Resolving candidate genes of mouse skeletal muscle QTL via RNA-Seq and expression network analyses

BACKGROUND:

We have recently identified a number of Quantitative Trait Loci (QTL) contributing to the 2-fold muscle weight difference between the LG/J and SM/J mouse strains and refined their confidence intervals. To facilitate nomination of the candidate genes responsible for these differences we examined the transcriptome of the tibialis anterior (TA) muscle of each strain by RNA-Seq.

13,726 genes were expressed in mouse skeletal muscle. Intersection of a set of 1061 differentially expressed transcripts with a mouse muscle Bayesian Network identified a coherent set of differentially expressed genes that we term the LG/J and SM/J Regulatory Network (LSRN). The integration of the QTL, transcriptome and the network analyses identified eight key drivers of the LSRN (Kdr, Plbd1, Mgp, Fah, Prss23, 2310014F06Rik, Grtp1, Stk10) residing within five QTL regions, which were either polymorphic or differentially expressed between the two strains and are strong candidates for quantitative trait genes (QTGs) underlying muscle mass. The insight gained from network analysis including the ability to make testable predictions is illustrated by annotating the LSRN with knowledge-based signatures and showing that the SM/J state of the network corresponds to a more oxidative state. We validated this prediction by NADH tetrazolium reductase staining in the TA muscle revealing higher oxidative potential of the SM/J compared to the LG/J strain (p<0.03).

Thus, integration of fine resolution QTL mapping, RNA-Seq transcriptome information and mouse muscle Bayesian Network analysis provides a novel and unbiased strategy for nomination of muscle QTGs.

School entry age outcomes for infants with birth weight ≤ 800 grams

To evaluate the mortality and long-term morbidity rates of extremely low birth weight (ELBW) infants admitted to neonatal intensive care units (NICUs).

Teenagers born at extremely low birth weight

Adolescence constitutes a major transition for extremely low birth weight (ELBW) teenagers. Recent studies of ELBW teenagers born in the 1980s have provided information about the growth and developmental characteristics of these individuals in adolescence and in early adulthood. ELBW teenagers are shorter and lighter than their full-term peers, and have a smaller head circumference. Cognitive and academic vulnerabilities documented during the school years, particularly difficulties with nonverbal intelligence and arithmetic, persist into late adolescence. Many ELBW children struggle in school and have lower academic achievement levels. The self-concept of ELBW teenagers is generally similar to that of their full-term peers, but their parents perceive them to be more vulnerable over a wide range of behavioural and psychosocial dimensions, particularly depression and attention. ELBW teenagers perceive themselves as needing more assistance in job seeking than do their peers. Physical activity levels and fitness in late adolescence are significantly lower in ELBW teenagers than in their full-term peers, constituting a potential additional health hazard in later life. The outcomes of ELBW teenagers are significantly influenced by socioeconomic, family and parenting factors.

Aerobic capacity, strength, flexibility, and activity level in unimpaired extremely low birth weight (

To compare aerobic capacity, strength, flexibility, and activity level in extremely low birth weight (ELBW) adolescents at 17 years of age with term-born control subjects.

Psychosocial and academic characteristics of extremely low birth weight (<or =800 g) adolescents who are free of major impairment compared with term-born control subjects

To compare academic and cognitive ability, attention, attitudes, and behavior of extremely low birth weight (ELBW) adolescents who are free of major impairments at 17 years of age with term-born control subjects.

Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks' postconceptional age?

Children with neurologic impairments have shown diminished pain response compared with control subjects; however, it remains unclear what mechanisms underlie this response or when it develops. If this were also true with premature infants who undergo neonatal intensive care, then infants with parenchymal brain injury (PBI) would be at increased risk of underrecognition and undertreatment of procedural pain. The purpose of this study was to determine whether infants with PBI display altered responses to acute procedural pain at 32 weeks' postconceptional age (PCA), compared with control subjects.

Pattern of learning disabilities in children with extremely low birth weight and broadly average intelligence

To examine the prevalence and pattern of specific areas of learning disability (LD) in neurologically normal children with extremely low birth weight (ELBW) (<or = 800 g) who have broadly average intelligence compared with full-term children with normal birth weight of comparable sociodemographic background, and to explore concurrent cognitive correlates of the specific LDs.

Developmental coordination disorder in extremely low birth weight children at nine years

Developmental coordination disorder (DCD) is defined as an impairment in the development of motor coordination that interferes with academic achievement or activities of daily living (DSM-IV). DCD has been reported to affect 5% to 9% of children in the normal population. This study describes the prevalence of DCD in a cohort of extremely low birth weight children (ELBW, <or = l800 g) at 8.9 years of age, from which were excluded children with major impairments. Seventy-three children were included in the study group, along with 18 term-born, socially matched controls. Of the 73 ELBW children, 37 (51%) were classified as having DCD. ELBW children with DCD also had significantly lower Performance IQ (PIQ) scores and were more likely (43%) to have a learning difficulty in arithmetic than ELBW children who did not have DCD. This study found that DCD is a common problem in school-aged ELBW children.

Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 Weeks' postconceptional Age

Management of pain in very low birth weight infants is limited by a lack of empiric knowledge about the multiple determinants of biobehavioral reactivity in infants receiving neonatal intensive care.

Behavior, pain perception, and the extremely low-birth weight survivor

This article explores the literature concerning responses to pain of both premature and term-born newborn infants, the evidence for short-term and long-term effects of pain, and behavioral sequelae in individuals who have experienced repeated early pain in neonatal life as they mature. There is no doubt that pain causes stress in babies and this in turn may adversely affect long-term neurodevelopmental outcome. Although there are methods for assessing dimensions of acute reactivity to pain in an experimental setting, there are no very good measures available at the present time that can be used clinically. In the clinical setting repeated or chronic pain is more likely the norm rather than infrequent discrete noxious stimuli of the sort that can be readily studied. The wind-up phenomenon suggests that, exposed to a cascade of procedures as happens with clustering of care in the clinical setting in an attempt to provide periods of rest for stressed babies, an infant may in fact perceive procedures that are not normally viewed as noxious, as pain. Pain exposure during lifesaving intensive medical care of ELBW neonates may also affect subsequent reactivity to pain in the neonatal period, but behavioral differences are probably not likely to be clinically significant in the long term. Prolonged and repeated untreated pain in the newborn period, however, may produce a relatively permanent shift in basal autonomic arousal related to prior NICU pain experience, which may have long-term sequelae. In the long run, the most significant clinical effects of early pain exposure may be on neurodevelopment, contributing to later attention, learning, and behavior problems in these vulnerable children. Although there is considerable evidence to support a variety of adverse effects of early pain, there is less information about the long-term effects of opiates and benzodiazepines on the developing central nervous system. Current evidence reviewed suggests that judicious use of morphine for adjustment to mechanical ventilation may ameliorate the altered autonomic response. It may be very important, however, to distinguish stress from pain. Animal evidence suggests that the neonatal brain is affected differently when exposed to morphine administered in the absence of pain than in the presence of pain. Pain control may be important for many reasons but overuse of morphine or benzodiazepines may have undesirable long-term effects. This is a rapidly evolving area of knowledge of clear relevance to clinical management likely to affect long-term outcomes of high-risk children.

Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?

The goal of this study was to examine whether body activity such as postural, trunk, and limb movements may be potential pain cues in preterm infants.

Biobehavioral pain responses in former extremely low birth weight infants at four months' corrected age

To compare biobehavioral responses to acute pain at 4 months' corrected age between former extremely low birth weight (ELBW) infants and term-born controls.

Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preterm and full-term controls

High-technology medical care of extremely low-birth-weight (ELBW) infants (<1001 g) involves repeated medical interventions which are potentially painful and may later affect reaction to pain. At 18 months corrected age (CCA), we examined parent ratings of pain sensitivity and how pain sensitivity ratings related to child temperament and parenting style in 2 groups of ELBW children (49 with a birth weight of 480-800 g and 75 with a birth weight of 801-1000 g) and 2 control groups (42 heavier preterm (1500-2499 g) and 29 full-birth-weight (FBW) children (> 2500 g). Both groups of ELBW toddlers were rated by parents as significantly lower in pain sensitivity compared with both control groups. The relationships between child temperament and pain sensitivity rating varied systematically across the groups. Temperament was strongly related to rated pain sensitivity in the FBW group, moderately related in the heavier preterm and ELBW 801-1000 g groups, and not related in the lowest birth-weight group (<801 g). Parental style did not mediate ratings of pain sensitivity. The results suggest that parents perceive differences in pain behavior of ELBW toddlers compared with heavier preterm and FBW toddlers, especially for those less than 801 g. Longitudinal research into the development of pain behavior for infants who experience lengthy hospitalization is warranted.

Language development at 3 years in pre-term children of birth weight below 1000 g

Language development at 3 years of pre-term children born below 1000 g birth weight was compared with full-term controls matched for social background. The pre-term group used less complex expressive language and showed lower receptive understanding, auditory memory and verbal reasoning. Language outcome was related to intraventricular haemorrhage but not to global indication of postnatal illness such as number of days on the ventilator. Average verbal intelligence in environmentally low risk, extremely low birth weight children is an insufficient indicator of complex language functioning.