Methods for the analysis of histone H3 and H4 acetylation in blood

LBH589 is one of the many histone deacetylase inhibitors (HDACi) that are currently in clinical trial. Despite their wide-spread use, there is little literature available describing the typical levels of histone acetylation in untreated peripheral blood, the treatment and storage of samples to retain optimal measurement of histone acetylation nor methods by which histone acetylation analysis may be monitored and measured during the course of a patient’s treatment. In this study, we have used cord or peripheral blood as a source of human leukocytes, performed a comparative analysis of sample processing methods and developed a flow cytometric method suitable for monitoring histone acetylation in isolated lymphocytes and liquid tumors. Western blotting and immunohistochemistry techniques have also been addressed. We have tested these methods on blood samples collected from four patients treated with LBH589 as part of an Australian Children’s Cancer Clinical Trial (CLBH589AAU03T) and show comparable results when comparing in vitro and in vivo data. This paper does not seek to correlate histone acetylation levels in peripheral blood with clinical outcome but describes methods of analysis that will be of interest to clinicians and scientists monitoring the effects of HDACi on histone acetylation in blood samples in clinical trials or in related research studies.

Capecitabine and oral cyclophosphamide : a novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

Oral baclofen in children with cerebral palsy : a double-blind cross-over pilot study

Aim: To assess the effectiveness of oral baclofen in reducing spasticity and improving function in children with cerebral palsy. Methods: A double-blind, randomised cross-over pilot study of oral baclofen versus placebo. Assessment tools included the Goal Attainment Scale, Pediatric Evaluation of Disability Inventory, Modified Tardieu Scale and parent questionnaire. Results: Fifteen children with mean age 7.4 years (SD = 2.7 years) and spastic or spastic/dystonic quadriplegia (Gross Motor Function Classification System Level IV or V) were enrolled. Children scored significantly better on the Goal Attainment Scale with baclofen compared with placebo (F(1,13) = 4.5, P = 0.05). There was no significant difference between baclofen and placebo for the Pediatric Evaluation of Disability Inventory or Modified Tardieu Scale. Parent questionnaire results are described. Conclusion: This pilot study demonstrates that oral baclofen has an effect beyond placebo in improving goal-oriented tasks, such as transfers, in children with spastic quadriplegic cerebral palsy.

A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania

Objective: Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC).

Methods: This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period.

Results: Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint.

Conclusions: Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.

Review of nursing care for patients undergoing percutaneous coronary intervention: a patient journey approach

Aim.  To evaluate the existing literature to inform nursing management of people undergoing percutaneous coronary intervention. Background.  Percutaneous coronary intervention is an increasingly important revascularisation strategy in coronary heart disease management and can be an emergent, planned or rescue procedure. Nurses play a critical role in delivering care in both the independent and collaborative contexts of percutaneous coronary intervention management. Design.  Systematic review. Method.  The method of an integrative literature review, using the conceptual framework of the patient journey, was used to describe existing evidence and to determine important areas for future research. The electronic data bases CINAHL, Medline, Cochrane and the Joanna Briggs data bases were searched using terms including: (angioplasty, transulminal, percutaneous coronary), nursing care, postprocedure complications (haemorrhage, ecchymosis, haematoma), rehabilitation, emergency medical services (transportation of patients, triage). Results.  Despite the frequency of the procedure, there are limited data to inform nursing care for people undergoing percutaneous coronary intervention. Currently, there are no widely accessible nursing practice guidelines focusing on the nursing management in percutaneous coronary intervention. Findings of the review were summarised under the headings: Symptom recognition; Treatment decision; Peri-percutaneous coronary intervention care, describing the acute management and Postpercutaneous coronary intervention management identifying the discharge planning and secondary prevention phase. Conclusions.  Cardiovascular nurses need to engage in developing evidence to support guideline development. Developing consensus on nurse sensitive patient outcome indicators may enable benchmarking strategies and inform clinical trial design. Relevance to clinical practice.  To improve the care given to individuals undergoing percutaneous coronary intervention, it is important to base practice on high-level evidence. Where this is lacking, clinicians need to arrive at a consensus as to appropriate standards of practice while also engaging in developing evidence. This must be considered, however, from the central perspective of the patient and their family.

Determinants of health-related quality of life in people with Parkinson’s disease: a path analysis

Purpose:
To identify the demographic factors, impairments and activity limitations that contribute to health-related quality of life (HRQOL) in people with idiopathic Parkinson’s disease (PD).

Method:
Two hundred and ten individuals with idiopathic PD who participated in the baseline assessment of a randomized clinical trial were included. The Parkinson’s Disease Questionnaire-39 summary index was used to quantify HRQOL. In order to provide greater clarity regarding the determinants of HRQOL, path analysis was used to explore the relationships between the various predictors in relation to the functioning and disability framework of the International Classification of Functioning model.

Results:
The two models of HRQOL that were examined in this study had a reasonable fit with the data. Activity limitations were found to be the strongest predictor of HRQOL. Limitations in performing self-care activities contributed the most to HRQOL in Model 1 (β = 0.38; p < 0.05), while limitations in functional mobility had the largest contribution in Model 2 (β = −0.31; p < 0.0005). Self-reported history of falls was also found to have a significant and direct relationship with HRQOL in both models (Model 1 β = −0.11; p < 0.05; Model 2 β = −0.21; p < 0.05).

Conclusions:
Health-related quality of life in PD is associated with self-care limitations, mobility limitations, self-reported history of falls and disease duration. Understanding how these factors are inter-related may assist clinicians focus their assessments and develop strategies that aim to minimize the negative functional and social sequelae of this debilitating disease.

Rural living and health-related quality of life in Australians with Parkinson's disease

Introduction: The motor and non-motor symptoms associated with idiopathic Parkinson’s disease (PD) may compromise the health-related quality of life (HRQOL) of some individuals living with this debilitating condition. Although growing evidence suggests that PD may be more prevalent in rural communities, there is little information about the life quality of these individuals. This study examines whether HRQOL ratings vary in relation to rural and metropolitan life settings.
Methods: An analytic cross-sectional study was conducted to compare the HRQOL of two separate samples of people with PD living in metropolitan Melbourne and rural Victoria. The metropolitan sample consisted of 210 individuals who had participated in the baseline assessment for an existing clinical trial. The rural sample comprised 24 participants who attended community-based rehabilitation programs and support groups in rural Victoria. Health-related quality of life was quantified using the Parkinson’s Disease Questionnaire-39 (PDQ-39).
Results: The HRQOL of participants in rural Australia differed from individuals living in a large metropolitan city (p=0.025). Participants in rural Australia reported worse overall HRQOL, after controlling for differences in disease duration. Their overall HRQOL was lower than for city dwellers. Rural living was also found to be a significant negative predictor of HRQOL (β=0.14; 95% CI -1.27 to -0.08; _p=0.027).
Conclusion: The findings of this study suggest that some people with PD living in rural Victoria perceive their HRQOL to be relatively poor. In order to minimise the debilitating consequences of this disease, further studies examining the factors that may contribute to the HRQOL of individuals living in rural and remote areas are required.

Impact of an active video game on healthy children’s physical activity

OBJECTIVE: This naturalistic study tests whether children receiving a new (to them) active video game spontaneously engage in more physical activity than those receiving an inactive video game, and whether the effect would be greater among children in unsafe neighborhoods, who might not be allowed to play outside.

METHODS: Participants were children 9 to 12 years of age, with a BMI >50th percentile, but <99th percentile; none of these children a medical condition that would preclude physical activity or playing video games. A randomized clinical trial assigned children to receiving 2 active or 2 inactive video games, the peripherals necessary to run the games, and a Wii console. Physical activity was monitored by using accelerometers for 5 weeks over the course of a 13-week experiment. Neighborhood safety was assessed with a 12 item validated questionnaire.

RESULTS: There was no evidence that children receiving the active video games were more active in general, or at anytime, than children receiving the inactive video games. The outcomes were not moderated by parent perceived neighborhood safety, child BMI z score, or other demographic characteristics.

CONCLUSIONS: These results provide no reason to believe that simply acquiring an active video game under naturalistic circumstances provides a public health benefit to children.

In-hospital falls and fall-related injuries: a protocol for a cost of fall study

Background:
In-hospital falls are common and pose significant economic burden on the healthcare system. To date, few studies have quantified the additional cost of hospitalisation associated with an in-hospital fall or fall-related injury. The aim of this study is to determine  the additional length of stay and hospitalisation costs associated with in-hospital falls and fall-related injuries, from the acute hospital perspective.

Methods and design: 
A multisite prospective study will be conducted as part of a larger falls-prevention clinical trial—the 6-PACK project. This study will involve 12 acute medical and surgical wards from six hospitals across Australia. Patient and admission characteristics, outcome and hospitalisation cost data will be prospectively collected on approximately 15 000 patients during the 15-month study period. A review of all inhospital fall events will be conducted using a multimodal method (medical record review and daily verbal report from the nurse unit manager, triangulated with falls recorded in the hospital incident reporting and administrative database), to ensure complete case ascertainment. Hospital clinical costing data will be used to calculate patient-level hospitalisation costs incurred by a patient during their inpatient stay. Additional hospital and hospital resource utilisation costs attributable to inhospital falls and fall-related injuries will be calculated using linear regression modelling, adjusting for a prioridefined potential confounding factors.

Discussion:
This protocol provides the detailed statement of the planned analysis. The results from this study will be used to support healthcare planning, policy making and allocation of funding relating to falls prevention within acute hospitals.

A low power micro deep brain stimulation device for murine preclinical research

Deep brain stimulation has emerged as an effective medical procedure that has therapeutic efficacy in a number of neuropsychiatric disorders. Preclinical research involving laboratory animals is being conducted to study the principles, mechanisms, and therapeutic effects of deep brain stimulation. A bottleneck is, however, the lack of deep brain stimulation devices that enable long term brain stimulation in freely moving laboratory animals. Most of the existing devices employ complex circuitry, and are thus bulky. These devices are usually connected to the electrode that is implanted into the animal brain using long fixed wires. In long term behavioral trials, however, laboratory animals often need to continuously receive brain stimulation for days without interruption, which is difficult with existing technology. This paper presents a low power and lightweight portable microdeep brain stimulation device for laboratory animals. Three different configurations of the device are presented as follows: 1) single piece head mountable; 2) single piece back mountable; and 3) two piece back mountable. The device can be easily carried by the animal during the course of a clinical trial, and that it can produce non-stop stimulation current pulses of desired characteristics for over 12 days on a single battery. It employs passive charge balancing to minimize undesirable effects on the target tissue. The results of bench, in-vitro, and in-vivo tests to evaluate the performance of the device are presented.

Reducing sitting time in office workers: short-term efficacy of a multicomponent intervention

Objective To investigate the short-term efficacy of a multicomponent intervention to reduce office workers' sitting time. Methods Allocation for this non-randomized controlled trial (n = 43 participants; 56% women; 26–62 years; Melbourne, Australia) was by office floor, with data collected during July–September 2011. The 4-week intervention emphasized three key messages: “Stand Up, Sit Less, Move More” and comprised organizational, environmental, and individual elements. Changes in minutes/day at the workplace spent sitting (primary outcome), in prolonged sitting (sitting time accumulated in bouts ≥ 30 min), standing, and moving were objectively measured (activPAL3). Results Relative to the controls, the intervention group significantly reduced workplace sitting time (mean change [95%CI]: − 125 [− 161, − 89] min/8-h workday), with changes primarily driven by a reduction in prolonged sitting time (− 73 [− 108, − 40] min/8-h workday). Workplace sitting was almost exclusively replaced by standing (+ 127 [+ 92, + 162] min/8-h workday) with non-significant changes to stepping time (− 2 [− 7, + 4] min/8-h workday) and number of steps (− 70 [− 350, 210]). Conclusions This multicomponent workplace intervention demonstrated that substantial reductions in sitting time are achievable in an office setting. Larger studies with longer timeframes are needed to assess sustainability of these changes, as well as their potential longer-term impacts on health and work-related outcomes.

Maternal supplementation with LGG reduces vaccine-specific immune responses in infants at high-risk of developing allergic disease

Probiotics are defined as live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Among their pleiotropic effects, inhibition of pathogen colonization at the mucosal surface as well as modulation of immune responses are widely recognized as the principal biological activities of probiotic bacteria. In recent times, the immune effects of probiotics have led to their application as vaccine adjuvants, offering a novel strategy for enhancing the efficacy of current vaccines. Such an approach is particularly relevant in regions where infectious disease burden is greatest and where access to complete vaccination programs is limited. In this study, we report the effects of the probiotic, Lactobacillus rhamnosus GG (LGG) on immune responses to tetanus, Haemophilus influenzae type b (Hib) and pneumococcal conjugate (PCV7) vaccines in infants. This study was conducted as part of a larger clinical trial assessing the impact of maternal LGG supplementation in preventing the development of atopic eczema in infants at high-risk for developing allergic disease. Maternal LGG supplementation was associated with reduced antibody responses against tetanus, Hib, and pneumococcal serotypes contained in PCV7 (N = 31) compared to placebo treatment (N = 30) but not total IgG levels. Maternal LGG supplementation was also associated with a trend to increased number of tetanus toxoid-specific T regulatory in the peripheral blood compared to placebo-treated infants. These findings suggest that maternal LGG supplementation may not be beneficial in terms of improving vaccine-specific immunity in infants. Further clinical studies are needed to confirm these findings. As probiotic immune effects can be species/strain specific, our findings do not exclude the potential use of other probiotic bacteria to modulate infant immune responses to vaccines.