en los que se había obtenido cultivos de sangre periférica presentaron un riesgo aumentado de mortalidad por cualquier causa (cociente de riesgos instantáneos, hazard ratio, HR 1,27, i.c. del 95% 1,20-1,35; P < 0.0001), peor supervivencia libre de enfermedad (HR 1,22, i.c. del 95% 1,16-1,29; P < 0,0001) y mayor riesgo de recidiva (HR 1,15, i.c. del 95% 1,07-1,23; P < 0,0001) que los pacientes en los que no se habían obtenido cultivos. CONCLUSIÓN: La presencia de una infección sospechada clínicamente para la cual se requiere obtener cultivos de sangre periférica en los primeros 30 días tras cirugía por cancer colorrectal se asoció con peores resultados oncológicos.

Attachment security and existential distress among patients with advanced cancer.

BACKGROUND: Felt security in close relationships may affect individual adaptation responses to existential threat in severe illness. We examined the contribution of attachment security to demoralization, a state of existential distress involving perceived pointlessness and meaninglessness in advanced cancer. METHOD: A mixed cross-sectional sample of 382 patients with advanced cancer (mean age 59, 60% female) was recruited from outpatient oncology clinics. Participants completed self-report measures of attachment security, demoralization, depression, and physical symptom burden. We used multiple linear regression to analyze the association between attachment security and demoralization, controlling for demographic factors and symptom burden and tested whether attachment security moderated the association of symptom burden with demoralization. Separate analyses compared the contribution of the dimensions of attachment anxiety and attachment avoidance. RESULTS: The prevalence of clinically relevant demoralization was 35%. Demoralization was associated with lower attachment security (ß = -0.54, 95%CI: -0.62 to 0.46). This effect was empirically stronger for attachment anxiety (ß = 0.52, 95%CI: 0.44 to 0.60) compared to attachment avoidance (ß = 0.36, 95%CI: 0.27 to 0.45). Attachment security also significantly moderated the association of physical symptom burden with demoralization, such that with less attachment security, there was a stronger association between symptom burden and demoralization. CONCLUSION: Attachment security may protect from demoralization in advanced cancer. Its relative lack, particularly on the dimension of attachment anxiety, may limit adaptive capacities to deal with illness burden and to sustain morale and purpose in life. An understanding of individual differences in attachment needs can inform existential interventions for severely ill individuals.

Correlations between contouring similarity metrics and simulated treatment outcome for prostate radiotherapy.

Many similarity metrics exist for inter-observer contouring variation studies, however no correlation between metric choice and prostate cancer radiotherapy dosimetry has been explored. These correlations were investigated in this study. Two separate trials were undertaken, the first a thirty-five patient cohort with three observers, the second a five patient dataset with ten observers. Clinical and planning target volumes (CTV and PTV), rectum, and bladder were independently contoured by all observers in each trial. Structures were contoured on T2-weighted MRI and transferred onto CT following rigid registration for treatment planning in the first trial. Structures were contoured directly on CT in the second trial. STAPLE and majority voting volumes were generated as reference gold standard volumes for each structure for the two trials respectively. VMAT treatment plans (78 Gy to PTV) were simulated for observer and gold standard volumes, and dosimetry assessed using multiple radiobiological metrics. Correlations between contouring similarity metrics and dosimetry were calculated using Spearman's rank correlation coefficient. No correlations were observed between contouring similarity metrics and dosimetry for CTV within either trial. Volume similarity correlated most strongly with radiobiological metrics for PTV in both trials, including TCPPoisson (ρ = 0.57, 0.65), TCPLogit (ρ = 0.39, 0.62), and EUD (ρ = 0.43, 0.61) for each respective trial. Rectum and bladder metric correlations displayed no consistency for the two trials. PTV volume similarity was found to significantly correlate with rectum normal tissue complication probability (ρ = 0.33, 0.48). Minimal to no correlations with dosimetry were observed for overlap or boundary contouring metrics. Future inter-observer contouring variation studies for prostate cancer should incorporate volume similarity to provide additional insights into dosimetry during analysis.

30-Day, 90-day and 1-year mortality after emergency colonic surgery.

PURPOSE: Emergency surgery is an independent risk factor in colonic surgery resulting in high 30-day mortality. The primary aim of this study was to report 30-day, 90-day and 1-year mortality rates after emergency colonic surgery, and to report factors associated with 30-day, 90-day and 1-year mortality. Second, the aim was to report 30-day postoperative complications and their relation to in-hospital mortality. METHODS: All patients undergoing acute colonic surgery in the period from May 2009 to April 2013 at Copenhagen University Hospital Herlev, Denmark, were identified. Perioperative data was collected from medical journals. RESULTS: 30-day, 90-day and 1-year mortality was 21, 30 and 41%, respectively. Age >70 years, Performance status ≥3 and resection with stoma were independent factors associated with 30-day mortality. Age >70 years, Performance status ≥3, resection with stoma and malignant disease were independent risk factors associated with 90-day mortality. Age >70 years, Performance status ≥3, resection with stoma and malignant disease were independent factors associated with 1-year mortality. Overall, 30-day complication rate was 63%, with cardiopulmonary complications leading to most postoperative deaths. CONCLUSION: Mortality and complication rates after emergency colonic surgery are high and associated with patient related risk factors that cannot be modified, but also treatment related outcomes that are modifiable. An increased focus on medical and other preventive measures should be explored in the future.

A consolidated analysis of the physiologic and molecular responses induced under acid stress in the legume-symbiont model-soil bacterium Sinorhizobium meliloti.

Abiotic stresses in general and extracellular acidity in particular disturb and limit nitrogen-fixing symbioses between rhizobia and their host legumes. Except for valuable molecular-biological studies on different rhizobia, no consolidated models have been formulated to describe the central physiologic changes that occur in acid-stressed bacteria. We present here an integrated analysis entailing the main cultural, metabolic, and molecular responses of the model bacterium Sinorhizobium meliloti growing under controlled acid stress in a chemostat. A stepwise extracellular acidification of the culture medium had indicated that S. meliloti stopped growing at ca. pH 6.0-6.1. Under such stress the rhizobia increased the O2 consumption per cell by more than 5-fold. This phenotype, together with an increase in the transcripts for several membrane cytochromes, entails a higher aerobic-respiration rate in the acid-stressed rhizobia. Multivariate analysis of global metabolome data served to unequivocally correlate specific-metabolite profiles with the extracellular pH, showing that at low pH the pentose-phosphate pathway exhibited increases in several transcripts, enzymes, and metabolites. Further analyses should be focused on the time course of the observed changes, its associated intracellular signaling, and on the comparison with the changes that operate during the sub lethal acid-adaptive response (ATR) in rhizobia.

Pregabalin prescriptions in the United Kingdom: a drug utilisation study of The Health Improvement Network (THIN) primary care database.

AIM: In Europe, pregabalin is approved for treatment of neuropathic pain, general anxiety disorder (GAD) and as adjunctive therapy for epilepsy. The purpose of this study was to assess utilisation of pregabalin in the UK, including patients with a recorded history of substance abuse, from a large general practice database. METHODS: This observational drug utilisation study (DUS) analysed pregabalin prescription data from the UK Health Improvement Network primary care database between September 2004 and July 2009. Patient demographics, diagnoses (by READ codes) and pregabalin dosing data were collected. Diagnosis codes were used as proxy for approved indication for pregabalin. RESULT: A cohort of 18,951 patients was prescribed pregabalin; dosing information was available for 13,480 (71.1%). Median age of patients was 58 years, and majority were female (60.1%). Median (interquartile range) prescribed average daily dose (ADD) of pregabalin for all patients was 150.0 (162.5) mg/day; this was highest in patients with epilepsy (191.9 mg/day), followed by neuropathic pain (158.0 mg/day) and GAD (150.0 mg/day). Only 1.0% (136/13,480) of patients were prescribed an ADD of pregabalin over the maximum approved dose of 600 mg/day. Of these, 18.4% (25/136) of patients had a history of substance abuse compared with 14.0% (1884/13,480) in the full population. CONCLUSION: Data from this DUS indicated that the majority of pregabalin prescribing in the UK was consistent with product labelling. The proportion of patients with prescribed ADD > 600 mg/day was small and with a similar proportion with a history of substance abuse as in the full population.

[Comparative analysis of photoselective vaporization of the prostate with the Greenlight laser and open prostatectomy for high volume prostate hypertrophy]. / Analyse comparative coût-efficacité de la photovaporisation prostatique par laser Greenlight et de l'adénomectomie pour hypertrophie de la prostate de gros volume.

PURPOSE: Comparative medical economic study between total prostatectomy and laser in the treatment of benign prostatic hyperplasia in patients whose prostate is more than 80g. MATERIALS AND METHODS: This study compared data registered retrospectively for the group AVH and prospective data for PVP patients. The patients whose prostate weighed more than 80g by echography were selected. The adopted point of view was the one of the hospital and the temporal horizon was of one year after the surgical operation. Direct costs per- and post-surgery were taken into account including specific surgical care and secondary surgical revision. The medical data per- and postoperative were also compared. Primary outcome measure was incremental cost per procedure. RESULTS: Forty-one patients in the AVH group and 53 in the PVP group. The mean length of stay (LOS) is significantly shorter in the PVP group (3.0±1.0 days vs 10.4±4.0; P<0.001). Re-operation rate was significantly lower in the PVP group (1.9% vs 19.5% P<0.001). The cost analysis shows a mean additional cost of 1450 euros for the AVH group. CONCLUSION: PVP was cost-effective because it was more economic and it lead to lower re-operation rate until one year of follow-up than in the AVH group. Nevertheless, these data deserve to be nuanced by unfavorable results of the AVH in comparison with those of the literature.

NK cell intrinsic regulation of MIP-1α by granzyme M.

Granzymes are generally recognized for their capacity to induce various pathways of perforin-dependent target cell death. Within this serine protease family, Granzyme M (GrzM) is unique owing to its preferential expression in innate effectors such as natural killer (NK) cells. During Listeria monocytogenes infection, we observed markedly reduced secretion of macrophage inflammatory protein-1 alpha (MIP-1α) in livers of GrzM-deficient mice, which resulted in significantly impaired NK cell recruitment. Direct stimulation with IL-12 and IL-15 demonstrated that GrzM was required for maximal secretion of active MIP-1α. This effect was not due to reduced protein induction but resulted from heightened intracellular accumulation of MIP-1α, with reduced release. These results demonstrate that GrzM is a critical mediator of innate immunity that can regulate chemotactic networks and has an important role in the initiation of immune responses and pathogen control.

Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141(+)XCR1+ dendritic cells.

Monocyte-derived dendritic cells (moDC) have been widely used in cancer immunotherapy but show significant donor-to-donor variability and low capacity for the cross-presentation of tumour-associated antigens (TAA) to CD8(+) T cells, greatly limiting the success of this approach. Given recent developments in induced pluripotency and the relative ease with which induced pluripotent stem (iPS) cell lines may be generated from individuals, we have succeeded in differentiating dendritic cells (DC) from human leukocyte antigen (HLA)-A(*)0201(+) iPS cells (iPS cell-derived DC (ipDC)), using protocols compliant with their subsequent clinical application. Unlike moDC, a subset of ipDC was found to coexpress CD141 and XCR1 that have been shown previously to define the human equivalent of mouse CD8α(+) DC, in which the capacity for cross-presentation has been shown to reside. Accordingly, ipDC were able to cross-present the TAA, Melan A, to a CD8(+) T-cell clone and stimulate primary Melan A-specific responses among naïve T cells from an HLA-A(*)0201(+) donor. Given that CD141(+)XCR1(+) DC are present in peripheral blood in trace numbers that preclude their clinical application, the ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumour-specific immune responses.

Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma.

Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture. Candidate drivers of cSCC development were derived by first defining a set of in vitro cancer genes and then comparing their expression in a range of clinical data sets containing normal skin, cSCC and the benign hyper-proliferative condition psoriasis. A small interfering RNA (siRNA) screen of the resulting 21 upregulated genes has yielded targets capable of reducing xenograft tumor volume in vivo. Small-molecule inhibitors for one target, Polo-like kinase-1 (PLK1), are already in clinical trials for other malignancies, and our data show efficacy in cSCC. Another target, C20orf20, is identified as being overexpressed in cSCC, and siRNA-mediated knockdown induces apoptosis in vitro and reduces tumor growth in vivo. Thus, our approach has shown established and uncharacterized drivers of tumorigenesis with potent efficacy as therapeutic targets for the treatment of cSCC.

Is mode of delivery associated with postpartum depression at 6 weeks: a prospective cohort study.

OBJECTIVE: To examine the relationship between delivery mode and postpartum depression at 6 weeks following hospital discharge. DESIGN: A prospective cohort study. SETTING: Eleven hospitals in Ontario, Canada. SAMPLE: A total of 2560 women ≥16 years of age who delivered singleton, live infants at term. METHODS: Women completed a questionnaire in hospital and 74% (n = 1897) participated in a structured telephone interview 6 weeks after discharge. Additional data were extracted from labour and delivery records. Generalised estimating equations (GEEs) were used to investigate factors associated with postpartum depression. MAIN OUTCOME MEASURE: Women were screened for depression at 6 weeks following hospital discharge using the Edinburgh Postnatal Depression Scale (EPDS). A score of ≥12 on the EPDS was used as a measure of the primary outcome, depression. RESULTS: Mode of delivery was not independently associated with postpartum depression, and did not factor into the main-effects model. The multivariable analysis identified 11 predictor variables for depression: young maternal age (OR 5.27; 95% CI 2.73-10.15); maternal hospital readmission (OR 3.02; 95% CI 1.46-6.24); non-initiation of breastfeeding (OR 2.02; 95% CI 0.99-4.11); good, fair, or poor self-reported postpartum health (OR 1.82; 95% CI 1.19-2.80); urinary incontinence (OR 1.79; 95% CI 1.06-3.03); multiparity (OR 1.59; 95% CI 1.22-2.08); low mental health functioning (OR 1.20; 95% CI 1.15-1.25); low subjective social status (OR 1.16; 95% CI 1.02-1.33); high number of unmet learning needs in hospital (OR 1.12; 95% CI 1.03-1.22); low social support (OR 1.06; 95% CI 1.03-1.09); and low physical health functioning (OR 1.03; 95% CI 1.003-1.055). An exploratory interaction model revealed that caesarean section was associated with higher odds of becoming depressed in Canadian-born women, but that in women born outside of Canada it was associated with a lower risk of becoming depressed. CONCLUSIONS: Delivery mode had no significant impact on the development of postpartum depression in the main-effects model. However, it may interact with place of birth and other unmeasured factors to create a risk for depression.

[A pocket pRb mutation induces the increase in its affinity to E2F4 coupled with activation of muscle differentiation].

Co-ordination of proliferation and differentiation in cells committed to muscle fate requires the interaction of the retinoblastoma gene product (pRb) with transcription factors of the E2F family. pRb has different affinities for distinct E2Fs, however, the mechanism involved in pRb-E2Fs interaction has not been completely investigated. We have found that pRb carrying a small deletion at the end of the T antigen binding region (deltaS/N), and unable to interact with large T antigen, could induce acute cell cycle block, stable prolongation of the cell cycle in G0/G1 and G2/M phases and suppression of the growth of tumor cells. The deltaS/N showed increased affinity for E2F4, bound hyperphosphorylated forms of E2F4 and induced its nuclear compartmentalization. The ability of deltaS/N to form complexes with E2F4 on DNA was associated with an increase in formation of "free" E2F4 and transsuppression of the specific reporter through preferential binding to E2F4 but not t o E2F1. Stable expression of deltaS/N in multi-potent fibroblasts promoted early muscle commitment. The results obtained suggest that a mutation in the T antigen binding region may increase in affinity of the pRb for E2F4 combined with activation of muscle differentiation.

Clinical stem cell therapies for severe autoimmune diseases.

Severe autoimmune diseases (ADs) are a major source of disability and reduced quality of life and may result in shortened life expectancy, particularly in treatment-resistant patients. For several decades, allogeneic and autologous haematopoietic stem cell transplantation (HSCT) has been the focus of scientific investigation as a potential means of delivering 'one-off' intensive treatment in severe ADs. Improvements in the clinical safety of HCST were followed by its increasing use in recent years as an experimental treatment for severe and resistant ADs. European and North American registries have accumulated between one and two thousand procedures. Retrospective analyses and prospective studies have demonstrated the feasibility, safety and initial efficacy data in various ADs. Profound cell biological changes induced by HSCT leading to stabilization or reversal of organ damage have been characterized. These have also shed light on basic disease mechanisms and support investigation of more specific cellular therapy in ADs. There is clear potential for harnessing a profound immunological effect through HSCT. However, there is a need for an ongoing balance against evolving non-transplant treatments for ADs. Ideally, these issues should be resolved in phase III studies, in which HSCT approaches are compared with the best comparator.

Stem cell-related therapies for vascular diseases.

The therapeutic potential of 'adult' or at least non-embryonic stem cells and their progeny has developed gradually over the past half century as a consequence of the wealth of knowledge derived from stem cell research. Translational research coupled with clinical trials and derived from basic research has led the way to the clinic. This commenced with the use of haematopoietic stem cell transplantation (HSCT), to treat haematological malignancies, to be followed by the most recent clinical trials to treat a variety of coronary and peripheral artery diseases. Stem cells and their progeny isolated from bone marrow or blood appear to exert an ameliorating effect in certain vascular disorders. Although promising, some of these treatments remain controversial and further research and, where indicated, appropriately powered trials are required to confirm the safety and determine the efficacy of these novel therapies.

The effect of catalytic converter legislation on suicide rates in Grampian and Scotland 1980-2003.

OBJECTIVE: To examine the effect of catalytic converter legislation on suicide rates in Grampian and Scotland since its implementation in 1993. METHODS: (1) Population study in Grampian and Scotland using national population and mortality statistics for 1980 to 2003. (2) Retrospective, controlled cohort study of individualswho had unsuccessfully attempted suicide by motor had unsuccessfully attempted suicide by motor vehicle exhaust gassing to examine the theory of method substitution. method substitution. RESULTS: There was a significant fall in suicides by motor vehicle exhaust gas inhalation in Scotland and Grampian following the introduction of compulsory catalytic converter legislation. However, in the same time period, there was a significant increase in numbers of suicides by hanging and total suicide rates in Scotland. There was a non-significant trend in a small sample of patients from a local hyperbaric unit for an increased rate of subsequent completed suicide between those who had previously attempted suicide by motor vehicle exhaust gas inhalation and controls. CONCLUSIONS: Catalytic converter legislation has resulted in a decrease in the number of suicides by motor vehicle exhaust gas inhalation. Overall suicide rates have not decreased. There is evidence to suggest that those who would have previously committed suicide by motor vehicle exhaust gas inhalation find alternative methods of suicide, so called 'method substitution'. Initiatives to reduce suicide rates should be directed at those means that are used by impulsive suicide attempters, as other, determined individuals, will commit suicide by another method.

5-Azacytidine-treated human mesenchymal stem/progenitor cells derived from umbilical cord, cord blood and bone marrow do not generate cardiomyocytes in vitro at high frequencies.

BACKGROUND AND OBJECTIVES: Mesenchymal stem/progenitor cells (MSCs) are multipotent progenitors that differentiate into such lineages as bone, fat, cartilage and stromal cells that support haemopoiesis. Bone marrow MSCs can also contribute to cardiac repair, although the mechanism for this is unclear. Here, we examine the potential of MSCs from different sources to generate cardiomyocytes in vitro, as a means for predicting their therapeutic potential after myocardial infarction. MATERIALS AND METHODS: Mesenchymal stem/progenitor cells were isolated from the perivascular tissue and Wharton's jelly of the umbilical cord and from cord blood. Their immunophenotype and differentiation potential to generate osteoblasts, chondrocytes, adipocytes and cardiomyoxcytes in vitro was compared with those of bone marrow MSCs. RESULTS: Mesenchymal stem/progenitor cells isolated from umbilical cord and cord blood were phenotypically similar to bone marrow MSCs, the exception being in the expression of CD106, which was absent on umbilical cord MSCs, and CD146 that was highly expressed in cord blood MSCs. They have variable abilities to give rise to osteoblasts, chondrocytes and adipocytes, with bone marrow MSCs being the most robust. While a small proportion (approximately 0.07%) of bone marrow MSCs could generate cardiomyocyte-like cells in vitro, those from umbilical cord and cord blood did not express cardiac markers either spontaneously or after treatment with 5-azacytidine. CONCLUSION: Although MSCs may be useful for such clinical applications as bone or cartilage repair, the results presented here indicate that such cells do not generate cardiomyocytes frequently enough for cardiac repair. Their efficacy in heart repair is likely to be due to paracrine mechanisms.