A scoping review on active vs. passive range of motion approaches to treat heterotopic ossification at the elbow.

Objective: The objective of this scoping review is to synthesize and clarify literature on the effectiveness of active and passive range of motion therapy techniques to address range of motion in people with heterotopic ossification (HO), and to provide guidance to therapists in clinical decision-making based on current evidence. Method: To find articles that included therapeutic interventions to maintain or improve range of motion in people with heterotopic ossification, the authors searched the following databases: Cochrane Database of Systematic Reviews, PubMed, CINAHL, PsychINFO, Web of Science, and OTSeeker. To ensure that the search was comprehensive, the authors also searched Burns and Trauma, Burns Journal, Burns Open, and the Journal of Hand Therapy. Searches were limited to peer-reviewed articles published in the English language. No publication date limits were set. The Physiotherapy Evidence Database PEDro scale was utilized to measure the validity of the methodological quality of each article. Results: Five studies met the inclusion criteria.. Two studies emphasized that passive range of motion was effective in less than 50% of their subjects, while the other three studies utilized active range of motion only, reporting 50% of patients did not require surgery. Discussion/conclusion: There is insufficient evidence to determine effective therapeutic management of HO and the literature that does exist is contradictory and inconclusive. Future research is necessary to determine if any effectiveness of manual therapeutic approaches exists for patients with HO.

A Cross-sectional Cohort Study to Assess Long-term Neurocognitive and Psychiatric Symptoms of Mefloquine Use in Veterans.

INTRODUCTION: To evaluate the associations between neurocognitive and psychiatric health outcomes with mefloquine or any antimalarial exposure. MATERIALS AND METHODS: Medical records were systematically reviewed to identify veterans that indicated antimalarial medication use. Linear regression was performed to examine associations between mefloquine/antimalarial exposure and health outcomes. The mefloquine-exposed group was further compared with normative populations for the same health outcomes. RESULTS: In the adjusted models, no significant differences were noted between the two exposure groups and the unexposed group for any of the health measures (P-value > 0.05). When compared to normative population samples, the mefloquine-exposed group had poorer health and greater neurobehavioral symptom severity or cognitive complaints. CONCLUSION: This study suggests that mefloquine use by veterans referred for intensive evaluation of their military deployment exposures and health was not associated with increased, long-term, neurocognitive/psychiatric symptoms compared to unexposed veterans.

A standardised approach for determining heat tolerance in cotton using triphenyl tetrazolium chloride.

Improving the heat tolerance of cotton is a major concern for breeding programs. To address this need, a fast and effect way of quantifying thermotolerant phenotypes is required. Triphenyl tetrazolium chloride (TTC) based enzyme viability testing following high-temperature stress can be used as a vegetative heat tolerance phenotype. This is because when live cells encounter a TTC solution, TTC undergoes a chemical reduction producing a visible, insoluble red product called triphenyl formazan, that can be quantified spectrophotometrically. However, existing TTC based cell viability assays cannot easily be deployed at the scale required in a crop improvement program. In this study, a heat stress assay (HSA) based on the use of TTC enzyme viability testing has been refined and improved for efficiency, reliability, and ease of use through four experiments. Sampling factors that may influence assay results, such as leaf age, plant water status, and short-term cold storage, were also investigated. Experiments conducted in this study have successfully downscaled the assay and identified an optimal sampling regime, enabling measurement of large segregating populations for application in breeding programs. The improved HSA methodology is important as it is proposed that long-term improvements in cotton thermotolerance can be achieved through the concurrent selection of superior phenotypes based on the HSA and yield performance in hot environments. Additionally, a new way of interpreting both heat tolerance and heat resistance was developed, differentiating genotypes that perform well at the time of a heat stress event and those that maintain a similar performance level to a non-stressed control.

Food Insecurity in US Military Veterans.

BACKGROUND: Food insecurity (FI) is an important public health issue for US veterans. For many veterans, civilian life is fraught with service-incurred health issues and socioeconomic challenges, each risk factors for FI. The FI literature on veterans is limited due to insufficient coverage of the topic's complexity and the methods used to study it in this population. No published analysis has evaluated how FI has been examined in US veterans. OBJECTIVES: We assessed how FI has been examined in US military veterans by identifying (1) the major content areas, or domains, studied in association with FI and (2) the existing research gaps. METHODS: A scoping literature review was conducted to map the main research domains of the FI literature and identify knowledge gaps. Electronic database and hand searches identified potentially relevant studies (n = 61). Data extraction, utilizing a standardized set of design parameters, was completed. Duplicate removal and application of inclusion/exclusion criteria resulted in the studies (n = 21) selected for critical review. RESULTS: Eight research domains were determined: FI prevalence, health status, dietary practices, health care utilization, economic instability, homelessness/housing instability, food program participation, and community/emergency preparedness-the most dominant was health status and the least dominant were social determinants (ie, homelessness/housing instability, food program participation). Research on validity and usability of FI assessment methods in veterans was virtually absent. Military service factors, longitudinal effects, FI among women, intervention effectiveness, and other areas lacked sufficient inquiry. CONCLUSION: Research is required on lesser examined content areas and methodology to optimize surveillance and policy for veteran FI.

Molecular Targeting of Cancer-Associated PCNA Interactions in Pancreatic Ductal Adenocarcinoma Using a Cell-Penetrating Peptide.

Pancreatic ductal adenocarcinoma is a particularly difficult cancer to treat due to a lack of effective screening or treatment. Pancreatic cancer cells exhibit high proliferating cell nuclear antigen (PCNA) expression, which is associated with poor prognosis. PCNA, an important nuclear DNA replication and repair protein, regulates a myriad of proteins via the interdomain connector loop. Within this region, amino acids 126-133 are critical for PCNA interactions in cancer cells. Here, we investigate the ability of a decoy cell-penetrating peptide, R9-caPeptide, that mimics the interdomain connector loop region of PCNA to disrupt PCNA-protein interactions in pancreatic cancer cells. Our data suggest that R9-caPeptide causes dose-dependent toxicity in a panel of pancreatic cancer cell lines by inhibiting DNA replication fork progression and PCNA-regulated DNA repair, ultimately causing lethal DNA damage. Overall, these studies lay the foundation for novel therapeutic strategies that target PCNA in pancreatic cancer.

Validating the disruption of proliferating cell nuclear antigen interactions in the development of targeted cancer therapeutics.

Human DNA replication and repair is a highly coordinated process involving the specifically timed actions of numerous proteins and enzymes. Many of these proteins require interaction with proliferating cell nuclear antigen (PCNA) for activation within the process. The interdomain connector loop (IDCL) of PCNA provides a docking site for many of those proteins, suggesting that this region is critically important in the regulation of cellular function. Previous work in this laboratory has demonstrated that a peptide mimicking a specific region of the IDCL (caPeptide) has the ability to disrupt key protein-protein interactions between PCNA and its binding partners, thereby inhibiting DNA replication within the cells. In this study, we confirm the ability of the caPeptide to disrupt DNA replication function using both intact cell and in vitro DNA replication assays. Further, we were able to demonstrate that treatment with caPeptide results in a decrease of polymerase δ activity that correlates with the observed decrease in DNA replication. We have also successfully developed a surface plasmon resonance (SPR) assay to validate the disruption of the PCNA-pol δ interaction with caPeptide.

Non-obligatory role of prostaglandin D2 receptor subtype 1 in rosacea: laropiprant in comparison to a placebo did not alleviate the symptoms of erythematoelangiectaic rosacea.

Erythematotelangiectatic rosacea shares facial flushing features with those seen after niacin. This study was performed to test the hypothesis whether prostaglandin D2 (PGD2) receptor subtype 1 antagonist (laropiprant) will improve the symptoms of rosacea. The purpose of this study was to evaluate the effect of laropiprant 100 mg administered once daily for 4 weeks on the signs and symptoms of erythematotelangiectatic rosacea. Subjects received laropiprant 100 mg once-daily (n = 30) or placebo (n = 30) for 4 weeks. The primary pharmacodynamics endpoint was change in Clinician's Erythema Assessment (CEA) score from baseline to week 4. The patient self-assessment (PSA) was a secondary endpoint. Laropiprant was generally well tolerated in this study for the primary endpoint of change in CEA score from Baseline to Week 4, the least-squares mean of change from baseline to visit 4/week 4 was -3.7 and -3.4 for placebo and laropiprant (100 mg), respectively. The least-squares mean difference (placebo minus laropiprant) with 90% confidence interval of change in CEA score from baseline to visit 4/week 4 was estimated as -0.3 (-1.6, 1.0). For the secondary endpoint, the least-squares mean difference (placebo minus laropiprant) with 90% confidence interval of change from baseline to visit 4/week 4 was estimated as -0.7 (-7.7, 6.4) for PSA total score, -4.5 (-14.2, 5.3) for PSA emotion score, -1.3 (-7.8, 5.3) for PSA symptoms score, and 3.6 (-4.3, 11.4) for PSA functioning score. Laropiprant administered once daily for 4 weeks was generally well tolerated in this population of subjects with rosacea. However, there were no clinically meaningful changes in the primary endpoint of CEA given that the response to laropiprant could not be differentiated from that to placebo. There was also no clinically meaningful change in the secondary endpoint, PSA. A DP1 antagonist is not likely to be effective in rosacea.

A Peptide mimicking a region in proliferating cell nuclear antigen specific to key protein interactions is cytotoxic to breast cancer.

Proliferating cell nuclear antigen (PCNA) is a highly conserved protein necessary for proper component loading during the DNA replication and repair process. Proteins make a connection within the interdomain connector loop of PCNA, and much of the regulation is a result of the inherent competition for this docking site. If this target region of PCNA is modified, the DNA replication and repair process in cancer cells is potentially altered. Exploitation of this cancer-associated region has implications for targeted breast cancer therapy. In the present communication, we characterize a novel peptide (caPeptide) that has been synthesized to mimic the sequence identified as critical to the cancer-associated isoform of PCNA. This peptide is delivered into cells using a nine-arginine linking mechanism, and the resulting peptide (R9-cc-caPeptide) exhibits cytotoxicity in a triple-negative breast cancer cell line, MDA-MB-436, while having less of an effect on the normal counterparts (MCF10A and primary breast epithelial cells). The novel peptide was then evaluated for cytotoxicity using various in vivo techniques, including ATP activity assays, flow cytometry, and clonogenetic assays. This cytotoxicity has been observed in other breast cancer cell lines (MCF7 and HCC1937) and other forms of cancer (pancreatic and lymphoma). R9-cc-caPeptide has also been shown to block the association of PCNA with chromatin. Alanine scanning of the peptide sequence, combined with preliminary in silico modeling, gives insight to the disruptive ability and the molecular mechanism of action of the therapeutic peptide in vivo.

A PCNA-derived cell permeable peptide selectively inhibits neuroblastoma cell growth.

Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was significantly expressed in a broad range of cancer cells and tumor tissues, but not in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interconnector domain of PCNA that is known to be a major binding site for many of PCNA's interacting proteins. We hypothesized that therapeutic agents targeting protein-protein interactions mediated through this region may confer differential toxicity to normal and malignant cells. To test this hypothesis, we designed a cell permeable peptide containing the PCNA L126-Y133 sequence. Here, we report that this peptide selectively kills human neuroblastoma cells, especially those with MYCN gene amplification, with much less toxicity to non-malignant human cells. Mechanistically, the peptide is able to block PCNA interactions in cancer cells. It interferes with DNA synthesis and homologous recombination-mediated double-stranded DNA break repair, resulting in S-phase arrest, accumulation of DNA damage, and enhanced sensitivity to cisplatin. These results demonstrate conceptually the utility of this peptide for treating neuroblastomas, particularly, the unfavorable MYCN-amplified tumors.

Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth.

Proliferating cell nuclear antigen (PCNA), a potential anticancer target, forms a homotrimer and is required for DNA replication and numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity to affect tumor cell proliferation. An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners. Nine compounds, termed PCNA inhibitors (PCNA-Is), were selected for further characterization. PCNA-I1 selectively bound to PCNA trimers with a dissociation constant (K(d)) of ~0.2 to 0.4 µM. PCNA-Is promoted the formation of SDS-refractory PCNA trimers. PCNA-I1 dose- and time-dependently reduced the chromatin-associated PCNA in cells. Consistent with its effects on PCNA trimer stabilization, PCNA-I1 inhibited the growth of tumor cells of various tissue types with an IC(50) of ~0.2 µM, whereas it affected the growth of nontransformed cells at significantly higher concentrations (IC(50), ~1.6 µM). Moreover, uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1. Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA, inducing cancer cell arrest at both the S and G(2)/M phases. Thus, we have identified a class of compounds that can directly bind to PCNA, stabilize PCNA trimers, reduce PCNA association with chromatin, and inhibit tumor cell growth by inducing a cell cycle arrest. They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy.

Parental feeding practices and concerns related to child underweight, picky eating, and using food to calm differ according to ethnicity/race, acculturation, and income.

The purpose of this study was to examine differences in parental feeding practices according to ethnicity/race, household income, parent education level, acculturation (for Hispanic participants only), and participation in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program among parents living in a southern state in the United States. For this cross-sectional study, parents of children ages 1-5 years living throughout Texas were recruited through random digit dialing with screening questions during Fall 2006. Eligible parents who agreed to participate completed the Preschooler Feeding Questionnaire (PFQ) and a demographic questionnaire over the phone in either English or Spanish. The PFQ included five subscales: child overeating concerns, child underweight concerns, difficulty with picky eating, using food to calm, and pushing child to eat. Demographic questions assessed ethnicity/race, household income, parent education level, acculturation, and WIC participation. Structural Equation Modeling (SEM), with the demographic variables as predictors, was used to predict the five PFQ subscales. Complete data were obtained from 721 parents, 50% of whom were Hispanic. Significant differences for the PFQ subscales were noted for ethnicity/race, acculturation, and income level. Spanish-speaking Hispanic participants were significantly more worried about their child being underweight than English-speaking Hispanic participants. High-income non-WIC respondents were more likely to report that they have difficulty with picky eaters compared to WIC respondents. Spanish-speaking Hispanics and Black respondents were more likely than English-speaking Hispanics to use food to calm the child. Health practitioners need to be aware of differences in parental feeding practices and concerns among parents of diverse demographic backgrounds. Results from this study can be used to tailor health programs that promote healthy feeding practices among parents.

Relationships of protective factors to stress and symptoms of illness.

OBJECTIVE: To examine relationships of work and individual protective factors to health outcomes. METHODS: Participants from 2 corporate samples completed measures of supervisor support, hardiness, coping, global stress, and symptoms of illness. RESULTS: Regression analyses indicated that higher scores on hardiness and approach coping and being male predicted lower scores on stress and symptoms of illness. Additionally, supervisor support predicted fewer symptoms of illness but did not have a spillover effect onto stress. CONCLUSIONS: Interventions that enhance individual protective factors primarily and work protective factors secondarily may be most effective in reducing stress and illness among employees.

Treatment seeking in populations in urban and rural settings on the border.

BACKGROUND: Only a small proportion of persons with alcohol or drug problems seek help in the form of treatment for these problems. To examine service disparities among Hispanics living in urban and rural border areas, an improved understanding of factors associated with service seeking is needed for this population. METHODS: In-person interviews were conducted with a sample of 1,200 colonia residents and urban residents living along the Texas border with Mexico. For the present study, the dataset was limited to Hispanic respondents (85% of the sample) and those who reported any indicator of need for treatment (38% of the sample). There were 380 respondents who met these criteria. Treatment seeking was measured by any past attempt, successful or unsuccessful, to obtain treatment or by their present stated desire for treatment. Factors influencing treatment seeking were compared across 3 sites. RESULTS: Path analyses indicated that, after taking demographics into account, severity of need (the total number of drug-related and alcohol-related problems experienced by an individual) was a strong influence on treatment seeking, but income-related variables were more influential than severity of need in 1 site. Generation of immigration was positively related to treatment seeking in 2 sites, and in colonias, high religiosity was related to treatment seeking. In 2 sites, need severity was related to neighborhood variables. In colonias, need severity was related to low income and low religiosity. CONCLUSIONS: This framework for understanding treatment seeking in border communities suggests that pathways to treatment seeking vary by locality in ways that may reflect variations in local environments and service systems. Design of outreach efforts should be tailored to the unique social and service system challenges of each local community. Although service seeking is low overall, findings are suggestive of an inequitable service access structure in 1 site where need is not the predominant factor for treatment seeking.