Deep-brain photoreception links luminance detection to motor output in Xenopus frog tadpoles.

Nonvisual photoreceptors are widely distributed in the retina and brain, but their roles in animal behavior remain poorly understood. Here we document a previously unidentified form of deep-brain photoreception in Xenopus laevis frog tadpoles. The isolated nervous system retains sensitivity to light even when devoid of input from classical eye and pineal photoreceptors. These preparations produce regular bouts of rhythmic swimming activity in ambient light but fall silent in the dark. This sensitivity is tuned to short-wavelength UV light; illumination at 400 nm initiates motor activity over a broad range of intensities, whereas longer wavelengths do not cause a response. The photosensitive tissue is located in a small region of caudal diencephalon-this region is necessary to retain responses to illumination, whereas its focal illumination is sufficient to drive them. We present evidence for photoreception via the light-sensitive proteins opsin (OPN)5 and/or cryptochrome 1, because populations of OPN5-positive and cryptochrome-positive cells reside within the caudal diencephalon. This discovery represents a hitherto undescribed vertebrate pathway that links luminance detection to motor output. The pathway provides a simple mechanism for light avoidance and/or may reinforce classical circadian systems.

Graphic health warnings and plain packaging in the Philippines: results of online and household surveys.

In line with Article 11 of the WHO Framework Convention on Tobacco Control, the Philippines has implemented graphic health warnings on cigarette packs. To date, there has been no published literature evaluating the perceived effectiveness of GHWs in the Philippines. This study aims to contribute to the evidence on the perceived effects of graphic health warnings (GHWs) in cigarette packaging and the potential impact of plain packaging in the Philippines. The study involved an online convenience survey and a nationwide household survey. Mock-up sets of cigarette packs based on the Philippines' law on GHWs, and Thailand's and Singapore's plain packaging were shown to respondents to rate their attractiveness, quality, taste, cost, social appeal, appeal to youth, noticeability, appeal to non-smokers, attempt to quit, ease of quitting, discouraging smoking, and perceived harm to health on a five-point Lickert scale. The online and household surveys recruited 2,701 respondents in total. Online and household survey respondents considered plain packaging with larger graphic health warnings and visible quitlines from Thailand and Singapore to be more effective in discouraging them from smoking. Both sets of survey respondents also found mock-ups from Thailand and Singapore more motivating for them to attempt quitting than cigarette pack mock-ups from the Philippines. The study concludes that current graphic health warnings in the Philippines are ineffective in instilling health consciousness among Filipinos. Policymakers should consider larger graphic health warnings and plain packaging of cigarettes to motivate smokers to quit and discourage Filipinos from smoking.

Association of copper-zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele.

BACKGROUND: A common and severe neural tube defect (NTD) phenotype, myelomeningocele (MM), results from the defective closure of the caudal end of the neural tube with herniation of the spinal cord and meninges through the vertebral column. The exact mechanisms for NTDs are unknown, but excessive oxidative stress, particularly in association with maternal diabetes, has been postulated as a mechanism for MM. METHODS: The SNPlex Genotyping (ABI, Foster City, CA) platform was used to investigate single nucleotide polymorphisms (SNPs) across the superoxide dismutase (SOD) 1 and 2 genes to assess their association with MM risk. The study population included 329 trio (affected child and both parents) and 281 duo (affected child and one parent) families. Only cases with documented MM were studied. Seventeen SNPs across the SOD1 and SOD2 genes met the quality-control criteria to be considered for statistical analysis. Genetic association was assessed using the family-based transmission disequilibrium test in PLINK (a genome association analysis toolset). RESULTS: Four SNPs in the SOD1 gene (rs 202446, rs202447, rs4816405, and rs2070424) and one SNP in the SOD2 gene ( rs5746105) [corrected] appeared to be associated with MM risk in our population. After adjusting for multiple testing, these SNPs remained significant. CONCLUSION: This study provides the first genetic evidence to support association of myelomeningocele with superoxide scavenging. The rare alleles of the five specific SNPs within SOD1 and SOD2 appear to confer a protective effect on the susceptibility for MM risk in the MM population tested. Further evaluation of the roles of superoxide scavenging and neural tube development is warranted.

Pain catastrophising, body mass index and depressive symptoms are associated with pain severity in tertiary referral orthopaedic foot/ankle patients.

INTRODUCTION: Patients with chronic foot/ankle pain are often referred for orthopaedic assessment. Psychological vulnerabilities influence pain states (including foot and ankle), therefore this study aimed to establish the prevalence and relative importance of compromised psychological health to perceived foot/ankle pain severity in people referred to an orthopaedic foot and ankle clinic with non-urgent presentations. METHODS: Patients with triaged non-urgent foot/ankle referrals to the Department of Orthopaedics at Gold Coast University Hospital were recruited over a 12-month period and completed the Manchester-Oxford Foot and Ankle Questionnaire which was the primary measure. Participants also completed questionnaires assessing their anthropometric, demographic and health characteristics (Self-Administered Comorbidity Questionnaire) as well as measures of health-related quality of life (EuroQol-5-Dimensions-5-Level Questionnaire and EQ Visual Analogue Scale) and psychological health (Center for Epidemiological Studies-Depression scale, Pain Catastrophizing Scale and Central Sensitization Inventory). Descriptive statistics were used to summarise participant characteristics and a hierarchical multiple linear regression was employed to establish the extent to which psychological variables explain additional variance in foot/ankle pain severity beyond the effects of participant characteristics (age, sex, body mass index (BMI)). RESULTS: One hundred and seventy-two adults were recruited ((64.0% female), median (IQR) age 60.9 (17.7) years and BMI 27.6 (7.5) kg/m2). Specific psychological comorbidities were prevalent including depressive symptoms (48%), central sensitisation (38%) and pain catastrophising (24%). Age, sex and BMI accounted for 11.7% of the variance in MOXFQ-index and psychological variables accounted for an additional 28.2%. Pain catastrophising was the most significant independent predictor of foot/ankle pain severity (accounting for 14.4% of variance), followed by BMI (10.7%) and depressive symptoms (2.3%). CONCLUSIONS: This study demonstrated that specific psychological comorbidities and increased BMI are common in this cohort and that these factors are associated with the symptoms for which patients are seeking orthopaedic assessment. This knowledge should prompt clinicians to routinely consider the psychosocial components of patient presentations and develop non-operative and pre-operative treatment strategies which consider these factors with the goal of improving overall patient outcomes.

Association of retinoic acid receptor genes with meningomyelocele.

BACKGROUND: Neural tube defects (NTDs) occur in as many as 0.5-2 per 1000 live births in the United States. One of the most common and severe neural tube defects is meningomyelocele (MM) resulting from failed closure of the caudal end of the neural tube. MM has been induced by retinoic acid teratogenicity in rodent models. We hypothesized that genetic variants influencing retinoic acid (RA) induction via retinoic acid receptors (RARs) may be associated with risk for MM. METHODS: We analyzed 47 single nucleotide polymorphisms (SNPs) that span across the three retinoic acid receptor genes using the SNPlex genotyping platform. Our cohort consisted of 610 MM families. RESULTS: One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and a single variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05. CONCLUSION: RAR genes were associated with risk for MM. For all associated SNPs, the rare allele conferred a protective effect for MM susceptibility.

Long-term culture of SH-SY5Y neuroblastoma cells in the absence of neurotrophins: A novel model of neuronal ageing.

BACKGROUND: Studying human ageing is of increasing importance due to the worldwide ageing population. However, it faces the challenge of lengthy experiments to produce an ageing phenotype. Often, to recreate the hallmarks of ageing requires complex empirical conditions that can confound data interpretation. Indeed, many studies use whole organisms with relatively short life spans, which may have little, or limited, relevance to human ageing. There has been extensive use of cell lines to study ageing in human somatic cells, but the modelling of human neuronal ageing is somewhat more complex in vitro. NEW METHOD: We cultured the well-characterised SH-SY5Y human neural cell line to produce high purity cultures of cells differentiated to express a neuronal phenotype, and designed a protocol to maintain these cells in culture until they accumulated biomarkers of cellular ageing. RESULTS: Our data validate a novel and simple technique for the efficient differentiation and long-term maintenance of SH-SY5Y cells, expressing markers of neuronal differentiation and demonstrating electrical activity in culture. Over time in vitro, these cells progressively accumulate markers of ageing such as enhanced production of reactive oxygen species and accumulation of oxidative damage. COMPARISON TO EXISTING METHODS: In comparison to existing techniques to model neuronal ageing our method is cost effective, requiring no specialist equipment or growth factors. CONCLUSIONS: We demonstrate that SH-SY5Y cells, grown under these culture conditions, represent a simple model of neuronal ageing that is amenable to cell biological, biochemical and electrophysiological investigation.

Association of folate receptor (FOLR1, FOLR2, FOLR3) and reduced folate carrier (SLC19A1) genes with meningomyelocele.

BACKGROUND: Meningomyelocele (MM) results from lack of closure of the neural tube during embryologic development. Periconceptional folic acid supplementation is a modifier of MM risk in humans, leading toan interest in the folate transport genes as potential candidates for association to MM. METHODS: This study used the SNPlex Genotyping (ABI, Foster City, CA) platform to genotype 20 single polymorphic variants across the folate receptor genes (FOLR1, FOLR2, FOLR3) and the folate carrier gene (SLC19A1) to assess their association to MM. The study population included 329 trio and 281 duo families. Only cases with MM were included. Genetic association was assessed using the transmission disequilibrium test in PLINK. RESULTS: A variant in the FOLR2 gene (rs13908), three linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987), and two variants in the SLC19A1 gene (rs1888530 and rs3788200) were statistically significant for association to MM in our population. CONCLUSION: This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to MM in the patient population that was tested.

Stroke awareness: surveillance, educational campaigns, and public health practice.

Stroke is a leading cause of death and disability in the United States. However, there is limited public knowledge about stroke signs and symptoms and the importance of seeking immediate medical care. Educational efforts such as stroke awareness campaigns are one way of informing the public about stroke symptoms and the need for early medical treatment following their onset. In this article, we present recent surveillance data concerning public awareness of stroke symptoms; summarize findings from 12 studies of the effectiveness of stroke awareness campaigns; and describe the efforts by three states to develop, implement, and evaluate heart disease and stroke programs, and the lessons to be learned from their experiences.

Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida.

OBJECTIVE: We tested putative functional single nucleotide polymorphisms (SNPs) in genes that regulate the folate/homocysteine metabolism pathway for their contribution to spina bifida (SB) susceptibility. STUDY DESIGN: The study consisted of 610 unrelated simplex SB patient families. Genotypes of 46 SNPs located in the coding sequence or promoter region of 11 genes were investigated. Associations between transmission of alleles and SB in the offspring were examined using the reconstruction combined transmission disequilibrium test. RESULTS: Significant association of SNP rs5742905 in cystathionine-beta-synthase, rs1643649 in dihydrofolate reductase, rs2853533 in thymidylate synthetase, and rs3737965 in methylenetetrahydrofolate reductase was found (P = .015, .041, .021, and .007 respectively). CONCLUSION: Transmission disequilibrium of SNP alleles in cystathionine-beta-synthase, dihydrofolate reductase, methylenetetrahydrofolate reductase, and thymidylate synthetase confers an increased susceptibility to SB.

Correction of rotational deformity of the pes with external skeletal fixation in four dogs.

OBJECTIVE: To report unilateral correction and initial stabilization with external skeletal fixation (ESF) of metatarsal rotation in 4 immature Bernese Mountain Dogs. STUDY DESIGN: Case series. ANIMALS: Bernese Mountain Dogs (n=4). METHODS: The limb deformity, including degree and origin of the deformity at the level of the proximal intertarsal joint and involvement of the central tarsal bone, was characterized by clinical and radiographic assessment. Unilateral surgical correction of the most severely affected limb was performed by disrupting the ligaments and debriding the articular cartilage of the proximal intertarsal joint to allow for derotation of the deformity and arthrodesis of the proximal intertarsal joint stabilized with either circular or linear ESF. RESULTS: Initial metatarsal rotation of the corrected limbs ranged from 60 degrees to 80 degrees of external rotation (mean, 72.5 degrees). Three limb corrections were stabilized with circular ESF and 1 with a biplanar linear ESF. Implants were removed at the time of radiographic bony union (range, 7-10 weeks; mean, 8.6 weeks). Residual deformity was minimal, ranging from 6 degrees to 15 degrees (mean, 11 degrees). Two minor complications (loosening of 1 pin, serous drainage from 1 pin) resolved with treatment. CONCLUSION: Correction of rotational deformity of the pes with intertarsal arthrodesis yielded an excellent clinical outcome, with only a mild residual deformity. CLINICAL RELEVANCE: Rotational metatarsal deformities can have a significant impact on gait, ambulation, and appearance. Correction of these deformities and stabilization with ESF and intratarsal arthrodesis can yield an excellent functional outcome, with improved gait and ambulation.

Developmental changes in the response of murine cerebellar granule cells to nitric oxide.

Nitric oxide is a diffusible messenger that plays a multitude of roles within the nervous system including modulation of cell viability. However, its role in regulating neuronal survival during a defined period of neurodevelopment has never been investigated. We discovered that expression of the messenger RNA for both neuronal and endothelial nitric oxide synthase increased in the early postnatal period in the cerebellum in vivo, whilst the expression of inducible nitric oxide synthase remained constant throughout this time in development. Whilst scavenging of nitric oxide was deleterious to the survival of early postnatal cerebellar granule neurons in vitro, this effect was lost in cultures derived at increasing postnatal ages. Conversely, sensitivity to exogenous nitric oxide increased with advancing postnatal age. Thus, we have shown that as postnatal development proceeds, cerebellar granule cells alter their in vitro survival responses to both nitric oxide inhibition and donation, revealing that the nitric oxide's effects on developing neurons vary with the stage of development studied. These findings have important consequences for our understanding of the role of nitric oxide during neuronal development.

Neurotrophic effects of leptin on cerebellar Purkinje but not granule neurons in vitro.

As recent evidence has revealed a pro-survival role for the anti-obesity hormone leptin in the nervous system, we investigated the generality of this finding on cerebellar Purkinje and granule neurons in vitro. We found that whilst leptin promoted cerebellar Purkinje neuron survival, it had no affect on cerebellar granule cells. In addition, we discovered that leptin promoted both the outgrowth of neurites from cerebellar Purkinje neurons and increased the complexity of the neurite arbor. Thus, leptin has different effects on two neighbouring populations of neurons within the cerebellum implying specificity of its actions in the central nervous system.

Characteristics of a spina bifida population including North American Caucasian and Hispanic individuals.

BACKGROUND: Meningomyelocele (MM) is a common human birth defect. MM is a disorder of neural development caused by contributions from genes and environmental factors that result in the NTD and lead to a spectrum of physical and neurocognitive phenotypes. METHODS: A multidisciplinary approach has been taken to develop a comprehensive understanding of MM through collaborative efforts from investigators specializing in genetics, development, brain imaging, and neurocognitive outcome. Patients have been recruited from five different sites: Houston and the Texas-Mexico border area; Toronto, Canada; Los Angeles, California; and Lexington, Kentucky. Genetic risk factors for MM have been assessed by genotyping and association testing using the transmission disequilibrium test. RESULTS: A total of 509 affected child/parent trios and 309 affected child/parent duos have been enrolled to date for genetic association studies. Subsets of the patients have also been enrolled for studies assessing development, brain imaging, and neurocognitive outcomes. The study recruited two major ethnic groups, with 45.9% Hispanics of Mexican descent and 36.2% North American Caucasians of European descent. The remaining patients are African-American, South and Central American, Native American, and Asian. Studies of this group of patients have already discovered distinct corpus callosum morphology and neurocognitive deficits that associate with MM. We have identified maternal MTHFR 667T allele as a risk factor for MM. In addition, we also found that several genes for glucose transport and metabolism are potential risk factors for MM. CONCLUSIONS: The enrolled patient population provides a valuable resource for elucidating the disease characteristics and mechanisms for MM development.

Neurotoxic effects of homocysteine on cerebellar Purkinje neurons in vitro.

Whilst a plethora of studies that describe the toxicity of homocysteine to CNS neurons have been published, the effects of homocysteine on the Purkinje neurons of the cerebellum that play a vital role in motor function remain wholly unexplored. We have therefore established cultures of embryonic cerebellar Purkinje neurons and exposed them to a range of concentrations of homocysteine and determined its effects on their survival. The experiments revealed that all concentrations of homocysteine studied, from 50 to 500microM, caused a significant decrease in cerebellar Purkinje neuron number. This loss could be counteracted by the pan-caspase inhibitor z-VAD-fmk in the first 24h following homocysteine exposure, revealing that the initial loss was apoptotic. However, z-VAD-fmk could not prevent homocysteine-mediated loss of cerebellar Purkinje neurons in the longer term, after 6 days in vitro. In addition to its effects on Purkinje neuron survival, homocysteine markedly reduced both the overall magnitude and the complexity of the neurite arbor extended by the cerebellar Purkinje neurons, following 6 days incubation with this agent in vitro. Taken together our data reveal that homocysteine is toxic to cerebellar Purkinje neurons in vitro, inhibiting both their survival and the outgrowth of neurites.

Validity of goniometric joint measurements in cats.

OBJECTIVE: To compare and validate goniometric joint measurements obtained from nonsedated and sedated cats with measurements from radiographic evaluation. ANIMALS: 20 adult cats with no evidence of joint disease. PROCEDURES: Measurements of flexion and extension of the carpus, elbow, shoulder, tarsus, stifle, and hip joints and of carpal and tarsal joints during varus and valgus angulation were made by a single investigator before and after sedation of cats. Measurements were made by use of a goniometer with a masked dial. Joint angle measurements were compared between nonsedated and sedated cats and also with measurements from radiographs made while cats were sedated. Each series of measurements was repeated 4 times. To evaluate repeatability, Cronbach alpha values were calculated for repeated measure results of goniometric joint measurements of nonsedated and sedated cats. An intraclass correlation was calculated to determine reliability among the 3 measurement types (ie, measurements from nonsedated and sedated cats and on radiographic evaluation). RESULTS: Joint measurements did not differ significantly by measurement type, when comparing radiographic measurements with goniometric measurements in sedated and nonsedated cats. Cronbach alpha values were > 0.99 for goniometric joint measurements within individual nonsedated and sedated cats and also for comparison of mean measurements obtained from sedated cats versus nonsedated cats versus radiographs. An intraclass correlation of 0.999 revealed high reliability among measurement types. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that goniometric joint measurements in nonsedated and sedated cats are repeatable and valid.

Mucositis pain induced by radiation therapy: prevalence, severity, and use of self-care behaviors.

Pain from radiation therapy (RT)-induced mucositis is a significant clinical problem for patients with head and neck cancer (HNC). The purpose of this study was to determine the pattern, severity, and time course of RT-induced mucositis pain; self-care behaviors (SCBs) used to manage mucositis pain; and the effectiveness of these behaviors in relieving such pain. Forty-nine patients with HNC were assessed using the MacDibbs Mouth Assessment Tool to determine the severity of RT-induced mucositis pain over their course of RT and at a one-month follow-up visit. All patients developed pain due to RT-induced mucositis. A Self-Care Diary was used weekly by patients to record SCBs and their effectiveness. The most effective SCBs for RT-induced mucositis pain were mouth rinsing and using oral analgesics. However, more severe pain with swallowing was not managed well throughout the study. Future studies need to test more effective strategies to manage RT-induced mucositis pain.

Embryonic cerebellar granule cells are resistant to necrosis induced by homocysteine.

Hyperhomocysteinemia is a risk factor for a range of neurodegenerative conditions, yet its effects in the developing nervous system have been poorly elucidated. We studied the in vitro response of cerebellar granule neurons (CGCs) to homocysteine. We have shown that embryonic CGCs are resistant to homocysteine-induced neurotoxicity, whilst postnatal CGCs are not. This is the first demonstration of a neuronal population undergoing a developmental switch in their response to homocysteine. Greater understanding of this change may have important implications for both neurodegenerative conditions and neurodevelopmental disorders.

Use of hinged transarticular external fixation for adjunctive joint stabilization in dogs and cats: 14 cases (1999-2003).

OBJECTIVES: To describe placement of hinged transarticular external fixation (HTEF) frames and evaluate their ability to protect the primary repair of unstable joints while allowing joint mobility in dogs and cats. DESIGN: Retrospective study. ANIMALS: 8 cats and 6 dogs. PROCEDURE: HTEF frames were composed of metal or epoxy connecting rods and a hinge. Measurements of range of motion of affected and contralateral joints and radiographs were made after fixator application and removal. RESULTS: 9 animals (4 cats and 5 dogs) had tarsal and 5 (4 cats and 1 dog) had stifle joint injuries. Treatment duration ranged from 45 to 100 days (median, 57 days). Ranges of motion in affected stifle and tarsal joints were 57% and 72% of control while HTEF was in place and 79% and 84% of control after frame removal. Complications were encountered in 3 cats and 2 dogs and included breakage of pins and connecting rods, hinge loosening, and failure at the hinge-epoxy interface. CONCLUSIONS AND CLINICAL RELEVANCE: HTEF in animals with traumatic joint instability provided adjunctive joint stabilization during healing and protection of the primary repair and maintained joint motion during healing, resulting in early weight bearing of the affected limb.

An overview of the global HIV/AIDS epidemic, with a focus on the United States.

The HIV/AIDS epidemic is a global human tragedy, especially in sub-Saharan Africa. The pandemic affects people in the primer of their lives moving from at-risk populations to broader cross-sections of society. There have been more than 47 million adults and children infected since the beginning of the epidemic, and more than 18.8 million people have died. Over 95% of the global total of all AIDS cases are in the developing world, with prevalence among adults at less than 1% in India and Europe, to more than 10% in several African countries. The overwhelming majority of all infections globally are acquired through unprotected sexual intercourse, with at least 70% resulting from heterosexual intercourse. There have been more than 733,374 AIDS cases reported to the Centers for Disease Control and Prevention (CDC) in the US since the beginning of the epidemic, and more than 430,000 deaths. The largest number and proportion of AIDS cases reported have occurred among gay and bisexual men. This trend continues today, although racial and ethnic minorities, women, and youth are becoming infected in increasing proportions. The south has the most people living with AIDS, followed by the north-east. The global situation is improving in some areas, but even if all HIV transmission could be completely stopped tomorrow, the long-term health, social and economic consequences will be devastating well into the 21st century. The magnitude of the epidemic and the continuing explosive risk of infection, coupled with the economic and infrastructural realities of the regions of the world, make prevention the only realistic approach.