Testing causal mechanisms of nonsyndromic craniosynostosis using path analysis of cranial contents in rabbits with uncorrected craniosynostosis.

OBJECTIVE: Various causal mechanisms of familial nonsyndromic craniosynostosis have been presented. One hypothesis suggests that overproduction of bone at the suture is the primary origin of craniosynostosis, which affects brain and cranial growth secondarily through altered intracranial pressure (Primary Suture Fusion Model). Other hypotheses suggest that decreased cranial base growth or abnormal brain growth are the primary cause of craniosynostosis (Cranial Base, Brain Parenchyma Models, respectively). This study was designed to investigate which model best describes neurocranial changes associated with craniosynostosis in a rabbit model through multivariate path analysis. DESIGN: Serial magnetic resonance imaging scans and intracranial pressure measurements were obtained at 10, 25, and 42 days of age from 18 rabbits: six controls, six with delayed-onset synostosis, and six with early-onset synostosis. Five variables were collected from each rabbit: calvarial thickness at the affected suture, cranial base length, brain volume, cerebrospinal fluid volume, and intracranial pressure. This data set was used to test causal pathway relationships generated by the proposed models. Goodness of fit was measured by experimental group for each model. RESULTS: Primary Suture Fusion Model best explained the variables in both delayed-onset and early-onset synostotic rabbits (Goodness of fit = 93%, 97%, respectively). Cranial Base Model (Goodness of fit = 94%) best explained the data in control rabbits. CONCLUSION: Results suggest that the primary site of craniosynostosis in craniosynostotic rabbits is most likely the synostosed suture. Other cranial vault anomalies are most likely secondary compensatory changes. Results of the present study may provide insight regarding the causal pathway of craniosynostosis.

Differences between arterial occlusive and cortical photothrombosis stroke models with magnetic resonance imaging and microtubule-associated protein-2 immunoreactivity.

The differences between two models of cerebral ischemia [middle cerebral arterial transection (MCAT) and cortical photothrombosis (PT)] were explored with multiparametric MRI of apparent diffusion coefficient trace (ADCtr), cerebral blood flow (CBF) and T1. Microtubule-associated protein-2 (MAP2) immunoreactivity sections aligned with the MR images in the same coronal plane were used to map the infarct and to guide region-of-interest selection. In ischemic cortex, the larger T1 increase in PT versus MCAT (42+/-7% vs. 16+/-5%) is related to the different character of edema between these models; yet, neither CBF nor ADCtr discriminated between them at 3.5 h, suggesting that different mechanisms of ischemic damage to the brain cells resulted in the same ADCtr value. CBF and ADCtr were depressed in immediately adjacent ischemic border by 27+/-7% and 47+/-10%, respectively, in MCAT but not in PT, suggesting marginal perfusion in MCAT. CBF in homotopic normal cortex in the opposite hemisphere was higher for PT compared with MCAT (199+/-20 and 134+/-10 ml/100 g/min, respectively). Different pathological processes in the two models affect CBF, ADCtr and T1 in a unique, regionally specific manner. The PT model differs substantially from the MCAT and is not a model of cortical ischemia with an appreciable border zone.

Age-related changes in lateral ventricle morphology in craniosynostotic rabbits using magnetic resonance imaging.

BACKGROUND AND AIMS: Craniosynostosis occurs in 300-500 per 1,000,000 live births and results in secondary craniofacial, ocular, and intracranial anomalies. Neurologic problems associated with craniosynostosis include changes in intracranial morphology such as dilation of the cerebral ventricles, however, clinical studies are confounded by small sample sizes, heterogenous samples, and lack of age-matched controls. The present study was designed to assess age-related changes in the lateral ventricle volume of the brain in normal rabbits and rabbits with naturally-occurring coronal suture synostosis using serial magnetic resonance imaging. METHODS: Eighteen rabbits (6 wild-type controls, 6 with early-onset [ approximately 21 days gestation], and 6 with delayed-onset [approximately 25 days post-gestation] coronal suture synostosis) had magnetic resonance imaging (MRI) at 10, 25, and 42 days of age. RESULTS: The results demonstrate that rabbits with early-onset synostosis had significantly (p<0.001) dilated and larger lateral ventricles (by 77% at 10 days of age) than wild-type and delayed-onset synostosis rabbits, which progressively worsened by day 42. CONCLUSION: This finding suggests that uncorrected coronal suture synostosis may have early effects on lateral ventricle volume hypertrophy, possibly through obstructed cerebrospinal fluid and/or venous drainage and circulation.

L-arginine potentiates negative inotropic and metabolic effects to myocardium partly through the amiloride sensitive mechanism.

Recently, cytokines have been proposed to cause cellular injury by nitric oxide (NO.) mediated pathway and L-arginine has been proposed to impair intracellular pH (pH(i)) regulation via vacuolar type H(+)-ATPase in macrophage. We conducted this investigation on Langendorff perfused hearts of rabbits to elucidate the mechanisms involving the NO. precursor L-arginine on myocardial contractile function, glycolysis, mitochondrial respiration, and intracellular alkalinization and tested the effects of amiloride. L-Arginine caused a significant loss of contractile function (96+/-4 mmHg in control, 53+/-16 during L-arginine perfusion, p<0.01) and a significant increase of pH(i) (7.01+/-0.02 prearginine infusion, 7.08+/-0.03 at the end of L-arginine infusion, p<0.01) along with decreased oxygen consumption (MVO(2)) (0.94+/-0.32 ml/min/g dry wt.), increased lactate release, and a loss of creatine phosphate (15% loss). Amiloride could prevent the cell alkalinization and contractile dysfunction, but not the derangement of oxidative metabolism caused by L-arginine in myocytes. We conclude that L-arginine has two distinct effects upon the myocardium: (1) an amiloride-sensitive loss of contractile function associated with intracellular alkalinization; and (2) an amiloride-insensitive inhibition of oxidative metabolism, possibly because of increased myocardial NO. production.