Skeletal muscle mitoflashes, pH, and the role of uncoupling protein-3.

Mitochondrial reactive oxygen species (ROS) are important cellular signaling molecules, but can cause oxidative damage if not kept within tolerable limits. An important proximal form of ROS in mitochondria is superoxide. Its production is thought to occur in regulated stochastic bursts, but current methods using mitochondrial targeted cpYFP to assess superoxide flashes are confounded by changes in pH. Accordingly, these flashes are generally referred to as 'mitoflashes'. Here we provide regulatory insights into mitoflashes and pH fluctuations in skeletal muscle, and the role of uncoupling protein-3 (UCP3). Using quantitative confocal microscopy of mitoflashes in intact muscle fibers, we show that the mitoflash magnitude significantly correlates with the degree of mitochondrial inner membrane depolarization and ablation of UCP3 did not affect this correlation. We assessed the effects of the absence of UCP3 on mitoflash activity in intact skeletal muscle fibers, and found no effects on mitoflash frequency, amplitude or duration, with a slight reduction in the average size of mitoflashes. We further investigated the regulation of pH flashes (pHlashes, presumably a component of mitoflash) by UCP3 using mitochondrial targeted SypHer (mt-SypHer) in skeletal muscle fibers. The frequency of pHlashes was significantly reduced in the absence of UCP3, without changes in other flash properties. ROS scavenger, tiron, did not alter pHlash frequency in either WT or UCP3KO mice. High resolution respirometry revealed that in the absence of UCP3 there is impaired proton leak and Complex I-driven respiration and maximal coupled respiration. Total cellular production of hydrogen peroxide (H2O2) as detected by Amplex-UltraRed was unaffected. Altogether, we demonstrate a correlation between mitochondrial membrane potential and mitoflash magnitude in skeletal muscle fibers that is independent of UCP3, and a role for UCP3 in the control of pHlash frequency and of proton leak- and Complex I coupled-respiration in skeletal muscle fibers. The differential regulation of mitoflashes and pHlashes by UCP3 and tiron also indicate that the two events, though may be related, are not identical events.

Smoking in pregnancy is a key factor for sudden infant death among Maori.

AIM: To examine the sudden unexpected death in infancy (SUDI) disparity between Maori and non-Maori in New Zealand. METHODS: A nationwide prospective case-control study ran from March 2012 to February 2015. Exposure to established SUDI risk factors was analysed to investigate the disparity experienced by Maori. Infant ethnicity was based on mother's ethnicity. Maori ethnicity was prioritised. Non-Maori includes Pacific, Asian, NZ European and Other. RESULTS: There were 137 cases and 649 controls. The Maori SUDI rate was 1.41/1000 live births compared to 0.53/1000 for non-Maori. Parents/caregivers of 132 cases (96%) and 258 controls (40%) were interviewed. Smoking in pregnancy was associated with an equally increased SUDI risk for Maori (adjusted OR = 8.11, 95% CI = 2.64, 24.93) and non-Maori (aOR = 5.09, 95% CI = 1.79, 14.47), as was bed-sharing (aOR = 3.66, 95% CI = 1.49, 9.00 vs aOR = 11.20, 95% CI = 3.46, 36.29). Bed-sharing prevalence was similar; however, more Maori controls smoked during pregnancy (46.7%) than non-Maori (22.8%). The main contributor relating to increased SUDI risk for Maori/non-Maori infants is the combination of smoking in pregnancy and bed sharing. CONCLUSION: The association between known SUDI risk factors, including bed sharing and/or smoking in pregnancy and SUDI risk, is the same regardless of ethnicity. Maori infants are exposed more frequently to both behaviours because of the higher Maori smoking rate.

Use of neutrophil to lymphocyte ratio for predicting histopathological grade of canine mast cell tumours.

Canine mast cell tumours (MCTs) are variable in their biological behaviour and treatment decisions depend heavily on the histopathological grade. Biomarkers such as neutrophil to lymphocyte ratio (NLR) and albumin to globulin ratio are used to predict the biological behaviour of human neoplasms, but have not been widely studied in dogs. A retrospective analysis identified 62 cases of gross MCT (14 high-grade, 48 low-grade tumours). Median NLR was significantly different between high- and low-grade MCT and tumours at different locations. A multivariable model identified increasing NLR (OR 2.0) and age (OR 1.7) to be associated with an increased risk of high-grade MCT. Receiver operating characteristic curve analysis identified an NLR threshold value of 5.67 (sensitivity 85.7 per cent; specificity 54.2 per cent) for predicting a high-grade MCT. An NLR threshold of 5.67 could be useful alongside existing tools (appearance, location, etc.) to help to predict the grade of MCT. With further validation, this biomarker could be used to guide clinical decisions before obtaining a histopathological diagnosis.

Caspase-8 tyrosine-380 phosphorylation inhibits CD95 DISC function by preventing procaspase-8 maturation and cycling within the complex.

Caspase-8 is a key initiator of apoptotic cell death where it functions as the apical protease in death receptor-mediated apoptosis triggered via the death-inducing signalling complex (DISC). However, the observation that caspase-8 is upregulated in many common tumour types led to the discovery of alternative non-apoptotic, pro-survival functions, many of which are contingent on phosphorylation of a tyrosine residue (Y380) found in the linker region between the two catalytic domains of the enzyme. Furthermore, Src-mediated Y380 phosphorylation leads to increased resistance to CD95-induced apoptosis; however, the mechanism underlying this impaired response to extrinsic apoptotic stimuli has not been identified. Consequently, we have employed a number of model systems to further dissect this protective mechanism. First, using an in vitro DISC model together with recombinant procaspase-8 variants, we show that Y380 phosphorylation inhibits procaspase-8 activation at the CD95 DISC, thereby preventing downstream activation of the caspase cascade. Second, we validated this finding in a cellular context using transfected neuroblastoma cell lines deficient in caspase-8. Reconstitution of these lines with phosphomimetic-caspase-8 results in increased resistance to CD95-mediated apoptosis and enhanced cell migration. When the in vitro DISC is assembled in the presence of cell lysate, caspase-8 Y380 phosphorylation attenuates DISC activity by inhibiting procaspase-8 autoproteolytic activity but not recruitment or homodimerization of caspase-8 within the complex. Once incorporated into the DISC, phosphorylated caspase-8 is unable to be released from the complex; this inhibits further cycling and release of active catalytic subunits into the cytoplasm, thus resulting in increased apoptotic resistance. Taken together, our novel findings expand our understanding of the key mechanisms underlying the anti-apoptotic functions of caspase-8 which may act as a critical block to existing antitumour therapies. Importantly, reversal or inhibition of caspase-8 phosphorylation may prove a valuable avenue to explore for sensitization of resistant tumours to extrinsic apoptotic stimuli.

Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.

Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

Efficacy and long-term outcomes of palivizumab prophylaxis to prevent respiratory syncytial virus infection in infants with cystic fibrosis in Northern Ireland.

BACKGROUND: RSV causes considerable morbidity and mortality in children. In cystic fibrosis (CF) viral infections are associated with worsening respiratory symptoms and bacterial colonization. Palivizumab is effective in reducing RSV hospitalization in high risk patient groups. Evidence regarding its effectiveness and safety in CF is inconclusive. CF screening in N. Ireland enabled timely palivizumab prophylaxis, becoming routine in 2002. OBJECTIVES: To determine the effect of palivizumab on RSV-related hospitalization and compare lung function and bacterial colonization at age 6 years for those born pre- and post-introduction of palivizumab prophylaxis. METHODS: A retrospective audit was conducted for all patients diagnosed with CF during the period from 1997 to 2007 inclusive. RSV-related hospitalization, time to Pseudomonas aeruginosa (PA) 1st isolate, lung function and growth parameters were recorded. Comparisons were made for outcomes pre- and post-introduction of routine palivizumab administration in 2002. A cost evaluation was also performed. RESULTS: Ninety-two children were included; 47 pre- and 45 post-palivizumab introduction. The overall RSV-positive hospitalization rate was 13%. The relative risk of RSV infection in palivizumab non-recipients versus recipients was 4.78 (95%CI: 1.1-20.7), P = 0.027. Notably, PA 1st isolate was significantly earlier in the palivizumab recipient cohort versus non-recipient cohort (median 57 vs. 96 months, P < 0.025) with a relative risk of 2.5. Chronic PA infection at 6 years remained low in both groups, with similar lung function and growth parameters. Total costs were calculated at £96,127 ($151,880) for the non-recipient cohort versus £137,954 ($217,967) for the recipient cohort. CONCLUSION: Palivizumab was effective in reducing RSV-related hospitalization infection in CF patients. Surprisingly, we found a significantly earlier time to 1st isolate of PA in palivizumab recipients which we could not explain by altered or improved diagnostic tests.

A retrospective evaluation of polyurethane, long-stay, peripheral venous cannulae in dogs undergoing radiotherapy.

OBJECTIVES: The aim of this retrospective study was to review placement duration and associated complications of long-stay, peripheral venous cannulae in dogs undergoing a radiotherapy protocol. Factors affecting duration of stay of the cannulae were evaluated. METHODS: The records of patients which had a single-lumen, 16-gauge, 16-cm polyurethane cannulae inserted into a peripheral vein between 2010 and 2014 were reviewed. RESULTS: Forty-one cannulae were placed in 41 patients. Median duration of cannula stay was 14 days (range 2 to 26). In 14 cases (~34%) the cannula was removed at the end of the radiotherapy course. In 13 (~32%) cases, cannula-related complications resulted in premature removal. Use of steroids and antibiotics appeared to be associated with a longer median duration of stay. CLINICAL SIGNIFICANCE: No life-threatening complications were encountered. Indwelling, polyurethane, saphenous cannulae were an effective and safe way to maintain venous access in this group of patients. Prednisolone and antibiotics were typically commenced for acute radiation side effects -midway through the protocol; therefore their association with length of stay may not be a direct result of their administration.

Resistance to HSP90 inhibition involving loss of MCL1 addiction.

Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality.

Diagnostic value of neutrophil-lymphocyte and albumin-globulin ratios in canine soft tissue sarcoma.

OBJECTIVE: To investigate the ability of neutrophil-to-lymphocyte ratio and albumin-to-globulin ratio to differentiate soft tissue sarcoma from benign soft tissue tumours. METHODS: A retrospective study of pretreatment haematology and biochemistry in dogs diagnosed with soft tissue sarcoma or benign soft tissue tumours. The neutrophil-to-lymphocyte ratio and albumin-to-globulin ratio were compared between the two groups. In dogs diagnosed with soft tissue sarcoma, the relationship of neutrophil-to-lymphocyte ratio and albumin-to-globulin ratio to histological tumour grade (I to III) was assessed. RESULTS: In the dogs with soft tissue sarcoma (n=22), the neutrophil-to-lymphocyte ratio was significantly increased and the albumin-to-globulin ratio decreased compared to those with benign soft tissue tumours (n=14). The neutrophil-to-lymphocyte ratio and albumin-to globulin ratio were not useful as predictors of tumour grade in dogs diagnosed with soft tissue sarcoma. CLINICAL SIGNIFICANCE: Pretreatment neutrophil-to-lymphocyte ratio and albumin-to globulin ratio may aid with diagnosis and optimal treatment planning. Further investigation into their prognostic implications is warranted.

A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.

Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5'-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.

A caspase-3 'death-switch' in colorectal cancer cells for induced and synchronous tumor apoptosis in vitro and in vivo facilitates the development of minimally invasive cell death biomarkers.

Novel anticancer drugs targeting key apoptosis regulators have been developed and are undergoing clinical trials. Pharmacodynamic biomarkers to define the optimum dose of drug that provokes tumor apoptosis are in demand; acquisition of longitudinal tumor biopsies is a significant challenge and minimally invasive biomarkers are required. Considering this, we have developed and validated a preclinical 'death-switch' model for the discovery of secreted biomarkers of tumour apoptosis using in vitro proteomics and in vivo evaluation of the novel imaging probe [(18)F]ML-10 for non-invasive detection of apoptosis using positron emission tomography (PET). The 'death-switch' is a constitutively active mutant caspase-3 that is robustly induced by doxycycline to drive synchronous apoptosis in human colorectal cancer cells in vitro or grown as tumor xenografts. Death-switch induction caused caspase-dependent apoptosis between 3 and 24 hours in vitro and regression of 'death-switched' xenografts occurred within 24 h correlating with the percentage of apoptotic cells in tumor and levels of an established cell death biomarker (cleaved cytokeratin-18) in the blood. We sought to define secreted biomarkers of tumor apoptosis from cultured cells using Discovery Isobaric Tag proteomics, which may provide candidates to validate in blood. Early after caspase-3 activation, levels of normally secreted proteins were decreased (e.g. Gelsolin and Midkine) and proteins including CD44 and High Mobility Group protein B1 (HMGB1) that were released into cell culture media in vitro were also identified in the bloodstream of mice bearing death-switched tumors. We also exemplify the utility of the death-switch model for the validation of apoptotic imaging probes using [(18)F]ML-10, a PET tracer currently in clinical trials. Results showed increased tracer uptake of [(18)F]ML-10 in tumours undergoing apoptosis, compared with matched tumour controls imaged in the same animal. Overall, the death-switch model represents a robust and versatile tool for the discovery and validation of apoptosis biomarkers.

Sustained tumour eradication after induced caspase-3 activation and synchronous tumour apoptosis requires an intact host immune response.

Effective anticancer treatments often result in the induction of large amounts of tumour cell death. In vivo, such dying tumour cells are a potential source of antigens for T-cell stimulation. Although apoptosis is generally considered nonimmunogenic, recent evidence suggests that some anticancer therapies that induce apoptosis can elicit antitumour immune responses. Here, a doxycycline-inducible, constitutively active caspase-3 ('death switch') was constructed in a murine tumour model to explore the impact of the host immune response to rapid, synchronous and substantial tumour cell apoptosis. In vitro, up to 80% of tumour cells underwent apoptotic cell death within 24 h and death was accompanied by the release of potential 'danger signal' molecules HMGB1 and HSP90. In vivo, death switch induction provoked rapid, pronounced tumour regression in immune-competent and immune-deficient mice, but sustained tumour eradication was observed only in immune-competent mice. Moreover, the majority of mice that were tumour free after death switch induction were protected from further tumour rechallenge. In addition, long-term remission after induction of the death switch was completely abrogated following depletion of CD8 T cells. These data suggest that sustained tumour eradication after substantial tumour apoptosis requires an antitumour host immune response that prevents tumour relapse. In many patients, cancer therapies produce encouraging initial responses that are only short lived. These results provide new insights that may have important implications for further development of strategies that result in long-term tumour clearance after initially effective anticancer treatment.

Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL.

TRAIL (TNF (tumour necrosis factor)-related apoptosis-inducing ligand) a putative anti-cancer cytokine induces apoptosis through DISC (death-inducing signalling complex)-mediated activation of caspase-8 and/or cleavage of Bid. TRAIL is relatively specific for tumour cells but primary chronic lymphocytic leukaemia and mantle cell lymphoma (MCL) cells are resistant. Herein, we show that cellular metabolism influences cell death and that MCL cells (Z138 cell line) can survive/proliferate in glucose-free media by switching from aerobic glycolysis to 'coupled' oxidative phosphorylation. Extracellular flux analysis and mitochondrial inhibitors reveal that in the absence of glycolysis, Z138 cells have enhanced respiratory capacity coupled to ATP synthesis, similar to 'classical' state 3 mitochondria. Conversely, 2-deoxyglucose (2DG) blocked glycolysis and partially inhibited glycolytic-dependent oxidative phosphorylation, resulting in a 50% reduction in cellular ATP levels. Also, 2DG sensitised Z138 cells to TRAIL and induced a marked decrease in caspase-8, -3, cFLIP(S), Bid and Mcl-1 expression but Bak remained unchanged, altering the Mcl-1/Bak ratio, facilitating cytochrome c release and cell death. Conversely, under glucose-free conditions, Z138 cells were less sensitive to TRAIL with reduced TRAIL-R1/R2 surface receptor expression and impaired DISC formation. Anti-apoptotic proteins Bcl-2 and XIAP were up-regulated while pro-apoptotic BAX was down-regulated. Additionally, mitochondria had higher levels of cytochrome c and ultrastucturally exhibited a condensed configuration with enhanced intracristal spaces. Thus, metabolic switching was accompanied by mitochondrial proteome and ultrastructural remodelling enabling enhanced respiration activity. Cytochrome c release was decreased in glucose-free cells, suggesting that either pore formation was inhibited or that cytochrome c was more tightly bound. Glucose-free Z138 cells were also resistant to intrinsic cell death stimuli (ABT-737 and ionising radiation). In summary, in MCL cells, the anti-glycolytic effects of 2DG and glucose restriction produced opposite effects on TRAIL-induced cell death, demonstrating that mitochondrial metabolism directly modulates sensitivity of tumour cells to apoptosis.

Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C.

BACKGROUND AND PURPOSE: Niemann-Pick disease type C (NPC) is a progressive neurovisceral disorder associated with dystonia, ataxia and a characteristic gaze palsy. Neuropathological studies have demonstrated brainstem atrophy associated with neuronal inclusions and loss, and neurofibrillary tangles, although it is not known whether this pathology can be detected in vivo or how these changes relate to illness variables, particularly ocular-motor changes. Our aim was to utilize a method for brainstem atrophy, validated in progressive supranuclear palsy (PSP), in a group of adult patients with NPC, and explore its relationship to illness variables and ocular-motor functioning. METHODS: We calculated the midbrain and pontine area, and pontine-to-midbrain ratio (PMR) from midsagittal images of 10 adult patients with NPC and 27 age- and gender-matched controls. Measures were correlated with illness variables, and measures of horizontal saccadic functioning. RESULTS: Pontine-to-midbrain ratio was 14% higher in the NPC group, but this difference was not significant. However, PMR showed a significant positive correlation with duration of illness and a measure of illness severity. Furthermore, PMR was significantly negatively correlated with saccadic peak velocity and gain, and self-paced saccadic performance. CONCLUSIONS: Pontine-to-midbrain ratio was increased in adult patients with NPC compared to controls, although not to the same degree as previously described in PSP, which also presents with significant gaze palsy. These changes were driven predominantly by progressive midbrain atrophy. The strong correlation with illness and ocular-motor variables suggests that it may be a useful marker for illness progression in NPC.

The second wave of 2009 pandemic influenza A(H1N1) in New Zealand, January-October 2010.

This paper uses data from multiple surveillance systems to describe the experience in New Zealand with the second complete wave of pandemic influenza A(H1N1)2009 in 2010. Measures such as hospitalisation rates suggest the overall impact of influenza A(H1N1)2009 in 2010 was between half and two thirds that of the first wave in 2009. There was considerable regional and sub-regional variation with a tendency for higher activity in areas that experienced low rates in 2009. Demographic characteristics of the second wave were similar to those in 2009 with highest rates seen in children under the age of five years, and in indigenous Maori and Pacific peoples. Hospital services including intensive care units were not under as much pressure as in 2009. Immunisation appears to have contributed to the reduced impact of the pandemic in 2010, particularly for those aged 60 years and older.

An investigation of the pre-injury risk factors associated with children who experience traumatic brain injury.

BACKGROUND AND OBJECTIVE: Traumatic brain injury (TBI) is a frequently occurring event in childhood that may have significant ongoing effects. Little is known about the child and family characteristics that predispose children to these injuries. A greater understanding of the risk factors associated with childhood TBI may provide an opportunity to prevent their occurrence. METHODS: Information provided by a large birth cohort study (n=1265) was used to determine the child and family risk factors of TBI in children aged 0-15 years (n=187). All information regarding child, family, and injury events were collected prospectively and unrelated to the injury event itself. Child variables included in the analysis were sex and the level of behavioural problems. Parental variables included were family socioeconomic status, mother's age, education level, depressive symptoms, number of adverse life events experienced by the family, and parenting style. RESULTS: The most important risk factors were sex, adverse life events, and parenting style. The results suggest evidence of modest increases in the rate of TBI for those in the highest risk categories (male, >or=4 life events per annum, high maternal punitiveness) compared to the lowest risk categories, with hazard ratios in the region of 1.4-1.6. CONCLUSIONS: Overall characteristics of both the family and child predicted a TBI event. An increased understanding of risks associated with TBI in childhood will provide an avenue to prevent these injuries by targeting at-risk families and aiding the development of appropriate intervention strategies.

Long-term behavioural outcomes of pre-school mild traumatic brain injury.

Abstract Background Mild traumatic brain injury (MTBI) is a leading cause of injury for children during their pre-school years. However, there is little information regarding the long-term outcomes of these injuries. Method We used fully prospective data from an epidemiological study of a birth cohort to examine behavioural effects associated with MTBI during the pre-school years. Cases of confirmed MTBI were divided into two groups, those that had received outpatient medical attention, and those that had been admitted to hospital for a brief period of observation (inpatient cases). The remainder of the cohort served as a reference control group. Results Mother/teacher ratings for behaviours associated with attention deficit/hyperactivity disorder and oppositional defiant/conduct disorder, obtained yearly from age 7 to 13, revealed evidence of deficits after inpatient MTBI (n = 21), relative to more minor outpatient injury MTBI (n = 55) and the reference control group (n = 852). For the inpatient group there was evidence of increasing deficits over years 7-13. Conclusions More severe pre-school MTBI may be associated with persistent negative effects in terms of psychosocial development. The vulnerability of pre-school children to MTBI signals a pressing need to identify high-risk cases that may benefit from monitoring and early intervention.

Cell death pathways--potential therapeutic targets.

Programmed cell death and its morphological manifestation termed apoptosis is a conserved pathway that appears to operate in all multicellular organisms. During embryonic development, cell death is essential for successful organogenesis, and apoptosis also operates in adult organisms to maintain normal cellular homeostasis. The removal of disordered cells by a controlled cellular mechanism is especially critical in long-lived mammals that must integrate multiple physiological as well as pathological death signals. Gain- and loss-of-function models of genes in the core apoptotic pathway suggest that perturbation of cellular homeostasis can be a primary pathogenic event that results in disease. Indeed, there is now compelling evidence that insufficient apoptosis can manifest as cancer or autoimmunity, whereas accelerated cell death is evident in acute and chronic degenerative diseases, further highlighting the fact that deregulation of cell death pathways has major health implications. Not surprisingly, during the past 25 years a huge endeavour aimed at unravelling this fundamental biological process has led to major advances in our understanding of cell death pathways. Therapeutic strategies to manipulate apoptosis have immense potential and this review highlights several potentially viable drug targets for modulating cell death that have been discovered from the elegant work of many scientists in elucidating the protein components and key regulators of apoptosis signalling pathways.

Chronic subdural haematomas are more common on the left than on the right.

Subdural haematomas (SDHs), and in particular chronic subdural haematomas (CSDHs), are commonly encountered in a neurosurgical practice. The aetiology, presentation, management and prognosis of these are well documented but there are few publications that report on their side prevalence (laterality). We report an analysis of all patients (both operated on and conservatively managed) who presented to the Neurosurgical Service at Christchurch Hospital with SDHs between 1 January 1996 and 30 June 2006. A total of 413 patients presented with a total of 450 SDHs, of which 150 (33.3%) were acute, 38 were (8.4%) subacute and 262 (58.2%) were chronic. The patients ranged in age from 3 months to 95 years. The mean (+/-standard deviation, SD) age of patients with acute SDH was 50.9+/-25.8 years, 65.4+/-19.8 years for subacute SDH and 68.9+/-19.7 years for chronic SDH. A total of 275 (67%) patients were male and 138 (33%) female, with the male predominance occurring in all subgroups. The SDHs were distributed unilaterally in the acute and subacute groups; however, CSDHs occurred more frequently on the left side (57.2% compared to 42.7% on the right; p=0.0345). We discuss the likely reasons behind the increased rate of CSDHs diagnoses on the left side.

Prevalence of traumatic brain injury among children, adolescents and young adults: prospective evidence from a birth cohort.

BACKGROUND: Little is known about the incidence and prevalence of traumatic brain injury (TBI), particularly for infants, children and young adults. PRIMARY OBJECTIVE: The purpose of this study was to provide an accurate estimate of the incidence and prevalence of TBIs for individuals between 0-25 years of age. METHOD AND PROCEDURES: A birth cohort of 1265 individuals was used, for which information regarding TBI events, both hospitalized and non-hospitalized, had been recorded. MAIN OUTCOMES AND RESULTS: The average incidence for this age group ranged from 1.10-2.36 per 100 per year, with an overall prevalence of approximately 30%. The most common source of injury was falls for individuals 0-14 years of age and contact sports and motor vehicle accidents for 15-25 year olds. Approximately one third of the individuals who experienced a TBI went on to have one or more additional injuries. CONCLUSIONS: The incidence rates reported here are much higher than those previously found. It is clear that TBIs constitute a major health issue and therefore it is important to have accurate information to enable planning for primary healthcare services and to inform prevention programmes.