Sparing of the brain in neonatal undernutrition: amino acid transport and incorporation into brain and muscle.

Rates of tyrosine and lysine transport and incorporation into protein were measured in control and undernourished weanling rats. Undernutrition was induced by feeding lactating dams a low protein diet (12 percent casein) from birth to day 21. At weaning, body and brain weights of undernourished rats were 50 percent and 88 percent, respectively, of control values. Lysine and tyrosine transport rates into skeletal muscle were reduced by over 75 percent, more than twice the reduction seen in brain. Rates of amino acid incorporation into muscle protein were reduced by approximately 50 percent; the change in rate of incorporation into brain protein was not statistically significant. These data indicate that, in spite of marked retardation of amino acid transport into brain, the brain seems fully capable of maintaining normal rates of protein synthesis.

Progressive sensory loss in familial dysautonomia.

Clinical variability in sensory impairment was demonstrated among 75 patients with familial dysautonomia. Older patients had a greater tendency toward increased dysfunction in pain sensation, joint position and Romberg's sign, and vibratory sense. Significant worsening with increased age was supported by retesting of 53 patients after a five-year interval. Sensory and motor axon loss were indicated by electrodiagnostic testing of peripheral nerves and abnormal cortical somatosensory evoked potentials. Familial dysautonomia is a hereditary disease with variable penetrance which involves both failure of intrauterine development of neurons and their postnatal maintenance.

Corneal surface irregularities and episodic pain in a patient with mucolipidosis IV.

Mucolipidosis IV is a lysosomal storage disease characterized by prominent involvement of the corneal epithelium. A 5-year-old boy with mucolipidosis IV experienced recurrent episodes of severe ocular pain, tearing, and ipsilateral facial flushing. This was suggestive of reflex sympathetic dystrophy, a syndrome of pain and sympathetic hyperactivity. The examination revealed marked corneal surface irregularities, corresponding to massive accumulations of intracytoplasmic storage material in the epithelium. Episodic pain in patients with mucolipidosis IV is an important symptom, presumably reflecting the distinctive corneal ultrastructural abnormality in this disease.

Amino acid transport inhibition: brain and behavioral correlates.

In vivo inhibition of uptake 14C-L-valine by brain following subcutaneous administration of either of two gamma-glutamyl cycle enzyme inhibitors, 2-imidazolidone-4-carboxylic acid (ICA), or, L-methionine-S-sulfoximine (MSO) is documented in C57BL/6J mice. Dose related decrease in exploratory activity, impairment of memory for foot shock, and reduced operant responding for food reinforcement parallels the time course for interference with uptake of a large neutral amino acid by these two compounds previously shown to inhibit different enzymes in the gamma-glutamyl cycle subserving active amino acid transport.

Pre-natal amino acid transport inhibition: long term influences on behavior and protein metabolism.

DBA/2J mice were exposed in utero, between days 15-18 of gestation, to either of two enzyme inhibitors, previously shown to decrease blood-brain, large-neutral amino acid transport in adults: L-methionine-RS-sulfoximine and 2-imidazolidone-4-carboxylic acid. The young mice demonstrated persistently altered motor behavior relative to saline controls when 40-42 days old and evidence of differences in the entry and incorporation of 14C-valine in brain at up to 80 days of age. The findings suggest that interference with blood-brain amino acid transport in utero has long term consequences. This may be related to some human conditions such as maternal phenylketonuria.

Baclofen in the treatment of polymyoclonus and ataxia in a patient with homocystinuria.

A patient with homocystinuria due to cystathionine beta-synthase deficiency developed severe progressive polymyoclonus and ataxia. To our knowledge, this is the first time polymyoclonus and ataxia have been reported in association with homocystinuria. Although cerebrovascular thrombosis is usually thought to be responsible for neurologic dysfunction in homocystinuric patients, no infarctions were demonstrated on magnetic resonance imaging scans in our case. We have previously reported that baclofen dramatically improved the polymyoclonus and ataxia in a patient with Unvericht-Lundborg disease. Baclofen given to our patient reversed the polymyoclonus and the ataxia as well. This suggests that patients with polymyoclonus and ataxia, no matter what the etiology, may benefit from the use of baclofen.

Use of a calcium channel blocker (nicardipine HCl) in the treatment of childhood moyamoya disease.

Moyamoya disease is a cerebrovascular disease characterized radiologically by progressive narrowing and occlusion of the arteries contributing to the circle of Willis and its branches. There is formation of an exuberant collateral network of blood vessels at the base of the brain, which is thought to arise in response to chronic ischemia. Clinically, the course is variable, with patients having repeated transient ischemic attacks, strokes, migraine, and seizures. Effective treatment is not available. The etiology and pathophysiology of moyamoya disease are largely unknown. Two patients with arteriographically proven moyamoya disease were identified. Both patients were symptomatic before age 5 years. Despite successful encephaloduroarteriosynangiosis revascularization procedures, they continued to experience an inexorable downhill course. A calcium channel blocker (nicardipine HCl) was introduced in order to prevent further symptoms. After the introduction of nicardipine, no further strokes occurred in either patient. There were no further episodes of transient ischemic attacks, seizures, or headache in one patient and decreased frequency in the other. In patients with moyamoya disease, nicardipine may have a beneficial effect on cerebral hemodynamics and may prevent ischemic sequelae by optimizing existing collateral circulation.

Asthma and epilepsy: are they related? A retrospective study.

Numerous studies have suggested that epilepsy and asthma may be related conditions. There has, however, been little epidemiologic data published to support this association. We conducted a retrospective study to determine whether the prevalence of epilepsy is increased among children with asthma, and the prevalence of asthma is increased among children with epilepsy, in comparison with the general pediatric population. We reviewed the medical records, at a large city hospital, of two groups of pediatric outpatients: (1) 400 consecutive patients with asthma followed regularly at the asthma and allergy clinic; and (2) 201 consecutive patients with idiopathic epilepsy followed regularly at the pediatric neurology clinic. Patients with a history of birth prior to 36 weeks' gestational age were excluded. Among the 400 cases of asthma, there were three patients with idiopathic epilepsy (prevalence of 0.75%). The prevalence of epilepsy was similar in mild (0.79%) and moderate-to-severe (0.73%) asthma. Among the 201 cases of idiopathic epilepsy, there were 12 patients with asthma (prevalence of 5.97%). Similar percentages of epilepsy patients with and without asthma reported generalized tonic-clonic, complex partial, simple partial, and myoclonic seizures as their predominant type. The prevalence values in this study are consistent with the prevalence of epilepsy and asthma in the general pediatric population. Our findings therefore suggest that idiopathic epilepsy and asthma are not etiologically related or mutually predisposing conditions. Small samples, failure to exclude patients born prematurely, and the equation of electroencephalographic (EEG) abnormalities with epilepsy may account for the results of previous studies.

The electroencephalogram in clinical pediatrics.

The electroencephalogram represents an electrical summary of the organizational patterns and the total physical-chemical processes taking place in the brain at the time of the recording. Itis affected by (1) artifacts secondary to head movements, muscle potentials, and eye movements, (2) physiological factors, such as state of consciousness, hyperventilation, and maturity of the brain, (3) metabolic factors such as temperature, thyroid function, electrolyte changes, and numerous other metabolic factors, and (4) drugs. Brain dysfunction also causes changes in the electroencephalogram. The electroencephalogram is useful in some, but not all, types of brain dysfunction. In general, the electroencephalogram is most likely to be abnormal if the underlying disease is acute or ongoing, or if the disease is associated with seizures. Focal lesions may appear when none is suspected clinically. The electroencephalogram can be an invaluable aid in dealing with epilepsy. Petit mal epilepsy cannot be diagnosed without it, and infantile spasms are diagnosed with considerably greater certainty if the electroencephalogram shows hypsarrhythmia. Patients with seizures which appear to be generalized may have an electroencephalogram with focal abnormalities; this may be the only clue that a focal lesion exists. Psychomotor epilepsy is sometimes difficult to differentiate from sociopathic behavior, and the electroencephalogram can be helpful. The electroencephalogram is less useful in chronic static conditions such as mental retardation, minimal cerebral dysfunction, or behavior disorders, unless there is associated epilepsy or ongoing brain pathology. More recently, the electroencephalogram has been used to estimate gestational age with reasonable accuracy. With the aid of a computer, responses to auditory and visual stimuli have been recorded on the electroencephalogram. These techniques, although not in general use at the present time, hold considerable promise for the future. They mark the beginnings of a new dimension in using the electroencephalogram as a tool in helping the clinician evaluate and understand brain development, and in helping him recognize early signs of disease in the developing brain.

Age related changes in blood-to-brain amino acid transport and incorporation into brain protein.

Blood-to-brain amino acid transport consists of at least two components: 1. a fast rate or early process, commonly measured by the intra-carotid bolus injection method and attributed to transport across the capillary endothelium and entry into the astrocytes, and, 2. a slow rate or later component measured over 2 to 15 minutes probably associated with exit from the astrocytes and entry into the neurons. Incorporation into brain protein is temporally related to the second process. In the present study the slow and fast rate transport components and the incorporation into brain protein of tyrosine (Tyr) and Valine (Val) was measured in young adult and aged male C57BL/6 mice. The results indicate that the fast rate transport component is unaffected by age while the rates of the slow process and protein turnover show an exponential decline most marked between 3 and 8 months of age. Changes in the relative incorporation of Tyr and Val suggest that brain protein metabolism is altered qualitatively as well as quantitatively in aging, in these animals.

Anticonvulsant activity of glycylglycine and delta-aminovaleric acid: evidence for glutamine exchange in amino acid transport.

We have proposed that glutamine serves in a facilitated diffusion process, mediated by the enzyme gamma-glutamyl transferase (gamma-glutamyl transpeptidase; gamma GT) and that it leaves the brain in exchange for entering amino acids. Glutamine is also a precursor of gamma-aminobutyric acid (GABA). Thus, providing an alternate substrate for gamma GT should spare brain glutamine, raise GABA, and cause an anticonvulsant effect. We have found that glycylglycine, the best-known substrate for gamma GT, and delta-aminovaleric acid (DAVA), a structural analog, have anticonvulsant activity in DBA/2J mice. Both compounds can decrease the incidence and severity of seizures induced by L-methionine-RS-sulfoximine or electroconvulsive shock. DAVA was also tested and found to be active against seizures caused by pentylenetetrazol or picrotoxin. [14C]DAVA entered the brain at the rate of 18.7 nmol/g/min. The activity of DAVA as a substrate of gamma GT was intermediate to that of glycylglycine and glutamine. Preliminary studies have shown that brain glutamine and perhaps GABA are elevated 3 h after administration of DAVA (7.5 mmol/kg). These findings support the theory that glutamine exchange plays a role in amino acid transport across the blood-brain barrier and suggests a new concept in anticonvulsant therapy.

Effect of gamma-glutamyl cycle inhibitors on brain amino acid transport and utilization.

Two inhibitors of the gamma-glutamyl cycle, methionine sulfoximine (MSO) and 2-imidazolidone-4-carboxylic acid (ICA) were administered to C57LB/6J mice. Both agents resulted in a reduced rate of transport of tyrosine from blood to brain and a decreased rate of incorporation of tyrosine from plasma into brain protein. MSO administration also diminished to concentrations of brain tyrosine, dopamine, and norepinephrine. MSO decreased the transport rate of valine by brain as well as the rate of its incorporation into protein when expressed in relation to the plasma specific activity. The results demonstrate a significant role for the gamma-glutamyl cycle in the transport of large neutral amino acids from blood to brain.

Evaluation of the careers of graduates of the University of Manitoba's BSc (Medicine) program.

The careers of graduates who had taken the BSc (Medicine) (BScMed) program at the University of Manitoba, Winnipeg, between 1950 and 1975 were compared with those of matched classmate controls to determine whether the program had any influence on the research careers of the graduates. More BScMed graduates than control subjects chose an academic career (49% v. 21%), achieved specialty certification (83% v. 65%), and obtained grants (51% v. 18%) and personal awards (37% v. 18%). The BScMed graduates also had significantly more publications than the control subjects. Although part of the difference between the two groups may be explained by the tendency of students who were more inclined toward an academic career to enter the BScMed program, it was evident that the program has a substantial effect on promoting the development of clinical investigators.

Effect of magnesium sulfate on the development of cystic periventricular leukomalacia in preterm infants.

To determine if magnesium sulfate has an effect on the development of cystic periventricular leukomalacia in preterm infants, this retrospective case control study was conducted. There were 23,382 infants born at three teaching hospitals in the metropolitan New York area from January 1992 to December 1994. Four hundred ninety-two infants met our entrance criteria. Criteria included a birth weight < 1750 g, survival to at least 7 days of life and at least one cranial ultrasound after 7 days of life. Infants exposed to magnesium sulfate in utero were less likely to develop periventricular leukomalacia. Two of 18 (11%) infants with periventricular leukomalacia were exposed to magnesium sulfate in-utero compared to 14 of 36 controls (39%) (p = 0.035) (OR = 0.196, 95% CI = 0.039-0.988). Pre-eclampsia as an independent factor was not associated with a reduced risk (p = 0.251) (OR = 0.294, 95% CI = 0.033-2.65). Preterm infants exposed to antenatal magnesium sulfate were found to have a reduced risk of developing cystic periventricular leukomalacia.