Molluscan memory of injury: evolutionary insights into chronic pain and neurological disorders.

Molluscan preparations have yielded seminal discoveries in neuroscience, but the experimental advantages of this group have not, until now, been complemented by adequate molecular or genomic information for comparisons to genetically defined model organisms in other phyla. The recent sequencing of the transcriptome and genome of Aplysia californica, however, will enable extensive comparative studies at the molecular level. Among other benefits, this will bring the power of individually identifiable and manipulable neurons to bear upon questions of cellular function for evolutionarily conserved genes associated with clinically important neural dysfunction. Because of the slower rate of gene evolution in this molluscan lineage, more homologs of genes associated with human disease are present in Aplysia than in leading model organisms from Arthropoda (Drosophila) or Nematoda (Caenorhabditis elegans). Research has hardly begun in molluscs on the cellular functions of gene products that in humans are associated with neurological diseases. On the other hand, much is known about molecular and cellular mechanisms of long-term neuronal plasticity. Persistent nociceptive sensitization of nociceptors in Aplysia displays many functional similarities to alterations in mammalian nociceptors associated with the clinical problem of chronic pain. Moreover, in Aplysia and mammals the same cell signaling pathways trigger persistent enhancement of excitability and synaptic transmission following noxious stimulation, and these highly conserved pathways are also used to induce memory traces in neural circuits of diverse species. This functional and molecular overlap in distantly related lineages and neuronal types supports the proposal that fundamental plasticity mechanisms important for memory, chronic pain, and other lasting alterations evolved from adaptive responses to peripheral injury in the earliest neurons. Molluscan preparations should become increasingly useful for comparative studies across phyla that can provide insight into cellular functions of clinically important genes.

BMP-SIGNALING REGULATES A COMMON TRANSCRIPTIONAL PROGRAM TO CONTROL FACIAL FORM AND SKELETAL MORPHOGENESIS

Much of the craniofacial skeleton, such as the skull vault, mandible and midface, develops through direct, intramembranous ossification of the cranial neural crest (CNC) derived progenitor cells. Bmp-signaling plays critical roles in normal craniofacial development, and Bmp4 deficiency results in craniofacial abnormalities, such as cleft lip and palate. We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in the CNC. Conditional Bmp4 overexpression, using a tetracycline regulated Bmp4 gain of function allele, resulted in facial form changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4 induced genes (BIG) composed predominantly of transcriptional regulators controlling self-renewal, osteoblast differentiation, and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4, and Bmp7, resulted in complete or partial loss of multiple CNC derived skeletal elements revealing a critical requirement for Bmp-signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss of function mutants indicating similar Bmp-regulated target genes underlying facial form modulation and normal skeletal morphogenesis. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45g and Gata3 that was bound by Smad1/5 in the developing mandible revealing direct, Smad-mediated regulation. These data indicate that Bmp-signaling regulates craniofacial skeletal development and facial form by balancing self-renewal and differentiation pathways in CNC progenitors.

Epidemiology of Acute Lung Injury and Acute Respiratory Distress Syndrome in children in Vietnam

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are life- threatening disorders that can result from many severe conditions and diseases. Since the American European Consensus Conference established the internationally accepted definition of ALI and ARDS, the epidemiology of pediatric ALI/ARDS has been described in some developed countries. In the developing world, however, there are very few data available regarding the burden, etiologies, management, outcome, and factors associated with outcomes of ALI/ARDS in children. ^ Therefore, we conducted this observational, clinical study to estimate the prevalence and case mortality rate of ALI/ARDS among a cohort of patients admitted to the pediatric intensive care unit (PICU) of the National Hospital of Pediatrics in Hanoi, the largest children's hospital in Vietnam. Etiologies and predisposing factors, and management strategies for pediatric ALI/ARDS were described. In addition, we determined the prevalence of HIV infection among children with ALI/ARDS in Vietnam. We also identified the causes of mortality and predictors of mortality and prolonged mechanical ventilation of children with ALI/ARDS. ^ A total of 1,051 patients consecutively admitted to the pediatric intensive care unit from January 2011 to January 2012 were screened daily for development of ALI/ARDS using the American-European Consensus Conference Guidelines. All identified patients with ALI/ARDS were followed until hospital discharge or death in the hospital. Patients' demographic and clinical data were collected. Multivariable logistic regression models were developed to identify independent predictors of mortality and other adverse outcome of ALI/ARDS. ^ Prevalence of ALI and ARDS was 9.6% (95% confidence interval, 7.8% to 11.4%) and 8.8% (95% confidence interval, 7.0% to 10.5%) of total PICU admissions, respectively. Infectious pneumonia and sepsis were the most common causes of ALI/ARDS accounting for 60.4% and 26.7% of cases, respectively. Prevalence of HIV infection among children with ALI/ARDS was 3.0%. The case fatality rate of ALI/ARDS was 63.4% (95% confidence interval, 53.8% to 72.9%). Multiple organ failure and refractory hypoxemia were the main causes of death. Independent predictors of mortality and prolonged mechanical ventilation were male gender, duration of intensive care stay prior to ALI/ARDS diagnosis, level of oxygenation defect measured by PaO2/FiO2 ratio at ALI/ARDS diagnosis, presence of non-pulmonary organ dysfunction at day one and day three after ALI/ARDS diagnosis, and presence of hospital acquired infection. ^ The results of this study demonstrated that ALI/ARDS was a common and severe condition in children in Vietnam. The level of both pulmonary and non-pulmonary organ damage influenced survival of patients with ALI/ARDS. Strategies for preventing ALI/ARDS and for clinical management of the disease are necessary to reduce the associated risks.^

Dengue transmission risk maps of the continental United States

Dengue fever is a strictly human and non-human primate disease characterized by a high fever, thrombocytopenia, retro-orbital pain, and severe joint and muscle pain. Over 40% of the world population is at risk. Recent re-emergence of dengue outbreaks in Texas and Florida following the re-introduction of competent Aedes mosquito vectors in the United States have raised growing concerns about the potential for increased occurrences of dengue fever outbreaks throughout the southern United States. Current deficiencies in vector control, active surveillance and awareness among medical practitioners may contribute to a delay in recognizing and controlling a dengue virus outbreak. Previous studies have shown links between low-income census tracts, high population density, and dengue fever within the United States. Areas of low-income and high population density that correlate with the distribution of Aedes mosquitoes result in higher potential for outbreaks. In this retrospective ecologic study, nine maps were generated to model U.S. census tracts’ potential to sustain dengue virus transmission if the virus was introduced into the area. Variables in the model included presence of a competent vector in the county and census tract percent poverty and population density. Thirty states, 1,188 counties, and 34,705 census tracts were included in the analysis. Among counties with Aedes mosquito infestation, the census tracts were ranked high, medium, and low risk potential for sustained transmission of the virus. High risk census tracts were identified as areas having the vector, ≥20% poverty, and ≥500 persons per square mile. Census tracts with either ≥20% poverty or ≥500 persons per square mile and have the vector present are considered moderate risk. Census tracts that have the vector present but have <20% poverty and <500 persons per square mile are considered low risk. Furthermore, counties were characterized as moderate risk if 50% or more of the census tracts in that county were rated high or moderate risk, and high risk if 25% or greater were rated high risk. Extreme risk counties, which were primarily concentrated in Texas and Mississippi, were considered having 50% or greater of the census tracts ranked as high risk. Mapping of geographic areas with potential to sustain dengue virus transmission will support surveillance efforts and assist medical personnel in recognizing potential cases. ^

Eye Movement Measures of Cognitive Control in Children with Tourette Syndrome

Tourette Syndrome begins in childhood and is characterized by uncontrollable repetitive actions like neck craning or hopping and noises such as sniffing or chirping. Worst in early adolescence, these tics wax and wane in severity and occur in bouts unpredictably, often drawing unwanted attention from bystanders. Making matters worse, over half of children with Tourette Syndrome also suffer from comorbid, or concurrent, disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). These disorders introduce anxious thoughts, impulsivity, inattention, and mood variability that further disrupt children with Tourette Syndrome from focusing and performing well at school and home. Thus, deficits in the cognitive control functions of response inhibition, response generation, and working memory have long been ascribed to Tourette Syndrome. Yet, without considering the effect of medication, age, and comorbidity, this is a premature attribution. This study used an infrared eye tracking camera and various computer tasks requiring eye movement responses to evaluate response inhibition, response generation, and working memory in Tourette Syndrome. This study, the first to control for medication, age, and comorbidity, enrolled 39 unmedicated children with Tourette Syndrome and 29 typically developing peers aged 10-16 years who completed reflexive and voluntary eye movement tasks and diagnostic rating scales to assess symptom severities of Tourette Syndrome, ADHD, and OCD. Children with Tourette Syndrome and comorbid ADHD and/or OCD, but not children with Tourette Syndrome only, took longer to respond and made more errors and distracted eye movements compared to typically-developing children, displaying cognitive control deficits. However, increasing symptom severities of Tourette Syndrome, ADHD, and OCD correlated with one another. Thus, cognitive control deficits were not specific to Tourette Syndrome patients with comorbid conditions, but rather increase with increasing tic severity, suggesting that a majority of Tourette Syndrome patients, regardless of a clinical diagnosis of ADHD and/or OCD, have symptoms of cognitive control deficits at some level. Therefore, clinicians should evaluate and counsel all families of children with Tourette Syndrome, with or without currently diagnosed ADHD and/or OCD, about the functional ramifications of comorbid symptoms and that they may wax and wane with tic severity.

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient's age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response.

Back pain in migrant farmworker families and farmworker high school students from Starr County, Texas

Back symptoms are a major global public health problem with the lifetime prevalence ranging between 50-80%. Research suggests that work-related factors contribute to the occurrence of back pain in various industries. Despite the hazardous nature, strenuous tasks, and awkward postures associated with farm work, little is known about back injury and symptoms in farmworker adults and children. Research in the United States is particularly limited. This is a concern given the large proportion of migrant farmworkers in the United States without adequate access to healthcare as well as a substantial number of youth working in agriculture. The present study describes back symptoms and identifies work-related factors associated with back pain in migrant farmworker families and farmworker high school students from Starr County, TX. Two separate datasets were used from two cohort studies "Injury and Illness Surveillance in Migrant Farmworkers (MANOS)" (study A: n=267 families) and "South Texas Adolescent Rural Research Study (STARRS)" (study B: n=345). Descriptive and inferential statistics including multivariable logistic regression were used to identify work-related factors associated with back pain in each study. In migrant farmworker families, the prevalence of chronic back pain during the last migration season ranged from 9.5% among youngest children to 33.3% among mothers. Chronic back pain was significantly associated with increasing age; fairly bad/very bad quality of sleep while migrating; fewer than eight hours of sleep at home in Starr County, TX; depressive symptoms while migrating; self-provided water for washing hands/drinking; weeding at work; and exposure to pesticide drift/direct spray. Among farmworker adolescents, the prevalence of severe back symptoms was 15.7%. Severe back symptoms were significantly associated with being female; history of a prior accident/back injury; feeling tense, stressed, or anxious sometimes/often; lifting/carrying heavy objects not at work; current tobacco use; increasing lifetime number of migrant farmworker years; working with/around knives; and working on corn crops. Overall, results support that associations between work-related exposures and chronic back pain and severe back symptoms remain after controlling for the effect of non-work exposures in farmworker populations. ^

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

Frequency, severity and distress of dialysis-related symptoms reported by patients on hemodialysis

Purpose. To determine which symptoms are the most reported, occur most frequently, have the greatest severity, and cause the most bother for hemodialysis (HD) patients and to determine if the symptoms experienced differ between the first (HD 1) and second (HD 2) treatments of the week. ^ Design. An observational, comparative design was used to determine participants' HD symptoms experience on HD 1 and HD 2, and the effect of the symptom experience on Quality of Life (QOL). One hundred subjects were recruited from five dialysis centers. ^ Methods. The adapted Dialysis Frequency, Severity and Symptom Burden Index (DFSSBI) and the Medical Outcomes Study Short Form 36 (MOS SF 36) were administered (N = 99) on HD 1 and the DFSSBI again on HD 2. Data were analyzed for significance among symptoms experience test scores in relation to HD 1 and HD 2, QOL, and gender and age. ^ Results. Of 31 symptoms assessed, respondents reported an average of 9.69 symptoms on HD 1 and 7.51 symptoms on HD 2. Overall, more symptoms were reported, and were more frequent, severe and bothersome on HD 1 when the level of metabolic waste is highest. The most reported symptoms included tiredness, dry skin, difficulty falling asleep, itching, numbness/tingling, difficulty staying asleep, decreased interest in sex, and bone/joint pain. Females scored consistently higher than males in the four symptom dimensions. The respondents reported about the same as the population norm (50) on the physical component summary score of the MOS SF 36 and higher than the norm (65.23) on the mental component summary score. ^ Conclusion. The study findings highlighted the fact that hemodialysis patients experience multiple symptoms that can be frequent, severe, and bothersome. Interventions should be developed and tested to reduce symptom burden and improve QOL. ^

A methodologic study of pain assessment in Anglo and Hispanic children with cancer

There is growing clinical evidence that even young children experience pain and accompanying anxiety. Few instruments have been validated to assess pain characteristics in children. The study of related demographic, illness, psychologic and parental factors in children has also been limited. This study examines the reliability and validity of pain assessment tools in an outpatient pediatric cancer population. A total of 78 children from three to fifteen years of age were observed and interviewed about the pain of invasive procedures. The effect of cultural factors and the stress of acculturation were examined by comparing data from two cultural groups, Anglo and Hispanic.^ Spielberger State-Trait Anxiety Scales were administered to children and parents prior to an invasive procedure. The Procedure Behavioral Checklist (PBCL) was used for observation of the child's response during the procedure. The Children's Procedural Interview (CPI) which contains items on the PBCL and visual analogues (scales of faces indicating varying degrees of pain and anxiety) was administered following the procedure.^ Reliability coefficients for Anglos were.78 on the PBCL,.79 on the CPI and.85 on the visual analogue scales. For Hispanics, the reliability for the PBCL was.54, while the CPI had a reliability of.72 and the visual analogue scales,.87. Construct validity was demonstrated by high correlations between the PBCL and CPI scores for both ethnic groups (.66 for Anglos and.64 for Hispanics) and by the significant correlation of State anxiety scores with both PBCL and CPI scores. Age was inversely correlated with PBCL and CPI scores for both ethnic groups. Hispanic parents' anxiety scores were higher than Anglo parents, but were not highly correlated with their child's PBCL, CPI or State-Trait anxiety scores. Caregivers' ratings were correlated with the PBCL scores for Anglos but not for Hispanics.^ The findings of this study indicate that pain responses may be reliably assessed using both observational and self-report methods in children, though differences in Anglo and Hispanic cultures exist. Differences in pain symptomatology and assessment in the two cultural groups warrant further study. ^