Cardiometabolic Risk in First Episode Psychosis Patients.

Previous research in patients with schizophrenia in European and USA population groups has demonstrated a high prevalence of metabolic syndrome and disease progression (~35%-40%) and increased risk for cardiovascular disease and long-term mortality. Limited research has determined the prevalence of existing cardiometabolic risk factors at onset of a first episode psychosis. This cross-sectional study presents a clinical overview of the cardiometabolic risk profile in young people with first episode psychosis in the UK. Forty-six participants (72% male) clinically diagnosed with first episode psychosis (n = 25), schizophrenia (n = 13), bipolar disorder (n = 4), unspecified non-organic psychosis (n = 2) or acute psychotic episode (n = 2) with < 6 months Duration of Untreated Psychosis (DUP; mean 33.4 ± 37.2 days) were assessed for anthropometric, health risk behaviors and clinical measurements including resting heart rate, blood pressure, blood lipids, glycated hemoglobin, and prolactin. Overall, participants (aged 18-37 years) had a high prevalence of cardiometabolic risk factors due to: elevated values for BMI (73%) and abdominal adiposity (50%), blood pressure (47% prehypertensive; 23% hypertensive), resting heart rate (43%); hypercholesterolemia (32%); suboptimal HDL-C levels (36%); and hypertriglyceridemia (40%). Participants also self-reported poor health risk habits including smoking (55%), alcohol use (39%), substance use (18%), poor diet (52%), and sedentary behavior (29%). Young people with psychosis are at increased risk for cardiometabolic disorders due to elevated clinical markers and health risk behaviors. Physical health interventions (including health behavior advice) are needed early in the treatment process to address this increased risk for cardiometabolic disorders in individuals recently diagnosed with psychosis.

Early Intervention in Psychosis: Effectiveness and Implementation of a Combined Exercise and Health Behavior Intervention Within Routine Care.

Aim: Young people with psychosis have higher rates of obesity, premature cardiovascular disease, and death compared to non-psychotic peers in the general population due to changes in metabolic regulation linked to antipsychotic medication and adverse health risk behaviors. The aim of this paper is to outline the development, implementation, and evaluation of a combined 12-week exercise and health behavior intervention delivered as part of an Early Intervention in Psychosis (EIP) routine service, within the UK. Methods: Participants (n = 27) completed a 12-week combined intervention program, engaging in weekly, 90-min sessions comprising a healthy behavior education session (45 min), followed by a facilitated exercise session (45 min). Anthropometric data from participants (n = 26) were collected at baseline, 12 weeks, and 12 months post-intervention. Health behaviors and clinical measurements were assessed at baseline and 12 months. Results: Mean baseline data suggests participants were at an increased health risk on entry to the program, with elevated values in mean body mass index (BMI; 70% overweight/obese), waist circumference, resting heart rate, and triglycerides. Fifty percent reported smoking daily, 64% ate < 5 fruits/vegetables per day, and 52% of participants were prescribed highly obesogenic antipsychotic medications (i.e., Olanzapine). At 12 weeks and 12 months, no changes were observed in mean BMI, waist circumference or any other clinical variable (p > 0.05). At 12 months, participants reported a positive impact on health behaviors including improved diet, increased physical activity levels, and cessation of substance use (n = 2), alcohol use (n = 2), and smoking (n = 4). Focus groups captured participant experiences, engagement with and satisfaction with the program, including challenges/barriers to program adherence. Conclusions: The 12-week exercise and health behaviors program supported participants to attenuate their physical health risk which was sustained at 12-month follow-up. Self-reported positive health behavior changes are likely to have contributed to the prevention of excessive weight gain in this high-risk period. The evaluation was designed to have validity for a "real world EIP setting" and reflect the complexity of delivery to this participant group. Evaluation findings influenced subsequent commissioning of the physical health intervention as an ongoing element of routine EIP care within the participant site.

Evoked and Ongoing Pain-Like Behaviours in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient-reported pain symptoms, aiding translation of new treatments to the clinic.

Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons.

Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to the development and maintenance of paclitaxel-induced pain.

Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy.

Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and antioxidant enzyme activity in sensory neurons following paclitaxel has been undertaken. As expected, repeated low doses of systemic paclitaxel in rats induced long-lasting pain behaviour with a delayed onset, akin to the clinical scenario. To elucidate the role of ROSinthe development and maintenance ofpaclitaxel-inducedpainful neuropathy, we have assessed ROS and antioxidant enzyme activity levels in the nociceptive system in vivo at three key behavioural time-points; prior to pain onset (day 7), peak pain severity and pain resolution. In isolated dorsal root ganglia (DRG) neurons, ROS levels were unchanged following paclitaxel-exposure in vitro or in vivo. ROS levels were further assessed in DRG and spinal cord in vivo following intrathecal MitoTracker®RedCM-H2XRos administration in paclitaxel-/vehicle-treated rats. ROS levels were increased at day 7, specifically in non-peptidergic DRG neurons. In the spinal cord, neuronally-derived ROS was increased at day 7, yet ROS levels in microglia and astrocytes were unaltered. In DRG, CuZnSOD and glutathione peroxidase (GPx) activity were increased at day 7 and peak pain time-points, respectively. In peripheral sensory nerves, CuZnSOD activity was increased at day 7, and at peak pain, MnSOD, CuZnSOD and GPx activity were increased. Catalase activity was unaltered in DRG and saphenous nerves. These data suggest that neuronally-derived mitochondrial ROS, accompanied with an inadequate endogenous antioxidant enzyme response, are contributory factors in paclitaxel-induced painful neuropathy.

Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome.

Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome. Methods Islets were isolated from C57Bl/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57Bl/6 mice. In one experimental series mice were also administered imatinib after islet transplantation. Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets. Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome.

Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.

UNLABELLED: Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. PERSPECTIVE: This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain.

The influence of rowing-related postures upon respiratory muscle pressure and flow generating capacity.

During the rowing stroke, the respiratory muscles are responsible for postural control, trunk stabilisation, generation/transmission of propulsive forces and ventilation (Bierstacker et al. in Int J Sports Med 7:73-79, 1986; Mahler et al. in Med Sci Sports Exerc 23:186-193, 1991). The challenge of these potentially competing requirements is exacerbated in certain parts of the rowing stroke due to flexed (stroke 'catch') and extended postures (stroke 'finish'). The purpose of this study was to assess the influence of the postural role of the trunk muscles upon pressure and flow generating capacity, by measuring maximal respiratory pressures, flows, and volumes in various seated postures relevant to rowing. Eleven male and five female participants took part in the study. Participants performed two separate testing sessions using two different testing protocols. Participants performed either maximal inspiratory or expiratory mouth pressure manoeuvres (Protocol 1), or maximal flow volume loops (MFVLs) (Protocol 2), whilst maintaining a variety of specified supported or unsupported static rowing-related postures. Starting lung volume was controlled by initiating the test breath in the upright position. Respiratory mouth pressures tended to be lower with recumbency, with a significant decrease in P (Emax) in unsupported recumbent postures (3-9 % compared to upright seated; P = 0.036). There was a significant decrease in function during dynamic manoeuvres, including PIF (5-9 %), FVC (4-7 %) and FEV(1) (4-6 %), in unsupported recumbent postures (p < 0.0125; Bonferroni corrected). Thus, respiratory pressure and flow generating capacity tended to decrease with recumbency; since lung volumes were standardised, this may have been, at least in part, influenced by the postural co-contraction of the trunk muscles.

Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy.

Paclitaxel (Taxol®) is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS), the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN) and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13) completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg) systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals alone.

Acute cardiorespiratory responses to inspiratory pressure threshold loading.

PURPOSE: We tested the acute responses to differing pressure threshold inspiratory loading intensities in well-trained rowers. The purpose of this study was to evaluate 1) how the magnitude of inspiratory pressure threshold loading influences repetition maximum (RM), tidal volume (VT), and external work undertaken by the inspiratory muscle; and 2) whether the inspiratory muscle metaboreflex is activated during acute inspiratory pressure threshold loading. METHODS: Eight males participated in seven trials. Baseline measurements of maximal inspiratory pressure (PImax), resting tidal volume (VT), and forced vital capacity (FVC) were made. During the remaining sessions, participants undertook a series of resistive inspiratory breathing tasks at loads corresponding to 50%, 60%, 70%, 80%, and 90% of PImax using a pressure threshold inspiratory muscle trainer. The number of repetitions completed at each load, VT, heart rate (fc), and measures of arterial blood pressure was assessed continuously during each trial. RESULTS: A standardized cutoff of 10% FVC was used to define the RM, which decreased as loading intensity increased (P < 0.05). This response was nonlinear, with an abrupt decrease in RM occurring at loads > or =70% of PImax. The most commonly used inspiratory muscle training regimen of 30RM corresponded to 62.5% +/- 4.6% of PImax and also resulted in the highest external work output. Tidal volume (VT) decreased significantly over time at 60%, 70%, and 80% of PImax (P < 0.05), as did the amount of external work completed (P<0.05). CONCLUSIONS: Although all loads elicited a sustained increase in fc, only the 60% load elicited a sustained rise in mean arterial blood pressure (P = 0.016), diastolic blood pressure (P = 0.015), and systolic blood pressure (P = 0.002), providing evidence for a metaboreflex response at this load.

The influence of inspiratory and expiratory muscle training upon rowing performance.

We investigated the effect of 4 week of inspiratory (IMT) or expiratory muscle training (EMT), as well as the effect of a subsequent 6 week period of combined IMT/EMT on rowing performance in club-level oarsmen. Seventeen male rowers were allocated to either an IMT (n = 10) or EMT (n = 7) group. The groups underwent a 4 week IMT or EMT program; after interim testing, both groups subsequently performed a 6 week program of combined IMT/EMT. Exercise performance and physiological responses to exercise were measured at 4 and 10 week during an incremental rowing ergometer 'step-test' and a 6 min all-out (6MAO) effort. Pressure threshold respiratory muscle training was undertaken at the 30 repetition maximum load (approximately 50% of the peak inspiratory and expiratory mouth pressure, P (Imax) or P (Emax), respectively). P (Imax) increased during the IMT phase of the training in the IMT group (26%, P < 0.001) and was accompanied by an improvement in mean power during the 6MAO (2.7%, P = 0.015). Despite an increase in P (Emax) by the end of the intervention (31%, P = 0.03), the EMT group showed no significant changes in any performance parameters during either the 'step-test' or 6MAO. There were no significant changes in breathing pattern or the metabolic response to the 6MAO test in either group, but the IMT group showed a small decrease in HR (2-5%, P = 0.001). We conclude that there were no significant additional changes following combined IMT/EMT. IMT improved rowing performance, but EMT and subsequent combined IMT/EMT did not.