Of mice and men: anatomy of the amelogenin gene

Mammalian enamel matrix is composed of two principal proteins, the enamelins and amelogenin. Recombinant complementary DNA (cDNA) molecules for the predominant mouse amelogenin have been identified, characterized by direct determination of the DNA sequence, and used as a specific hybridization probe. The spatial- and temporal-restricted pattern for amelogenin gene expression within developing mouse molars has been traced at the level of a single cell using in situ hybridization. The mouse genome has been shown to contain only one copy of the amelogenin (AMEL) gene which is not amplified or rearranged during ameloblast determination. In contrast, the human genome contains two copies of the AMEL gene, one residing on the X chromosome and one upon the Y chromosome. These observations, the availability of specific enamel gene probes coupled with the application of new techniques in molecular biology now afford unique opportunities for the analysis of the molecular basis of inherited defects of human enamel such as amelogenesis imperfecta. Recent advances towards obtaining a physical map and the complete nucleotide sequence for the human genome, as well as the documented developmental biology, defined genetics and transgenic capability of the mouse, suggest that mouse and man are the most relevant and potentially informative models for analysis of normal and abnormal enamel biomineralization.     

Effects of training specificity on the lactate threshold and VO2 peak

We examined the effects of training specificity on the lactate threshold (LT) and VO2peak. Sixteen male subjects completed VO2peak/LT protocols on the cycle ergometer (CE) and treadmill (TM) before and after a training program. The subjects were assigned to run training (N = 5), cycle training (N = 6), and control groups (N = 5). Subjects trained 4 day/week for 10 weeks at approximately 89% of pre-training VO2peak. Results indicated that run training increased VO2 at LT (VO2LT) within both the CE and TM protocols (17.9 to 22.5 ml/kg.min-1 for CE, 22.7 to 36.0 ml/kg.min-1 for TM, p less than 0.05) with the 58.5% increase in VO2LT for TM being greater than the 30.3% increase for CE (p less than 0.05). Cycle training resulted in a 38.7% increase in CE VO2LT (19.7 to 27.4 ml/kg.min-1, p less than 0.05) with no significant improvement in TM VO2LT (23.6 to 24.0 ml/kg.min-1). Similar increases in VO2peak were observed for CE and TM protocols for both cycle and run training groups (VO2peak increased by 11.9 to 20.7% in both CE and TM regardless of training mode). No changes were observed in the control group for any variable. The present data suggest that increases in LT resulting from training may be specific to the mode of exercise.     

γ-Hydroxybutyric Acid

γ-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in mammalian brain where it is derived metabolically from γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. GHB was synthesised over 40 years ago and its presence in the brain and a number of aspects of its biological, pharmacological and toxicological properties have been elucidated over the last 20–30 years. However, widespread interest in this compound has arisen only in the past 5–10 years, primarily as a result of the emergence of GHB as a major recreational drug and public health problem in the US. There is considerable evidence that GHB may be a neuromodulator in the brain. GHB has multiple neuronal mechanisms including activation of both the γ-aminobutyric acid type B (GABA_B) receptor, and a separate GHB-specific receptor. This complex GHB-GABA_B receptor interaction is probably responsible for the protean pharmacological, electroencephalographic, behavioural and toxicological effects of GHB, as well as the perturbations of learning and memory associated with supra-physiological concentrations of GHB in the brain that result from the exogenous administration of this drug in the clinical context of GHB abuse, addiction and withdrawal. Investigation of the inborn error of metabolism succinic semialdehyde deficiency (SSADH) and the murine model of this disorder (SSADH knockout mice), in which GHB plays a major role, may help dissect out GHB- and GABA_B receptor-mediated mechanisms. In particular, the mechanisms that are operative in the molecular pathogenesis of GHB addiction and withdrawal as well as the absence seizures observed in the GHB-treated animals.     

Treatment of infantile spasms with high-dose ACTH: efficacy and plasma levels of ACTH and cortisol

Fifteen children with infantile spasms and a hypsarrhythmic EEG defined by EEG-videotelemetry monitoring received a regimen of high-dose (150 IU/m2/d) ACTH for their seizures. We carried out an endocrinologic evaluation before and after initiation of the ACTH and conducted a time course study of plasma ACTH and cortisol levels after ACTH dosing. Spasms were controlled and the EEG normalized in 14 of the 15 children. Prior to starting ACTH therapy all the patients had normal prolactin, insulin, cortisol, and ACTH levels in plasma and normal thyroid function. Although the pattern of rise of ACTH levels in plasma after ACTH dosing was similar in all the children, there was great individual variation in the absolute concentrations. However, both the pattern of rise and absolute level of cortisol in plasma after ACTH was highly predictable in all patients. Plasma cortisol rose rapidly within 1 hour of ACTH administration and continued a slower rise for 12 to 24 hours after the ACTH dose. High-dose ACTH therapy seems quite effective in infantile spasms, perhaps because of a sustained high level of plasma cortisol. This sustained plateau of cortisol may be more effective in controlling infantile spasms than the pulse effect expected with oral steroids or lower doses of ACTH.     

Percentages of maximal heart rate, heart rate reserve, and VO2peak for determining endurance training intensity in sedentary women

The use of 60%-95% of maximal heart rate (HR max), heart rate reserve (HRR), and VO2peak as exercise training intensities was examined in sedentary women, and these intensities were related to HR and VO2 observed at the lactate threshold (LT) and fixed blood lactate concentrations of 2.0, 2.5, and 4.0 mM. Thirty-three subjects (means age = 32.5 +/- 3.9 yrs; means ht = 164.2 +2- 5.0 cm; means wt = 67.6 +/- 13.9 kg) completed a VO2/LT treadmill test using a level running protocol. The values at LT, 2.0, 2.5, 4.0 mM, and peak for VO2 were 22.3, 29.0, 31.0, 36.2, and 39.1 ml/kg.min-1, respectively; for velocity were 107.0, 128.9, 135.8, 152.8, and 164.4 m/min, respectively; and for HR were 142.1, 162.9, 169.4, 183.2, and 189.7 bts/min, respectively. The minimum intensity necessary for the majority of subjects to be above LT (n = 17) was 75% HR max while 90% HR max was required for the majority of subjects to be above 2.0 mM (n = 23) and 2.5 mM (n = 19). At 95% HR max 12 subjects were above 4.0 mM. For the majority of subjects to be above LT (n = 18), 55% HRR was necessary; 75%, 85%, and 95% HRR was required for the majority of subjects to be above 2.0 mM (n = 18), 2.5 mM (n = 19), and 4.0 mM (n = 20), respectively. For percent VO2peak, the intensities required for the majority of subjects to be above LT, 2.0 mM, 2.5 mM, and 4.0 mM were 55%, 75%, 80%, and 95% VO2peak, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull.

The coordinate growth of the brain and skull is achieved through a series of interactions between the developing brain, the growing bones of the skull, and the fibrous joints, or sutures, that unite the bones. These interactions couple the expansion of the brain to the growth of the bony plates at the sutures. Craniosynostosis, the premature fusion of the bones of the skull, is a common birth defect (1 in 3000 live births) that disrupts coordinate growth and often results in profoundly abnormal skull shape. Individuals affected with Boston-type craniosynostosis, an autosomal dominant disorder, bear a mutated copy of MSX2, a homeobox gene thought to function in tissue interactions. Here we show that expression of the mouse counterpart of this mutant gene in the developing skulls of transgenic mice causes craniosynostosis and ectopic cranial bone. These mice provide a transgenic model of craniosynostosis as well as a point of entry into the molecular mechanisms that coordinate the growth of the brain and skull.