Genetic and Environmental Contributions to Subcortical Gray Matter Microstructure and Volume in the Developing Brain.

Using baseline (ages 9-10) and two-year follow-up (ages 11-12) data from monozygotic and dizygotic twins enrolled in the longitudinal Adolescent Brain Cognitive DevelopmentSM Study, we investigated the genetic and environmental contributions to microstructure and volume of nine subcortical gray matter regions. Microstructure was assessed using diffusion MRI data analyzed using restriction spectrum imaging (RSI) and diffusion tensor imaging (DTI) models. The highest heritability estimates (estimate [95% confidence interval]) for microstructure were found using the RSI model in the pallidum (baseline: 0.859 [0.818, 0.889], follow-up: 0.835 [0.787, 0.871]), putamen (baseline: 0.859 [0.819, 0.889], follow-up: 0.874 [0.838, 0.902]), and thalamus (baseline: 0.855 [0.814, 0.887], follow-up: 0.819 [0.769, 0.857]). For volumes the corresponding regions were the caudate (baseline: 0.831 [0.688, 0.992], follow-up: 0.848 [0.701, 1.011]) and putamen (baseline: 0.906 [0.875, 0.914], follow-up: 0.906 [0.885, 0.923]). The subcortical regions displayed high genetic stability (rA = 0.743-1.000) across time and exhibited unique environmental correlations (rE = 0.194-0.610). Individual differences in both gray matter microstructure and volumes can be largely explained by additive genetic effects in this sample.

Psychedelics: Alternative and Potential Therapeutic Options for Treating Mood and Anxiety Disorders.

The word "psychedelic" (psyche (i.e., the mind or soul) and delos (i.e., to show)) has Greek origin and was first coined by psychiatrist Humphry Osmond in 1956, who had been conducting research on lysergic acid diethylamide (LSD) at the time. Psychedelic drugs such as N,N-DMT/DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), LSD (lysergic acid diethylamide), MDMA (3,4-methylenedioxymethamphetamine) and psilocybin have had significant value as an entheogen in spiritual, religious (shamanic) and sociocultural rituals in Central and South American cultures for thousands of years. In the 1960s, the globalization of these drugs and their subsequent spread outside of their indigenous, old-world cultures, led to the subsequent implementation of strict drug control laws in many Western countries. Even today, psychedelics are still classified as Schedule I drugs, resulting in a still lingering negative stigmatization/perception, vilification, and ultimate criminalization of psychedelics. This controversy still lingers and still limits scientific research and full medical acceptance. For many years up until recently, the spiritual, religious and medicinal value of these drugs could not be explored in a scientific context. More recently, a second wave of psychedelic research is now focusing on psychedelics as neuropharmaceuticals to treat alcohol and tobacco addiction, general mood and anxiety disorders and cancer-related depression. There is now a vast array of promising evidence-based data to confirm the years of anecdotal evidence of the medicinal values of psychedelics. Natural therapeutic alternatives such as psychedelic drugs may provide a safe and efficacious alternate to conventional drugs used to treat mood and anxiety disorders. In a Western context in particular, psychedelic drugs as therapeutic agents for mood and anxiety disorders are becoming increasingly of interest amidst increasing rates of such disorders globally, changing social constructions, the implementation of government regulations and increasing investment opportunities, that ultimately allow for the scientific study to generate evidenced-based data. Alternative psychotherapeutic interventions are gaining interest also, because of their low physiological toxicity, relatively low abuse potential, safe psychological effects, and no associated persisting adverse physiological or psychological effects during and after use. On the other hand, conventional psychotic drugs and anti-depressants are becoming less favorable because of their adverse side effects. Psychedelic neuropharmaceutical interventions may with medical oversight be the solution to conventional psychiatric disorders such as depression and anxiety, and an alternative to conventional psychiatric treatment options. This paper will review the therapeutic potential of psychedelic drugs as alternative therapeutic options for mood and anxiety disorders in a controlled, clinical setting, where the chances of adverse psychological episodes occurring are mitigated.

Ice Ingestion Maintains Cognitive Performance during a Repeated Sprint Performance in The Heat.

This study investigated the effects of precooling via crushed ice ingestion on cognitive performance during repeated-sprint cycling in the heat. Nine males, non-heat acclimatised to heat (mean age: 28.2 ± 2.7 y; height: 175.7 ± 9.7 cm; body-mass: 76.9 ± 10.6 kg) completed a 30 min bout of repeated-sprint (36 × 4 s sprints, interspersed with 56 s rest-breaks) on a cycle ergometer in a climate chamber (35°C, 70% relative humidity). Crushed ice ingestion (7g·kg-1, -0.4°C, ICE) or no cooling (CON) interventions were completed at rest, in the climate chamber, 30 min prior to exercise. Working memory was assessed via the serial seven test (S7) and the automated operation span task (OSPAN) at various time points before, during, and post-exercise. Core body temperature (Tc), forehead temperature (Th), and thermal sensation (TS) were assessed throughout the protocol. Working memory significantly declined during exercise in CON as measured by S7 (p = 0.01) and OSPAN (p = 0.03); however, it was preserved in ICE with no change at the end of exercise in either S7 or OSPAN scores compared to baseline (p = 0.50, p = 0.09, respectively). Following precooling, Th (-0.59°C, p < 0.001) and Tc (-0.67°C, p = 0.005) were significantly decreased in ICE compared to CON. At the end of the exercise, ICE significantly reduced Tc compared to CON (p = 0.03), but no significant differences were recorded for Th. Further, TS was lower following precooling in ICE (p = 0.008) but not during exercise. In conclusion, ice ingestion significantly reduced Th and Tc and facilitated maintenance of cognitive performance during repeated-sprint exercise in the heat, which may lead to better decision making.

A Combination of Ice Ingestion and Head Cooling Enhances Cognitive Performance during Endurance Exercise in the Heat.

This study assessed the effectiveness of head cooling during exercise in the heat on cognitive performance, either alone or with ice ingestion. Ten healthy males, non-acclimatized to heat, ran (70% V̇O2peak) for 2×30 min in heat (35 ± 0.9°C, 68.2 ± 6.9% RH). Participants completed 3 trials: 10 min of head cooling during exercise (HC); precooling with crushed ice (7gikg-1) and head cooling during exercise (MIX); or no-cooling/control (CON). Working memory was assessed using the automated operation span task (OSPAN) and serial seven test (S7). Following MIX, S7 scores were improved compared to CON (12 ± 9.5, p = 0.004, d = 1.42, 0.34-2.28) and HC (4 ± 5.5, p = 0.048, d = 0.45, -0.47 to 1.3) during exercise. Moderate to large effect sizes were recorded for S7 and OSPAN following MIX and HC compared to CON, suggesting a tendency for improved cognitive performance during exercise in heat. Following precooling (MIX), core body temperature (Tc) and forehead temperature (Th) were lower compared to baseline (-0.75 ± 0.37°C, p < 0.001; -0.31 ± 0.29°C, p = 0.008, respectively) but not in HC or CON (p > 0.05). Thermal sensation (TS) was lower in MIX and HC compared to CON during exercise (p < 0.05). The reduction in Tc, Th and TS with MIX may have attenuated the effect of heat and subsequently improved working memory during exercise in heat.

The Therapeutic Potential of Psilocybin.

The psychedelic effects of some plants and fungi have been known and deliberately exploited by humans for thousands of years. Fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. The mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. Psychedelic use was largely associated with the "hippie" counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. As a result, in 1970, the U.S. government rescheduled psychedelics as Schedule 1 drugs, ultimately ending scientific research on psychedelics. This prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. A 2004 pilot study from the University of California, Los Angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. Since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. This review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. This is not a systematic review.

Head Cooling Prior to Exercise in the Heat Does Not Improve Cognitive Performance.

This study investigated the effectiveness of head cooling on cognitive performance after 30 min and 60 min of running in the heat. Ten moderately-trained, non-heat-acclimated, male endurance athletes (mean age: 22 ± 6.6 y; height: 1.78 ± 0.10 m; body-mass: 75.7 ± 15.6 kg; VO2peak: 51.6 ± 4.31 mL-1>kg-1>min) volunteered for this study. Participants performed two experimental trials: head cooling versus no-cooling (within-subjects factor with trial order randomized). For each trial, participants wore a head-cooling cap for 15 min with the cap either cooled to 0°C (HC) or not cooled (22°C; CON). Participants then completed 2 × 30 min running efforts on a treadmill at 70% VO2peak in hot conditions (35°C, 70% relative humidity), with a 10 min rest between efforts. Working memory was assessed using an operation span (OSPAN) task immediately prior to the 15 min cooling/no-cooling period (22°C, 35% RH) and again after 30 min and 60 min of running in the heat. Numerous physiological variables, including gastrointestinal core temperature (Tc) were assessed over the protocol. Scores for OSPAN were similar between trials, with no interaction effect or main effects for time and trial found (p = 0.58, p = 0.67, p = 0.54, respectively). Forehead temperature following precooling was lower in HC (32.4 ± 1.6°C) compared with CON (34.5 ± 1.1°C) (p = 0.01), however, no differences were seen in Tc, skin temperature, heart rate and ratings of perceived exertion between HC and CON trials at any time point assessed (p > 0.05). In conclusion, despite HC reducing forehead temperature prior to exercise, it did not significantly improve cognitive performance during (half-time break) or after subsequent exercise in hot environmental conditions, compared to a no cooling control.

Tracking adiponectin biodistribution via fluorescence molecular tomography indicates increased vascular permeability after streptozotocin-induced diabetes.

Adiponectin, a highly abundant polypeptide hormone in plasma, plays an important role in the regulation of energy metabolism in a wide variety of tissues, as well as providing important beneficial effects in diabetes, inflammation, and cardiovascular disease. To act on target tissues, adiponectin must move from the circulation to the interstitial space, suggesting that vascular permeability plays an important role in regulating adiponectin action. To test this hypothesis, fluorescently labeled adiponectin was used to monitor its biodistribution in mice with streptozotocin-induced diabetes (STZD). Adiponectin was, indeed, found to have increased sequestration in the highly fenestrated liver and other tissues within 90 min in STZD mice. In addition, increased myocardial adiponectin was detected and confirmed using computed tomography (CT) coregistration. This provided support of adiponectin delivery to affected cardiac tissue as a cardioprotective mechanism. Higher adiponectin content in the STZD heart tissues was further examined by ex vivo fluorescence molecular tomography (FMT) imaging, immunohistochemistry, and Western blot analysis. In vitro mechanistic studies using an endothelial monolayer on inserts and three-dimensional microvascular networks on microfluidic chips further confirmed that adiponectin flux was increased by high glucose. However, in the in vitro model and mouse heart tissue, high glucose levels did not change adiponectin receptor levels. An examination of the tight junction (TJ) complex revealed a decrease in the TJ protein claudin (CLDN)-7 in high glucose-treated endothelial cells, and the functional significance of this change was underscored by increased endothelium permeability upon siRNA-mediated knockdown of CLDN-7. Our data support the idea that glucose-induced effects on permeability of the vascular endothelium contribute to the actions of adiponectin by regulating its transendothelial movement from blood to the interstitial space. These observations are physiologically significant and critical when considering ways to harness the therapeutic potential of adiponectin for diabetes.

Sex-specific patterns of reproductive senescence in a long-lived reintroduced raptor.

For many species, there is evidence that breeding performance changes as an individual ages. In iteroparous species, breeding performance often increases through early life and is expected to level out or even decline (senesce) later in life. An individual's sex and conditions experienced in early life may also affect breeding performance and how this changes with age. Long-term monitoring of individuals from reintroduced populations can provide unique opportunities to explore age-related trends in breeding performance that might otherwise be logistically challenging. We used a unique dataset from a reintroduced population of white-tailed eagles Haliaeetus albicilla in Scotland, which has been intensively monitored since their initial reintroduction in 1975, to study age- and sex-specific trends in two measures of breeding performance. This monitoring provided data on the breeding performance of known individuals ranging in age from 3 to 26 years. We also explored changes in breeding performance in relation to early life experience (i.e., whether they were released or fledged in the wild). Breeding performance increased with age in early life in a similar manner for both sexes. We found stronger evidence for senescence in breeding performance in males than females. However, late-life female breeding success was associated with early life experience, while male senescent trends were not apparently impacted by conditions experienced during early life. Sexual differences in senescence mean that older males are less likely to breed successfully compared to older females, and this may influence females' mate changes later in life. This difference may suggest a linked sexual difference in survival rates or the possibility of proactive partner change by females in later life in this typically monogamous biparental species.

Crushed Ice Ingestion Does Not Improve Female Cycling Time Trial Performance in the Heat.

This study examined the effects of precooling via ice ingestion on female cycling performance in hot, humid conditions. Ten female endurance athletes, mean age (28 ± 6 y), height (167.6 ± 6.5 cm) and body-mass (68.0 ± 11.5 kg) participated in the study. Participants completed an 800 kJ cycle time-trial in hot, humid conditions (34.9 ± 0.3 °C, 49.8 ± 3.5% RH). This was preceded by the consumption of 7 g∙kg-1 of crushed ice (ICE) or water (CON). There was no difference in performance time (CON 3851 ± 449 s; ICE 3767 ± 465 s), oxygen consumption (CON 41.6 ± 7.0 ml∙kg∙min-1; ICE 42.4 ± 6.0 ml∙kg∙min-1) or respiratory exchange ratio (CON 0.88 ± 0.05; ICE 0.90 ± 0.06) between conditions (p > .05, d < 0.5). Core and skin temperature following the precooling period were lower in ICE (Tc 36.4 ± 0.4 °C; Tsk 31.6 ± 1.2 °C) compared with CON (Tc 37.1 ± 0.4 °C; Tsk 32.4 ± 0.7 °C) and remained lower until the 100 kJ mark of the cycle time-trial (p < .05, d > 1.0). Sweat onset occurred earlier in CON (228 ± 113 s) compared with ICE (411 ± 156 s) (p < .05, d = 1.63). Mean thermal sensation (CON 1.8 ± 2.0; ICE 1.2 ± 2.5, p < .05, d = 2.51), perceived exertion (CON 15.3 ± 2.9; ICE 14.9 ± 3.0, p < .05, d = 0.38) and perceived thirst (CON 5.6 ± 2.2; ICE 4.6 ± 2.4, p < .05, d = 0.98) were lower in ICE compared with CON. Crushed ice ingestion did not improve cycling performance in females, although perceptual responses were reduced.

Delivering epilepsy care in low-resource settings: the role of technology.

INTRODUCTION: The implementation of technology in the field of epileptology has traditionally focused on its use for diagnosis and treatment and has, unsurprisingly, been capital-intensive, making it therefore mainly implementable in advanced high-income countries. Because of technological innovations over the past 20 years there has been almost a paradigm shift, particularly in access to and the potential for implementing relevant technology in lesser developed environments. Nearly 80% of people living with epilepsy live in low and middle-income countries. AREAS COVERED: The challenge and the purpose of this paper is to discuss how technology can be implemented into lesser-resourced contexts not only cost-effectively but in a cost-saving way while also building capacity and thus sustainability. EXPERT OPINION: The rate of technological advancement presents the risk of progressive widening of the technology and care gaps between advanced and lesser developed regions. Implementing technology is both about finding relevant appropriate technologies for the individual contexts of a diverse range of countries but also about repurposing low-tech technologies for application in epilepsy care in these areas. Finally exciting advances such as autonomous driving, digital twinning and robotic surgery will likely transform epilepsy care in several lower-resourced settings in the next 5-10 years.

Sickle Cell Disease and Pain: Is it all Vaso-occlusive Crises?

OBJECTIVES: Acute pain is the main complication of sickle cell disease. Chronic pain (CP) and neuropathic pain (NP) may also be experienced, but have not been formally described in Jamaican patients. A cross-sectional study was conducted to determine their prevalence and characteristics, and to determine the common pain locations and modalities of management. MATERIALS AND METHODS: All well individuals with sickle cell disease patients 14 years and older, not pregnant and without a history of clinical stroke were consecutively recruited. Anthropometric measurements, hematology studies, an analgesia checklist, and the Adult Sickle Cell Quality of Life Measurement Information System questionnaire were completed. The painDETECT questionnaire was completed to describe NP and pain patterns-from which CP was defined. RESULTS: There were 257 patients in total, with 55.6% being females; the mean age of the patients was 31.7±12 years, and 75% had the SS genotype. Almost all patients (92.6%) had had an acute pain crisis in their lifetime and 72.4% in the last year. The mean severity at last attack was 6.8±3.1 on a scale of 0 to 10. The prevalences of CP and NP were 21.5% and 17.9%, respectively. Female sex, the presence of current leg ulcers, and the use of a strong opioid in the last 4 weeks produced higher odds of NP, whereas older age, milder genotypes, and daily analgesic use had the highest odds of CP. Opioids were used by 40.1% of the patients in the previous 4 weeks, whereas nonpharmacological treatments such as physiotherapy was less used, but reported to be very effective. DISCUSSION: CP and NP should be assessed during routine care of sickle cell pain so that targeted therapies can be applied.

Health-related quality of life and neuropathic pain in sickle cell disease in Jamaica.

BACKGROUND: Health related quality of Life (HRQOL) is an important consideration when managing chronic diseases, like sickle cell disease (SCD). Assessment of neuropathic pain (NP) and its association with HRQOL in SCD are rarely reported. OBJECTIVES: To examine the prevalence of NP and its association with HRQOL in adult Jamaicans with SCD. METHODS: Adult SCD patients were recruited consecutively and data were collected on socio-demographics, NP using Douleur Neuropathique 4 (DN4), and HRQOL using the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me). Means, medians, t-tests, ANOVA tests, Wilcoxon Rank-sum tests, Kruskal-Wallis tests, Pearson's correlation and multivariate linear regression analyses were performed using STATA 14.2. RESULTS: There were 236 respondents, with 56.8% female, mean age 33.2 years (SD: 11.6; range: 18-67 years), and 75% had homozygous SS genotype. NP was likely present in 26.7% of the population. The standardized ASCQ-Me (mean ± SD; ordered from lowest to best HRQOL domain scores) were: emotional impact 53.3 ± 10.1; sleep impact 56.1 ± 9.7; social function 57.7 ± 10.6; pain impact 58.6 ± 7.8; and stiffness impact 61.0 ± 7.3. On multivariate analyses, NP significantly reduced emotional and social functioning and worsened sleep and stiffness. Higher acute pain scores significantly worsened all HRQOL domains, while higher disease severity worsened all except stiffness. Obesity was associated with worse sleep and greater stiffness. Females with leg ulcers reported lower social functioning and unemployed females had greater pain impact. CONCLUSIONS: NP is increasingly prevalent in SCD and worsens HRQOL. Gender specific studies are needed to understand the significantly poorer HRQOL in women.

Increasing Resident Physician Well-Being through a Motivational Fitness Curriculum: A Pilot Study.

INTRODUCTION: Healthcare professionals who participate in regular exercise better manage job related stressors, utilize fewer sick days, and discuss fitness with patients at increased rates. Although resident physicians are aware of the health benefits of exercise their rates of exercise are much lower than among medical trainees and practicing physicians. Resident physicians have reported lack of time for traditional structured workouts as one of the greatest barriers to fitness. This study sought to increase resident physician well-being by providing brief workouts through a motivational fitness curriculum. METHODS: This pilot study utilized a nonexperimental design; a pre-/post-intervention consisted of a 10-month motivational fitness curriculum. Thirteen family medicine residents at a training program in the midwestern United States participated in this study. The Depression Anxiety Stress Scale-21 (DASS-21) and the Abbreviated Maslach Burnout Inventory (MBI-9) were used to measure the participants' well-being, pre- and post-curriculum. Standard descriptive statistics and paired samples t-test were used to analyze the data. RESULTS: Twenty-eight percent (13/36) of eligible first-year and second-year family medicine resident physicians participated in the study. On the DASS-21, study participants displayed an improvement in depression, anxiety, and stress scores post-curriculum. On the MBI-9, the participants reported decreased score in emotional exhaustion, but there were no changes in depersonalization and personal accomplishment scores over time. CONCLUSION: A motivational fitness curriculum may be a convenient way to support well-being among resident physicians. These findings were salient, as graduate medical education programs can implement similar initiatives to support resident physicians' psychological and physical well-being.

Intermolecular interactions and morphology of aqueous polymer/surfactant mixtures containing cationic chitosan and nonionic sorbitan esters.

In this study, the impact of surfactant molecular composition (saturated sorbitan monolaurate or unsaturated sorbitan monooleate) on polymer/surfactant assemblies was examined. Specifically, the associations between the cationic chitosan and the uncharged surfactants were monitored by surface tension, turbidity, and conductivity measurements. Bright field, confocal laser scanning, and transmission electron microscopy revealed that nanometer-sized chitosan/surfactant aggregates comprised of a chitosan-rich shell and a chitosan-poor core agglomerate at high surfactant concentrations to yield micrometer-scaled supramolecular structures with highly ordered internal structure. The size and architecture of these chitosan/surfactant assemblies were dependent on the structure and concentration of the surfactant employed. The association mechanism among chitosan, surfactant, and the chitosan/surfactant aggregates was discussed in terms of the semirigid polyelectrolyte character of chitosan and the hydrophobic character of sorbitan esters. This study provides important insight into the structural and physical parameters of surfactant that govern the formation of multicompartment polymer/surfactant assemblies.

Drug release mechanism of paclitaxel from a chitosan-lipid implant system: effect of swelling, degradation and morphology.

Localized and sustained delivery of anti-cancer agents to the tumor site has great potential for the treatment of solid tumors. A chitosan-egg phosphatidylcholine (chitosan-ePC) implant system containing PLA-b-PEG/PLA nanoparticles has been developed for the delivery of paclitaxel to treat ovarian cancer. Production of volumes of ascites fluid in the peritoneal cavity is a physical manifestation of ovarian cancer. In vitro release studies of paclitaxel from the implant were conducted in various fluids including human ascites fluid. A strong correlation (r2=0.977) was found between the release of paclitaxel in ascites fluid and PBS containing lysozyme (pH 7.4) at 37 degrees C. The drug release mechanism for this system was proposed based on swelling, degradation and morphology data. In addition, in vitro release of paclitaxel was found to be a good indicator of the in vivo release profile (correlation between release rates: r2=0.965). Release of paclitaxel was found to be sustained over a four-week period following implantation of the chitosan-ePC system into the peritoneal cavity of healthy Balb/C mice. Also, the concentrations of paclitaxel in both plasma and tissues (e.g. liver, kidney and small intestine) were found to be relatively constant.

Influence of molecular organization and interactions on drug release for an injectable polymer-lipid blend.

An injectable blend composed of a water soluble chitosan (WSC) derivative, egg phosphatidylcholine (ePC), and fatty acid chlorides (FACl) was explored for localized delivery of anticancer agents. The composition-property relationships of the injectable WSC-FACl-ePC blend were determined by investigating the physico-chemical and performance properties of the blend as a function of the ratio of the components, as well as the acyl chain length of the FACl (C10-C16) employed. Thermal and rheological measurements revealed that the melting transitions and viscosities of the blends increased as a function of FACl acyl chain length. FTIR analysis demonstrated that the stability of the blends was attributed to the specific interactions among the molecules. In addition, confocal laser scanning microscopy revealed that the incorporation of C10-C16 FACl altered the molecular organization of ePC and WSC within the blends, which resulted in distinct physico-chemical properties. Specifically, the formation of micro-domains within the blends increased the stability, as well as delayed the release of paclitaxel from the formulation under physiologically relevant conditions. Overall, the interactions identified among the components, and the relationships established between the composition and properties of the blend can be used as a tool to develop advanced injectable drug delivery systems for pharmaceutical applications.

Novel biocompatible intraperitoneal drug delivery system increases tolerability and therapeutic efficacy of paclitaxel in a human ovarian cancer xenograft model.

PURPOSE: We compared the safety, toxicity, biocompatibility and anti-tumour efficacy of a novel chitosan-egg phosphatidylcholine (ePC) implantable drug delivery system that provides controlled and sustained release of paclitaxel (PTX(ePC)) versus commercial paclitaxel formulated in Cremophor EL (PTX(CrEL)). METHODS: Toxicity studies were conducted in healthy CD-1 female mice, whereas efficacy studies were performed in the SKOV-3 xenograft model of ovarian cancer. Treatments consisted of intraperitoneal (IP) implantation of drug-free or PTX(ePC) formulations, IP bolus PTX(CrEL), or Cremophor EL (CrEL) vehicle. Toxicity was assessed as number of deaths, weight loss, serum hepatic enzyme levels and histopathological changes. RESULTS: Mice implanted with drug-free or PTX(ePC) formulations did not exhibit observable toxicities, local inflammation or fibrous encapsulation of the implant. In contrast, mice receiving PTX(CrEL) or CrEL encountered significant toxicity, lethality, abnormal peritoneal organ morphology and hepatic inflammation. The maximum tolerable dose (MTD) of PTX(CrEL) was 20 mg/kg/week, whereas PTX doses of up to 280 mg/kg/week were well tolerated when administered as PTX(ePC). Enhanced anti-tumour efficacy was achieved with PTX(ePC) in contrast to PTX(CrEL) with the same total dose of 60 mg/kg PTX. CONCLUSIONS: The novel PTX(ePC) formulation is a safer and better tolerated method for PTX administration, with significant increase in MTD and enhanced anti-tumour efficacy, suggesting improved therapeutic index with possible clinical implications in the treatment of ovarian tumours.

The effect of ice ingestion on female athletes performing intermittent exercise in hot conditions.

Studies have reported the benefits of pre-cooling prior to exercise in the heat for male athletes, but at this time no research has investigated female athletes. The aim of the following study was to test the effects of pre-cooling on female repeat sprint performance in hot, humid conditions; namely is ice ingestion effective in reducing core temperature (Tc) and does this reduced Tc lead to improved repeat sprint performance in female athletes? Nine female team sport athletes with mean age (21.0 ± 1.2 y), height (169.8 ± 4.1 cm) and body mass (62.3 ± 5.0 kg) participated in this study. Participants completed 72 min of an intermittent sprint protocol (ISP) consisting of 2 × 36 min halves in hot, humid conditions (33.1 ± 0.1 °C, 60.3 ± 1.5% RH) on a cycle ergometer. This was preceded by 30 min of either ice ingestion (ICE) or water consumption (CON) in a randomised order. At the end of the pre-cooling period, Tc significantly decreased following ICE (-0.7 ± 0.3 °C) compared to CON (-0.1 ± 0.2 °C; p = 0.001). Tc also remained lower in ICE compared to CON during the ISP (p = 0.001). Ratings of perceived thermal sensation were lower in ICE compared to CON (p = 0.032) at the beginning (p = 0.022) and mid-point (p = 0.035) of the second half. No differences in work, mean power, peak power, rating of perceived exertion, heart rate or sweat loss between conditions were recorded (p > 0.05). Ice ingestion significantly reduced female Tc prior to intermittent exercise in the heat and reduced thermal sensation; however, this did not coincide with improved performance.

Thermosensitive depot-forming injectable phosphatidylcholine blends tailored for localized drug delivery.

A thermosensitive depot-forming system was developed for sustained and localized delivery of the anticancer drug, paclitaxel. The formulation is injectable as a melt slightly above the body temperature and forms a solid depot upon cooling to 37°C. The thermosensitive system was prepared by blending various combinations of phosphatidylcholines at specific weight ratios solubilized in laurinaldehyde. Of the blends investigated, distearoyl-phosphatidylcholine (DSPC) and egg-phosphatidylcholine (ePC) were found to be most miscible. A liquid-to-gel phase transition temperature (TC ) of 39°C was observed for the 70:30 (w/w) DSPC-ePC blend and a TC of 38.4°C with the addition of paclitaxel. Blends containing higher concentrations of ePC had a greater degree of swelling and weight loss. Furthermore, microscopy revealed an increase in porosity and erosion as the amount of ePC was increased in blends incubated in biologically relevant media. DSPC-ePC blends provided sustained release of paclitaxel over a 30-day period and the rate of drug release increased as the amount of ePC increased. Overall, the relationships established between the composition and properties of the blend may be employed to tailor the thermosensitive injectable formulation for localized chemotherapy of solid tumors.