Ross River virus and Barmah Forest virus infections: a review of history, ecology, and predictive models, with implications for tropical northern Australia

The purpose of the present article is to present a review of the Ross River virus (RRV) and Barmah Forest virus (BFV) literature in relation to potential implications for future disease in tropical northern Australia. Ross River virus infection is the most common and most widespread arboviral disease in Australia, with an average of 4,800 national notifications annually. Of recent concern is the sudden rise in BFV infections; the 2005-2006 summer marked the largest BFV epidemic on record in Australia, with 1,895 notifications. Although not life-threatening, infection with either virus can cause arthritis, myalgia, and fatigue for 6 months or longer, resulting in substantial morbidity and economic impact. The geographic distribution of mosquito species and their seasonal activity is determined in large part by temperature and rainfall. Predictive models can be useful tools in providing early warning systems for epidemics of RRV and BFV infection. Various models have been developed to predict RRV outbreaks, but these appear to be mostly only regionally valid, being dependent on local ecological factors. Difficulties have arisen in developing useful models for the tropical northern parts of Australia, and to date no models have been developed for the Northern Territory. Only one model has been developed for predicting BFV infections using climate and tide variables. It is predicted that the exacerbation of current greenhouse conditions will result in longer periods of high mosquito activity in the tropical regions where RRV and BFV are already common. In addition, the endemic locations may expand further within temperate regions, and epidemics may become more frequent in those areas. Further development of predictive models should benefit public health planning by providing early warning systems of RRV and BFV infection outbreaks in different geographical locations.     

Existing agents,novel agents,or transplantation for high-risk MDS

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Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development

To identify genes linked to normal plasma cell (PC) differentiation and to classify multiple myeloma (MM) with respect to the expression patterns of these genes, we analyzed global mRNA expression in CD19-enriched B cells (BCs) from 7 tonsils, CD138-enriched PCs from 11 tonsils, 31 normal bone marrow samples, and 74 MM bone marrow samples using microarrays interrogating 6800 genes. Hierarchical clustering analyses with 3288 genes clearly segregated the 4 cell types, and chi-square and Wilcoxin rank sum tests (P <.0005) identified 359 and 500 previously defined and novel genes that distinguish tonsil BCs from tonsil PCs (early differentiation genes [EDGs]), and tonsil PCs from bone marrow PCs (late differentiation genes [LDGs]), respectively. MM as a whole was found to have dramatically variable expression of EDGs and LDGs, and one-way analysis of variance (ANOVA) was used to identify the most variable EDGs (vEDGs) and LDGs (v1LDG and v2LDG). Hierarchical cluster analysis with these genes revealed that previously defined MM gene expression subgroups (MM1-MM4) could be linked to one of the 3 normal cell types. Clustering with 30 vEDGs revealed that 13 of 18 MM4 cases clustered with tonsil BCs (P =.000 05), whereas 14 of 15 MM3 cases clustered with tonsil PCs when using 50 v1LDG (P =.000 008), and 14 of 20 MM2 cases clustered with bone marrow PCs when using 50 v2LDG (P =.000 09). MM1 showed no significant linkage with normal cell types studied. Thus, genes whose expression is linked to distinct transitions in late-stage B-cell differentiation can be used to classify MM.     

Hidden Genetic Variation in LCA9‐Associated Congenital Blindness Explained by 5′UTR Mutations and Copy‐Number Variations of NMNAT1

Leber congenital amaurosis (LCA) is a severe autosomal‐recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9‐associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5′UTR variant, c.‐70A>T. Moreover, an adjacent 5′UTR variant, c.‐69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5′UTR variants resulted in decreased NMNAT1 mRNA abundance in patients’ lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE‐1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu‐rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1‐associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat‐mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness.     

Muscle-Activation Onset Times With Shoes and Foot Orthoses in Participants With Chronic Ankle Instability

Context

Participants with chronic ankle instability (CAI) use an altered neuromuscular strategy to shift weight from double-legged to single-legged stance. Shoes and foot orthoses may influence these muscle-activation patterns.

Objective

To evaluate the influence of shoes and foot orthoses on onset times of lower extremity muscle activity in participants with CAI during the transition from double-legged to single-legged stance.

Design

Cross-sectional study.

Setting

Musculoskeletal laboratory.

Patients or Other Participants

A total of 15 people (9 men, 6 women; age = 21.8 ± 3.0 years, height = 177.7 ± 9.6 cm, mass = 72.0 ± 14.6 kg) who had CAI and wore foot orthoses were recruited.

Intervention(s)

A transition task from double-legged to single-legged stance was performed with eyes open and with eyes closed. Both limbs were tested in 4 experimental conditions: (1) barefoot (BF), (2) shoes only, (3) shoes with standard foot orthoses, and (4) shoes with custom foot orthoses (SCFO).

Main Outcome Measure(s)

The onset of activity of 9 lower extremity muscles was recorded using surface electromyography and a single force plate.

Results

Based on a full-factorial (condition, region, limb, vision) linear model for repeated measures, we found a condition effect (F_3,91.8 = 9.39, P < .001). Differences among experimental conditions did not depend on limb or vision condition. Based on a 2-way (condition, muscle) linear model within each region (ankle, knee, hip), earlier muscle-activation onset times were observed in the SCFO than in the BF condition for the peroneus longus (P < .001), tibialis anterior (P = .003), vastus medialis obliquus (P = .04), and vastus lateralis (P = .005). Furthermore, the peroneus longus was activated earlier in the shoes-only (P = .02) and shoes-with-standard-foot-orthoses (P = .03) conditions than in the BF condition. No differences were observed for the hip muscles.

Conclusions

Earlier onset of muscle activity was most apparent in the SCFO condition for ankle and knee muscles but not for hip muscles during the transition from double-legged to single-legged stance. These findings might help clinicians understand how shoes and foot orthoses can influence neuromuscular control in participants with CAI.Key Words: footwear, insoles, ankle sprains, neuromuscular system, electromyography

Key Points

• Shoes and foot orthoses accelerated muscle-activation onset times of the ankle and knee but not the hip in participants with chronic ankle instability.
• Earlier muscle-activation onset times were most prominent in the shoes-with-custom-foot-orthoses condition.
• At the ankle, the muscle-activation onset time of the peroneus longus was earlier in the shoes-only, shoes-with-standard-foot-orthoses, and shoes-with-custom-foot-orthoses conditions than in the barefoot condition, and the muscle-activation onset time of the tibialis anterior was earlier in the shoes-with-custom-foot-orthoses condition than in the barefoot condition.
• At the knee, the muscle-activation onset times of the vastus medialis obliquus and vastus lateralis were earlier in the shoes-with-custom-foot-orthoses condition than in the barefoot condition.
• The results may help clinicians understand how shoes and foot orthoses can influence neuromuscular control of the lower extremity in participants with chronic ankle instability.

Lateral ankle sprains are estimated to account for approximately 15% of all sport injuries.¹ Even more concerning than the initial ankle sprain is the large proportion of patients with residual symptoms and recurrent ankle sprains for months to years after the initial injury.² The occurrence of repetitive ankle sprains and the feeling of the ankle “giving way” with slight or no perturbation has been defined as chronic ankle instability (CAI).³The transition task from double-legged to single-legged stance during barefoot (BF) conditions has been shown to discriminate between uninjured participants and participants with CAI. Researchers have reported that muscle-activation onset times typically were delayed^4,5 and postural stability was impaired⁶ in participants with CAI, indicating the use of another strategy to shift weight from double-legged to single-legged stance. However, it is unclear whether findings from BF tests represent typical daily situations when shoes, and for some persons foot orthoses, are often worn.The human foot is the first point of contact between the body and a supporting surface. The cutaneous mechanoreceptors on the planar surface of the foot are an important source of sensory information,⁷ which is considered essential for achieving and maintaining functional joint stability.⁸ Shoes and foot orthoses act as an interface between the body and a supporting surface and can influence the sensory feedback from these mechanoreceptors by increasing the contact area between the foot and the supporting surface.^7,9 Furthermore, the small kinematic alterations of the rear foot and tibia that have been described with the use of shoes and foot orthoses¹⁰ may put the ankle joint in a more neutral position, thereby improving the capacity of the ankle mechanoreceptors to provide more accurate proprioceptive input toward the central nervous system.¹¹ Changing the sensory input to these mechanisms consequently would change the motor output.⁷Evidence is increasing that shoes and foot orthoses can influence lower extremity muscle activation.^10,12–14 Dingenen et al¹⁴ were the first investigators to measure the influence of shoes and foot orthoses on muscle-activation onset times of the entire lower extremity in uninjured participants during the transition from double-legged to single-legged stance. Their results showed that shoes and foot orthoses can accelerate muscle-activation onset times of the peroneus longus. No differences were reported in more proximal muscles. Recently, researchers have suggested that future investigators should be focused on the influence of shoes and foot orthoses on neuromuscular control, especially in participants with injuries, such as CAI,^10,13,14 to increase our understanding of how positive clinical outcomes from the use of shoes and foot orthoses can be achieved.¹¹ Altering or improving proprioceptive information and muscle-activation patterns in participants with CAI would be clinically beneficial, given that their proprioceptive and neuromuscular deficits have been described.¹⁵To our knowledge, no investigators have focused on the influence of shoes and foot orthoses on muscle-activation onset times of the entire lower extremity in participants with CAI during the transition from double-legged to single-legged stance. Therefore, the purpose of our study was to evaluate the influence of shoes and foot orthoses on muscle-activation onset times during the transition from double-legged to single-legged stance in participants with CAI. Based on the proposed effects of shoes and foot orthoses on lower extremity neuromuscular control, we hypothesized that shoes and foot orthoses would accelerate muscle-activation onset times compared with a BF condition.     

Oral Prolonged‐Release Oxycodone/Naloxone for Managing Pain and Opioid‐Induced Constipation: A Review of the Evidence

Background

Opioids provide effective relief from moderate‐to‐severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed‐dose oxycodone/naloxone prolonged‐release tablets (OXN PR) were designed to address the opioid class effect of opioid‐induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse‐deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone.

Methods

A literature search was conducted to assess the evidence base for OXN PR to treat moderate‐to‐severe pain and its impact on bowel function, based on published clinical trials and observational studies.

Results

Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate‐to‐severe cancer‐related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease–related pain. No unanticipated safety concerns have been reported in elderly patients.

Conclusions

Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate‐to‐severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).     

Associations of Mortality with Long-Term Exposures to Fine and Ultrafine Particles,Species and Sources: Results from the California Teachers Study Cohort

Background

Although several cohort studies report associations between chronic exposure to fine particles (PM_2.5) and mortality, few have studied the effects of chronic exposure to ultrafine (UF) particles. In addition, few studies have estimated the effects of the constituents of either PM_2.5 or UF particles.

Methods

We used a statewide cohort of > 100,000 women from the California Teachers Study who were followed from 2001 through 2007. Exposure data at the residential level were provided by a chemical transport model that computed pollutant concentrations from > 900 sources in California. Besides particle mass, monthly concentrations of 11 species and 8 sources or primary particles were generated at 4-km grids. We used a Cox proportional hazards model to estimate the association between the pollutants and all-cause, cardiovascular, ischemic heart disease (IHD), and respiratory mortality.

Results

We observed statistically significant (p < 0.05) associations of IHD with PM_2.5 mass, nitrate, elemental carbon (EC), copper (Cu), and secondary organics and the sources gas- and diesel-fueled vehicles, meat cooking, and high-sulfur fuel combustion. The hazard ratio estimate of 1.19 (95% CI: 1.08, 1.31) for IHD in association with a 10-μg/m³ increase in PM_2.5 is consistent with findings from the American Cancer Society cohort. We also observed significant positive associations between IHD and several UF components including EC, Cu, metals, and mobile sources.

Conclusions

Using an emissions-based model with a 4-km spatial scale, we observed significant positive associations between IHD mortality and both fine and ultrafine particle species and sources. Our results suggest that the exposure model effectively measured local exposures and facilitated the examination of the relative toxicity of particle species.

Citation

Ostro B, Hu J, Goldberg D, Reynolds P, Hertz A, Bernstein L, Kleeman MJ. 2015. Associations of mortality with long-term exposures to fine and ultrafine particles, species and sources: results from the California Teachers Study cohort. Environ Health Perspect 123:549–556; http://dx.doi.org/10.1289/ehp.1408565     

The effects of a hearing education program on recreational noise exposure,attitudes and beliefs toward noise,hearing loss,and hearing protector devices in young adults

Excessive recreational noise exposure in young adults might result in noise-induced hearing loss (NIHL) and tinnitus. Inducing behavioral change in young adults is one of the aims of a hearing conservation program (HCP). The goal of the current study was to evaluate the effect of a hearing education program after 6 months in young adults in relation to knowledge regarding their individual hearing status. The results of a questionnaire regarding the weekly equivalent recreational noise exposure, attitudes and beliefs toward noise, and hearing loss and hearing protector devices (HPDs) were compared between both sessions. Seventy-eight young adults completed the questionnaire concerning recreational noise exposure, youth attitude to noise scale (YANS), and beliefs about hearing protection and hearing loss (BAHPHL). Their hearing status was evaluated based on admittance measures, audiometry, transient-evoked otoacoustic emissions (TEOAEs), and distortion-product otoacoustic emissions (DPOAEs). The main analysis consisted of a mixed model analysis of variance with dependent variables of either the noise exposure or the scores on (subscales of) YANS and BAHPHL. The independent variables were hearing status and session one versus session two. There was a significant decrease in recreational noise exposure and several (sub) scales of YANS and BAHPHL between both the sessions. This behavioral change resulted in a more frequent use of HPDs in 12% of the participants. However, the behavioral change was not completely related to the knowledge of young adults’ individual hearing status. To prevent hearing damage in young people, investing in HCPs is necessary, apart from regulating sound levels and its compliance at various leisure-time activities. Also, the long-term effect of HCPs and their most cost-efficient repetition rates should be further investigated.