Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma.

BACKGROUND: Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV). METHODS: Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment. RESULTS: The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed. CONCLUSIONS: Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

Relationships between psychosocial outcomes in adolescents who are obese and their parents during a multi-disciplinary family-based healthy lifestyle intervention: One-year follow-up of a waitlist controlled trial (Curtin University's Activity, Food and Attitudes Program).

BACKGROUND: Limited studies have investigated relationships in psychosocial outcomes between adolescents who are obese and their parents and how psychosocial outcomes change during participation in a physical activity and healthy eating intervention. This study examined both adolescent and parent psychosocial outcomes while participating in a one - year multi-disciplinary family-based intervention: Curtin University's Activity, Food, and Attitudes Program (CAFAP). METHODS: Following a waitlist control period, the intervention was delivered to adolescent (n = 56, ages 11-16) and parent participants over 8 weeks, with one-year maintenance follow-up. Adolescent depression and quality of life, family functioning, and parent depression, anxiety, and stress were assessed at six time points: baseline and prior to intervention (e.g., waitlist control period), immediately following intervention, and at 3, 6, and 12 months post-intervention. Relationships between adolescent and parent psychosocial outcomes were assessed using Spearman correlations and changes in both adolescent and parent outcomes were assessed using linear mixed models. Changes in adolescent psychosocial outcomes were compared to changes in behavioural (physical activity and healthy eating) and physical (weight) outcomes using independent samples t-tests. RESULTS: The majority of psychosocial outcomes were significantly correlated between adolescents and parents across the one-year follow-up. Adolescent depression, psychosocial and physical quality of life outcomes significantly improved before or following intervention and were maintained at 6-months or one-year follow-up. Parent symptoms of depression, anxiety, and stress were reduced during waitlist and primarily remained improved. Changes in adolescent psychosocial outcomes were shown to be partially associated with behavioural changes and independent of physical changes. CONCLUSIONS: Adolescents in CAFAP improved psychosocial and physical quality of life and reversed the typical trajectory of depressive symptoms in adolescents who are obese during a one-year maintenance period. CAFAP was also effective at maintaining reductions in parent symptoms of depression, anxiety, and stress demonstrated during the waitlist period. TRIAL REGISTRATION: The trial was registered with the Australian and New Zealand Clinical Trials Registry (No. 12611001187932 ).

Rationale, design and methods for a staggered-entry, waitlist controlled clinical trial of the impact of a community-based, family-centred, multidisciplinary program focussed on activity, food and attitude habits (Curtin University's Activity, Food and Attitudes Program--CAFAP) among overweight adolescents.

BACKGROUND: Current estimates place just under one quarter of adolescents in Australia as overweight or obese. Adolescence has been identified as a critical period for the development of obesity, yet despite this recognition, there is limited systematic research into or evaluation of interventions for overweight adolescents. Reviews have concluded that there is a substantive evidence gap for effective intervention, but physical activity, lifestyle change and family involvement have been identified as promising foci for treatment. METHODS: This paper reports on the development of a staggered-entry, waitlist controlled clinical trial to assess the impact of a multidisciplinary intervention aiming to change the poor health trajectory of overweight adolescents and help them avoid morbid obesity in adulthood-Curtin University's Activity, Food and Attitudes Program (CAFAP). 96 adolescents, aged 11-16 years, and parents, will attend twice weekly during an 8 week intensive multidisciplinary program with maintenance follow-up focussed on improving activity, food and attitude habits. Follow-up assessments will be conducted immediately after completing the intensive program, and at 3, 6 and 12 months post intensive program. Main outcomes will be objectively-measured physical activity, sedentary behaviour and activity behaviours; food intake (measured by 3 day diary) and food behaviours; body composition, fitness and physical function; mental and social well-being (quality of life, mood and attitudes), and family functioning. DISCUSSION: This trial will provide important information to understand whether a community based multidisciplinary intervention can have short and medium term effects on activity and food habits, attitudes, and physical and mental health status of overweight adolescents. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611001187932.

Methotrexate encephalopathy: Two cases in adult cancer patients, who recovered with pathophysiologically based therapy.

BACKGROUND/OBJECTIVES: Neurotoxicity is a serious and sometimes fatal adverse effect that can occur following methotrexate treatment. We describe two adult patients with hematological malignancies with methotrexate encephalopathy who recovered with dextromethorphan therapy. RESULTS: Case 1: A 24-year-old male with acute lymphoblastic leukemia developed the acute onset of bilateral facial weakness and slurred speech after his first treatment with high-dose intravenous methotrexate. The clinical scenario and a head magnetic resonance imaging supported a diagnosis of methotrexate encephalopathy. Treatment with dextromethorphan was coincident with recovery. Case 2: A 65-year-old female with recurrent diffuse large B-cell lymphoma was treated with high-dose intravenous methotrexate. Two weeks after a cycle, she developed hypoactive delirium, marked lethargy, ocular ataxia, and a right-sided facial weakness. Within 2 days of starting dextromethorphan, there was improvement with clinical recovery. CONCLUSIONS: These two cases suggest that N-methyl d-aspartate receptor activation by homocysteine may play an important role in the pathogenesis of methotrexate neurotoxicity.

Preventing Internalizing Problems in 6-8 Year Old Children: A Universal School-Based Program.

The Aussie Optimism Program: Feelings and Friends (AOP-FF) is a 10 week, universal mental health promotion program based on social/emotional and cognitive and behavioral strategies. The aim of the current study was to evaluate the efficacy of a universal Cognitive Behavioral Therapy based program in preventing and reducing internalizing problems in 6-8 year olds (Years 1-3 in Australia). Year 1-3 students from a low SES primary school (N = 206) were randomly assigned in classes to either an intervention or a control group and assessed at baseline and post-test. Results showed a significant (p = 0.009) and small to moderate (partial eta-squared = 0.034) pre-post decrease in parent-reported anxiety symptoms for the intervention group, in conjunction with a non-significant (p = 0.708) and negligible (partial eta-squared = 0.001) pre-post increase for the control group. A larger randomized controlled trial assessing longer term effects is needed. In addition the program needs to be simplified for year 1-2 students with a separate more developmentally appropriate program for year 3 students.

Assessment of a model for achieving competency in administration and scoring of the WAIS-IV in post-graduate psychology students.

There is a need for an evidence-based approach to training professional psychologists in the administration and scoring of standardized tests such as the Wechsler Adult Intelligence Scale (WAIS) due to substantial evidence that these tasks are associated with numerous errors that have the potential to significantly impact clients' lives. Twenty three post-graduate psychology students underwent training in using the WAIS-IV according to a best-practice teaching model that involved didactic teaching, independent study of the test manual, and in-class practice with teacher supervision and feedback. Video recordings and test protocols from a role-played test administration were analyzed for errors according to a comprehensive checklist with self, peer, and faculty member reviews. 91.3% of students were rated as having demonstrated competency in administration and scoring. All students were found to make errors, with substantially more errors being detected by the faculty member than by self or peers. Across all subtests, the most frequent errors related to failure to deliver standardized instructions verbatim from the manual. The failure of peer and self-reviews to detect the majority of the errors suggests that novice feedback (self or peers) may be ineffective to eliminate errors and the use of more senior peers may be preferable. It is suggested that involving senior trainees, recent graduates and/or experienced practitioners in the training of post-graduate students may have benefits for both parties, promoting a peer-learning and continuous professional development approach to the development and maintenance of skills in psychological assessment.

Layered droplet microstructures in sheared emulsions: finite-size effects.

We investigate the influence of confinement on the steady state microstructure of emulsions sheared between parallel plates, in a regime where the average droplet dimension is comparable to the gap width between the confining walls. Utilizing droplet velocimetry, we find that the droplets can organize into discrete layers under the influence of shear. The number of layers decreases from two (at relatively higher shear rates) to one (at lower shear rates), as the drops grow slightly larger due to coalescence. We argue that the layering and overall composition profile may be controlled by the interplay of droplet collisions (which can cause separation of droplet centers in the velocity gradient direction), droplet migration toward the centerline (due to wall effects), and droplet packing constraints. We also study the effects of mixture composition on droplet microstructure, and summarize these results in the form of a morphology diagram in the parameter space of mass fraction and shear rate. We find that formation of strings of the suspended phase (reported earlier by our group in flow-visualization studies on confined emulsions) is observed over a broad composition window. We also find a stable (nontransient) morphology wherein the droplets are arranged in highly ordered pearl-necklace chain structures.

Bidirectional relationships between cigarette use and spinal pain in adolescents accounting for psychosocial functioning.

OBJECTIVES: The objective of this study was to determine the presence of possible bidirectional causal pathways between cigarette use and spinal pain in adolescents controlling for psychosocial functioning, using a prospective longitudinal research design. DESIGN: The data for this study was collected from a cohort of Australian adolescents at 14 (n = 1596) and 17 (n = 1291) years of age. METHODS: Multivariable logistic regression was used to assess i) if cigarette use at 14 predicted low back pain (LBP), mid back pain (MBP) or neck shoulder pain (NSP) at 17 in those adolescents without each condition at 14, and ii) if back pain only (BP), neck shoulder pain only (NSP) or comorbid BP and NSP at 14 predicted cigarette use at 17 in those adolescents who did not smoke at 14. RESULTS: After controlling for psychosocial factors, cigarette use at 14 predicted MBP at 17 (OR = 3.05, p = 0.049, 95% CI [1.01-9.24]). BP only at 14 was a significant risk factor for smoking at 17 (OR = 1.84, p = 0.006, 95% CI [1.19-2.84]) after controlling for psychosocial factors. CONCLUSION: The findings indicate that there are bi-directional relationships between cigarette use and spinal pain and that these relationships vary with pain location.

Hypertrophic osteoarthropathy as a clinical manifestation of lung cancer.

Hypertrophic osteoarthropathy is a paraneoplastic syndrome most often found in non-small cell lung cancer. Diagnosis is confirmed by the presence of clubbing on physical examination and periostitis on bone scintigram, and the syndrome generally resolves with treatment of the underlying malignancy. This article presents a case study and describes symptom management options, including nonsteroidal anti-inflammatory agents, octreotide, and bisphosphonates.

Adolescent drug use, psychosocial functioning and spinal pain.

This study tested whether there is an independent relationship between adolescent drug use and neck and shoulder pain (NSP) and back pain (BP) when psychosocial functioning is controlled in a community sample of 1608 14-year-old Australian adolescents. Multivariable logistic regression was used to calculate the odds ratios of alcohol and cigarette use for NSP and BP before and after adjusting for a range of psychosocial variables. Results showed that the use of alcohol, but not cigarettes or marijuana, has a significant independent association with adolescent spinal pain. Future research needs to investigate these variables longitudinally to inform interventions for adolescent spinal pain.

Time-dependent changes in skeletal response to teriparatide: escalating vs. constant dose teriparatide (PTH 1-34) in osteoporotic women.

Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6-12 months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 µg daily for 18months or 20 µg daily for 6 months, then 30 µg daily for 6 months, and then 40 µg daily for 6 months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6 months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18 months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific.