Shorter Telomere Length Is Associated With Older Age, Poor Sleep Hygiene, and Orthopedic Injury, but Not Mild Traumatic Brain Injury, in a Cohort of Canadian Children.

BACKGROUND: Predicting recovery following pediatric mild traumatic brain injury (mTBI) remains challenging. The identification of objective biomarkers for prognostic purposes could improve clinical outcomes. Telomere length (TL) has previously been used as a prognostic marker of cellular health in the context of mTBI and other neurobiological conditions. While psychosocial and environmental factors are associated with recovery outcomes following pediatric mTBI, the relationship between these factors and TL has not been investigated. This study sought to examine the relationships between TL and psychosocial and environmental factors, in a cohort of Canadian children with mTBI or orthopedic injury (OI). METHODS: Saliva was collected at a postacute (median 7 days) timepoint following injury to assess TL from a prospective longitudinal cohort of children aged 8 to 17 years with either mTBI (n = 202) or OI (n = 90), recruited from 3 Canadian sites. Questionnaires regarding psychosocial and environmental factors were obtained at a postacute follow-up visit and injury outcomes were assessed at a 3-month visit. Univariable associations between TL and psychosocial, environmental, and outcome variables were assessed using Spearman's correlation. Further adjusted analyses of these associations were performed by including injury group, age, sex, and site as covariates in multivariable generalized linear models with a Poisson family, log link function, and robust variance estimates. RESULTS: After adjusting for age, sex, and site, TL in participants with OI was 7% shorter than those with mTBI (adjusted mean ratio = 0.93; 95% confidence interval, 0.89-0.98; P = .003). As expected, increasing age was negatively associated with TL (Spearman's r = -0.14, P = .016). Sleep hygiene at 3 months was positively associated with TL (adjusted mean ratio = 1.010; 95% confidence interval, 1.001-1.020; P = .039). CONCLUSION: The relationships between TL and psychosocial and environmental factors in pediatric mTBI and OI are complex. TL may provide information regarding sleep quality in children recovering from mTBI or OI; however, further investigation into TL biomarker validity should employ a noninjured comparison group.

Comparative analysis in continuous expansion of bovine and human primary nucleus pulposus cells for tissue repair applications.

Autologous NP cell implantation is a potential therapeutic avenue for intervertebral disc (IVD) degeneration. However, monolayer expansion of cells isolated from surgical samples may negatively impact matrix production by way of dedifferentiation. Previously, we have used a continuous expansion culture system to successfully preserve a chondrocyte phenotype. In this work, we hypothesised that continuous expansion culture could also preserve nucleus pulposus (NP) phenotype. We confirmed that serial passaging drove NP dedifferentiation by significantly decreasing collagen type II, aggrecan and chondroadherin (CHAD) gene expression, compared to freshly isolated cells. Proliferation, gene expression profile and matrix production in both culture conditions were compared using primary bovine NP cells. Both standard culture and continuous culture produced clinically relevant cell populations. However, continuous culture cells maintained significantly higher collagen type II, aggrecan and CHAD transcript expression levels. Also, continuous expansion cells generated greater amounts of proteoglycan, collagen type II and aggrecan protein deposition in pellet cultures. To our surprise, continuous expansion of human intervertebral disc cells - isolated from acute herniation tissue - produced less collagen type II, aggrecan and CHAD genes and proteins, compared to standard culture. Also, continuous culture of cells isolated from young non-degenerate tissue did not preserve gene and protein expression, compared to standard culture. These data indicated that primary bovine and human NP cells responded differently to continuous culture, where the positive effects observed for bovine cells did not translate to human cells. Therefore, caution must be exercised when choosing animal models and cell sources for pre-clinical studies.

Imidazolium and benzimidazolium-containing compounds: from simple toxic salts to highly bioactive drugs.

The toxicity of simple imidazolium and benzimidazolium salts started to be more and more investigated in the last few years and was taken in consideration in the context of microorganisms, plants and more evolved organisms' exposure. However, the toxicity of these salts can be exploited in the development of different biological applications by incorporating them in the structure of compounds that specifically target microorganisms and cancer cells. We highlight in this minireview the way researchers became aware of the inherent problem of the stability and bioaccumulation of imidazolium and benzimidazolium salts and how they found inspiration to exploit their toxicity by incorporating them into new highly potent drugs.

Modulation of respiratory activity by locomotion in lampreys.

In vertebrates, locomotion is associated with changes in respiratory activity, but the neural mechanisms by which this occurs remain unknown. We began examining this in lampreys using a semi-intact preparation of young adult Petromyzon marinus, in which respiratory and locomotor behaviors can be recorded simultaneously with the activity of the underlying neural control systems. Spontaneous fictive respiration was recorded with suction electrodes positioned over the glossopharyngeal or the rostral vagal motor nucleus. In this preparation, locomotor activity, characterized by symmetrical tail movements (electromyogram recordings), was evoked by mechanical stimulation of the skin. During locomotion, the mean respiratory frequency and the mean area of the motor bursts were significantly increased (81.6+/-28.6% and 62.8+/-25.4%, respectively; P<0.05). The frequency returned to normal 92+/-51 s after the end of locomotion. There were fluctuations in the instantaneous respiratory and locomotor frequencies that were rhythmical but antiphasic for the two rhythmic activities. The changes in respiratory activity were also examined during bouts of locomotion occurring spontaneously, and it was found that a modification in respiratory activity preceded the onset of spontaneous locomotion by 3.5+/-2.6 s. This suggests that the early respiratory changes are anticipatory and are not caused by feedback generated by locomotion. The increase in respiratory frequency during locomotion induced by sensory stimulation persisted after removal of the mesencephalon. When both the mesencephalon and spinal cord were removed, resulting in the isolation of the rhombencephalon, changes in the respiratory activity were also present following skin stimulations that would have normally induced locomotion. Altogether, the results suggest that respiratory changes are programmed to adjust ventilation prior to motor activity, and that a central rhombencephalic mechanism is involved.

Respiratory rhythms generated in the lamprey rhombencephalon.

Brainstem networks generating the respiratory rhythm in lampreys are still not fully characterized. In this study, we described the patterns of respiratory activities and we identified the general location of underlying neural networks. In a semi-intact preparation including the brain and gills, rhythmic discharges were recorded bilaterally with surface electrodes placed over the vagal motoneurons. The main respiratory output driving rhythmic gill movements consisted of short bursts (40.9+/-15.6 ms) of discharge occurring at a frequency of 1.0+/-0.3 Hz. This fast pattern was interrupted by long bursts (506.3+/-174.6 ms) recurring with an average period of 37.4+/-24.9 s. After isolating the brainstem by cutting all cranial nerves, the frequency of the short respiratory bursts did not change significantly, but the slow pattern was less frequent. Local injections of a glutamate agonist (AMPA) and antagonists (6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or D,L-amino-5-phosphonopentanoic acid (AP5)) were made over different brainstem regions to influence respiratory output. The results were similar in the semi-intact and isolated-brainstem preparations. Unilateral injection of AP5 or CNQX over a rostral rhombencephalic region, lateral to the rostral pole of the trigeminal motor nucleus, decreased the frequency of the fast respiratory rhythm bilaterally or stopped it altogether. Injection of AMPA at the same site increased the rate of the fast respiratory rhythm and decreased the frequency of the slow pattern. The activity recorded in this area was synchronous with that recorded over the vagal motoneurons. After a complete transverse lesion of the brainstem caudal to the trigeminal motor nucleus, the fast rhythm was confined to the rostral area, while only the slow activity persisted in the vagal motoneurons. Our results support the hypothesis that normal breathing depends on the activity of neurons located in the rostral rhombencephalon in lampreys, whereas the caudal rhombencephalon generates the slow pattern.

Alphaherpesvirus-associated disease in greater bilbies (Macrotis lagotis).

CASE REPORT: A captive breeding colony of 9 greater bilbies (Macrotis lagotis) exhibited mild upper respiratory signs and sudden deaths with 100% mortality over a 2-week period. Histologically, acute necrotising and erosive epithelial lesions throughout the upper respiratory system and bronchi were associated with eosinophilic intranuclear inclusion bodies. Inclusions were also present in hepatocytes and adrenocortical cells, but were not always associated with necrosis. Transmission electron microscopy of lung sections revealed nucleocapsids forming arrays within some nuclei. A pan-herpesvirus PCR yielded a 440-bp product, with sequencing confirming homology with the alphaherpesviruses. Viral culture in a marsupial cell line resulted in cytopathic effect consistent with an alphaherpesvirus. CONCLUSION: This is the first report of a herpesvirus-associated disease in greater bilbies.

Effects of exposure to Bovine viral diarrhoea virus 1 on risk of bovine respiratory disease in Australian feedlot cattle.

Viruses play a key role in the complex aetiology of bovine respiratory disease (BRD). Bovine viral diarrhoea virus 1 (BVDV-1) is widespread in Australia and has been shown to contribute to BRD occurrence. As part of a prospective longitudinal study on BRD, effects of exposure to BVDV-1 on risk of BRD in Australian feedlot cattle were investigated. A total of 35,160 animals were enrolled at induction (when animals were identified and characteristics recorded), held in feedlot pens with other cattle (cohorts) and monitored for occurrence of BRD over the first 50days following induction. Biological samples collected from all animals were tested to determine which animals were persistently infected (PI) with BVDV-1. Data obtained from the Australian National Livestock Identification System database were used to determine which groups of animals that were together at the farm of origin and at 28days prior to induction (and were enrolled in the study) contained a PI animal and hence to identify animals that had probably been exposed to a PI animal prior to induction. Multi-level Bayesian logistic regression models were fitted to estimate the effects of exposure to BVDV-1 on the risk of occurrence of BRD. Although only a total of 85 study animals (0.24%) were identified as being PI with BVDV-1, BVDV-1 was detected on quantitative polymerase chain reaction in 59% of cohorts. The PI animals were at moderately increased risk of BRD (OR 1.9; 95% credible interval 1.0-3.2). Exposure to BVDV-1 in the cohort was also associated with a moderately increased risk of BRD (OR 1.7; 95% credible interval 1.1-2.5) regardless of whether or not a PI animal was identified within the cohort. Additional analyses indicated that a single quantitative real-time PCR test is useful for distinguishing PI animals from transiently infected animals. The results of the study suggest that removal of PI animals and/or vaccination, both before feedlot entry, would reduce the impact of BVDV-1 on BRD risk in cattle in Australian feedlots. Economic assessment of these strategies under Australian conditions is required.

Associations between exposure to viruses and bovine respiratory disease in Australian feedlot cattle.

Bovine respiratory disease (BRD) is the most important cause of clinical disease and death in feedlot cattle. Respiratory viral infections are key components in predisposing cattle to the development of this disease. To quantify the contribution of four viruses commonly associated with BRD, a case-control study was conducted nested within the National Bovine Respiratory Disease Initiative project population in Australian feedlot cattle. Effects of exposure to Bovine viral diarrhoea virus 1 (BVDV-1), Bovine herpesvirus 1 (BoHV-1), Bovine respiratory syncytial virus (BRSV) and Bovine parainfluenza virus 3 (BPIV-3), and to combinations of these viruses, were investigated. Based on weighted seroprevalences at induction (when animals were enrolled and initial samples collected), the percentages of the project population estimated to be seropositive were 24% for BoHV-1, 69% for BVDV-1, 89% for BRSV and 91% for BPIV-3. For each of the four viruses, seropositivity at induction was associated with reduced risk of BRD (OR: 0.6-0.9), and seroincrease from induction to second blood sampling (35-60 days after induction) was associated with increased risk of BRD (OR: 1.3-1.5). Compared to animals that were seropositive for all four viruses at induction, animals were at progressively increased risk with increasing number of viruses for which they were seronegative; those seronegative for all four viruses were at greatest risk (OR: 2.4). Animals that seroincreased for one or more viruses from induction to second blood sampling were at increased risk (OR: 1.4-2.1) of BRD compared to animals that did not seroincrease for any viruses. Collectively these results confirm that prior exposure to these viruses is protective while exposure at or after feedlot entry increases the risk of development of BRD in feedlots. However, the modest increases in risk associated with seroincrease for each virus separately, and the progressive increases in risk with multiple viral exposures highlights the importance of concurrent infections in the aetiology of the BRD complex. These findings indicate that, while efficacious vaccines could aid in the control of BRD, vaccination against one of these viruses would not have large effects on population BRD incidence but vaccination against multiple viruses would be expected to result in greater reductions in incidence. The findings also confirm the multifactorial nature of BRD development, and indicate that multifaceted approaches in addition to efficacious vaccines against viruses will be required for substantial reductions in BRD incidence.

Reversible chronic cerebellar ataxia after phenytoin intoxication: possible role of cerebellum in cognitive thought.

Reversible chronic cerebellar ataxia followed phenytoin treatment in two epileptic women. Cerebellar ataxia in both patients and axonal polyneuropathy in one patient were improved after administration of thiamine alone or with folate. In one patient, some specific behavioral functions improved. However, recovery could have been spontaneous.

Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society.

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Otitis media in neonatal intensive care unit graduates: a 1-year prospective study.

A group of 46 high-risk infants (graduates of a neonatal intensive care unit) and 19 full-term infants were observed prospectively for middle ear status beginning at 40 weeks' postconceptional age. All infants were born to families living in low socioeconomic urban neighborhoods. Pneumootoscopy was used to determine the presence or absence of middle ear effusion during periodic medical and nonmedical visits throughout a 1-year period. Of all infants studied, 91% had at least one episode of otitis media with effusion during the observation interval. There were no differences in the percentages of visits during which high-risk and full-term infants experienced either normal middle ears bilaterally or otitis media with effusion in one or both ears. Furthermore, the age of onset of otitis media with effusion was similar for the two groups of babies. No differences were found between boys and girls in the age of onset for otitis media or in the percentage of visits at which otitis media with effusion was detected. Hispanic infants experienced their initial episode at significantly younger ages than did black infants in the sample. Both groups had similar percentages of visits attributable to otitis media with effusion during the observation period. The results indicate a high incidence among the infants studied and similar otologic courses for neonatal intensive care unit graduates and full-term infants during the first year of life.

The screening and diagnosis of autistic spectrum disorders.

The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.

Early otitis media and phonological development at age 2 years.

The effect of early otitis media on phonology and articulation in the presence of expressive language delay was investigated in 16 2-year-olds followed prospectively from birth. Eight of the children were designated otitis-positive and 8 were considered otitis-negative as determined by bilateral pneumatic otoscopy outcomes during year 1 of life. The groups differed significantly on measures of expressive, not receptive, language development. All members of the otitis-positive group were expressive language delayed. Phonological analyses were completed on spoken language samples elicited from each child at age 24 months. Results showed similar developmental tendencies in speech sound acquisition between the groups, but the otitis-positive group had established significantly fewer initial consonant phones and produced them less accurately than the otitis-negative subject group. The otitis-positive group acquired significantly fewer consonants with back place of articulation. Similar phonological error patterns of deletion and phoneme class deficiency were used by the groups, but the otitis-positive group used the error patterns more frequently. Findings here lend support to the otitis media effect as one of interaction among risk factors.

Otitis media, auditory sensitivity, and language outcomes at one year.

The relationship among otitis media, auditory sensitivity, and emerging language was examined in a group of 1-year-old children who were prospectively followed since birth. Pneumatic otoscopy was used to document the otologic status of the children's ears at each medical visit. There were 13 babies with normal ratings in each ear at 80% more of their visits (designated as "otitis free") and 12 babies with bilaterally positive otoscopy results at 30% or more of their first year visits (designated "otitis positive"). In comparison to the otitis free infants, the group of otitis positive babies demonstrated reduced auditory sensitivity as measured by auditory brain stem response (ABR) and poorer expressive language abilities. However, differences in receptive language were not detected. These results suggest that otitis media may have an impact on auditory sensitivity and developing language as early as 1 year of age.

Otitis media, communication style of primary caregivers, and language skills of 2 year olds: a preliminary report.

The association between early otitis media, styles of primary caregivers, and language development was prospectively examined in 26 2-year-old children from lower socioeconomic backgrounds (of mixed perinatal status) followed prospectively since birth. Based on otoscopic evaluations during the first year of life, there were 14 children who were classified as bilaterally otitis-free (OM-) and 12 children who were classified as bilaterally otitis-positive (OM+). At 2 years of age, all children were administered standardized measures of cognitive and language function along with a 20-minute videotaped play session with one of their primary caregivers. The language of both the children and caregivers was analyzed. Results indicate that caregivers of OM+ and OM- children used language nearly identically when interacting with their children. However, caregivers of OM+ children whose communication style was marked by a high percentage of directives and a corresponding low percentage of both questions and information-giving had the children with the lowest scores on all measures of naturalistic language. Controlling for neonatal illness did not alter the relationships found. The results suggest that caregiver language may compensate for some of the auditory deprivations associated with otitis media.

Experience with the audiologic assessment of infants and toddlers.

Experience with the behavioral assessment of hearing sensitivity is reported for 211 babies and toddlers aged 6-24 months. The visually reinforced head-turn procedure, visual reinforcement audiometry (VRA), was utilized to obtain threshold estimates for infants evaluated for both research and clinical purposes. At the initial test session, 90% of the infants and toddlers provided useful audiometric threshold data for air-conducted tonal signals; 84% could be assessed using standard earphones. The equipment arrangement described allows a single audiologist to complete the VRA assessment. The behavioral test technique offers the clinician a simple, efficient procedure for the routine audiometric assessment of the vast majority of very young children.

Long-term communication deficiencies in children with otitis media during their first year of life.

A cohort of lower socio-economic children who experienced multiple episodes of otitis media (OM) during their first year of life were compared to a group of children who were largely free of OM during their first year. Both groups were followed until 9 years of age. The data indicate that some children with positive histories of OM performed poorer on a variety of communicative tasks across the 9 year age span than the children with the negative histories of OM. The results suggest that the effect of otitis media and its accompanying hearing loss on communication skills may extend throughout childhood.

Early otitis media and later educational risk.

Fourteen children aged 6 years received screening for educational risk status and formal measures of academic performance. These children have been followed prospectively from birth for their otitis media status. Seven of the children were considered positive for otitis media in year one (recurrent episodes bilaterally), while 7 were considered otitis free. Academic status was related to early hearing acuity (as determined by repeated ABR assessment). Moreover, teachers' ratings of academic risk status were related to a measure at 4 years that examined the children's capacity to listen in background noise.

A prospective study of otitis media in infants born at very-low birthweight.

Forty-six infants born at very-low birthweight were followed prospectively for a one-year period after their discharge from a neonatal intensive care unit. Pneumatic otoscopy was used to diagnose otitis media at periodic visits to a medical/developmental follow-up program. Twenty-one normal, full-term infants routinely cared for in a well-baby nursery served as control subjects and were followed similarly for the same time period. No difference was found between the two infant groups for the either the percentage of visits infants were considered to have normal middle ears bilaterally or otitis media unilaterally or bilaterally. Further, for the premature infants, no relationship was found between gestational age at birth, birthweight, or length of stay in the intensive care unit and percent-visits with otitis media during the first year.

Auditory consequences of early mild hearing loss associated with otitis media.

Two groups of children received periodic documentation of their middle ear status by pneumatic otoscopy in the first year of life and had hearing sensitivity estimated by multiple auditory brainstem response (ABR) assessments during the same period. One group was considered otitis media (OM)-positive, with repeated bilateral episodes of OM and mild conductive hearing loss. The second group was considered OM-free with normal middle ear function bilaterally and normal hearing sensitivity in the first year of life. Children's higher-order auditory abilities were examined at 4, 6 and 9 years of age. Various measures such as speech recognition-in-competition, visual-auditory learning, sound blending, auditory memory, and masking level difference estimates were utilized to probe the children's auditory abilities. Results show that children with a first-year history of otitis media demonstrate deficits in the long term in some aspects of higher-order auditory processing. Performance appears to be associated with the mild hearing loss experienced during an important period of early development.