Dyslipidemias in patients with diabetes mellitus: classification and risks and benefits of therapy.

To characterize the lipid and lipoprotein abnormalities in patients with diabetes mellitus and evaluate the risks and benefits of marketed pharmacologic therapies, a MEDLINE search of the National Library of Medicine data base was performed of studies published from January 1966 to March 1994. Clinical trials assessing effects on lipids and lipoproteins, and adverse effects of marketed lipid-lowering agents were extracted. Reviews and other relevant articles were included if they provided information regarding lipid and lipoprotein metabolism or guidelines on the treatment of dyslipidemias in patients with diabetes mellitus. An extensive review of clofibrate was not included. The most common dyslipidemia in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM) is combined elevated triglyceride and cholesterol levels, with reduced high-density lipoprotein (HDL) cholesterol (mixed hyperlipidemia). Hypertriglyceridemia combined with a reduced HDL cholesterol is the most common dyslipidemia in patients with noninsulin-dependent diabetes mellitus, but essentially any pattern of dyslipidemia may be present. Small and dense low-density lipoprotein (LDL), glycosylation of lipoproteins, and increased oxidized lipoproteins may be present in patients with diabetes mellitus; all contribute to accelerated atherosclerotic cardiovascular disease. Insulin therapy generally corrects quantitative lipid abnormalities in patients with IDDM, so drug treatment is seldom indicated. Diet, exercise, and insulin or oral sulfonylureas will improve hypertriglyceridemia and low HDL concentrations, but do not always return them to normal. Drug therapy is indicated when nonpharmacologic measures are inadequate. It is administered based on the effects of each agent on lipids and lipoproteins, patient age, adverse effect profile, patient tolerability, and drug-disease and drug-drug interactions. A fibric acid derivative is the drug of choice for marked hypertriglyceridemia in patients with diabetes mellitus. Niacin can worsen glycemic control, but it may be required in severe hypertriglyceridemia, hypercholesterolemia, or mixed hyperlipidemia. Bile-acid binding resins may accentuate hypertriglyceridemia but may be useful in selected patients with marked hypercholesterolemia and normal triglycerides. Hydroxymethylglutaryl coenzyme A reduced inhibitors are preferred in patients with elevated LDL cholesterol and mild hypertriglyceridemia. Patients with marked lipid abnormalities or mixed hyperlipidemias may require carefully dosed combinations of lipid-lowering drugs.

Family leave policies, job share, and child care at U.S. schools and colleges of pharmacy.

A 10-question survey was mailed to the deans of 74 schools and colleges of pharmacy to characterize family leave policies, child care, and job share opportunities. Data were tabulated as percentage response received, and analyzed by geographic region and by public compared with private institutions. Sixty-four surveys were completed (response rate 86%). Forty-eight (75%) schools reported having a formal written family leave policy: 47 offered maternity leave, 31 parental leave, 27 caregiver leave, 24 paternal leave, and 24 adoptive or foster parent leave. The duration and compensation for family leave varied among schools. A statistical difference was found between the Northeast (100%) and South (55%) in having such a policy. On-site child care was available at 26 (41%) schools, including both infant and child care in 12 and additional sick child care in 2. Three (5%) schools reported faculty job share positions.

Classical Rett syndrome in sisters: variability of clinical expression.

Familial cases of Rett syndrome (RS) are rare. No significant differences have been reported in the clinical courses of concordant monozygotic twins with RS. We present the variability of clinical expression in two Japanese sisters with classic RS. The younger sister, currently 6 years and 6 months old, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly and developed sleep-wake rhythm disturbance from age 4 years and seizures from age 5 years. The elder, currently 7 years and 9 months old, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm and no seizures. RS is most likely to be transmitted as an X-linked dominant, male-lethal (XDML) disorder, although this is still contested. If RS is an XDML disorder, lyonization may account for variability of expression in the sisters.

CTG trinucleotide repeat length and clinical expression in a family with myotonic dystrophy.

Unstable expansion of the CTG repeats in the 3' untranslated region encoding a member of the protein kinase family in the q13.3 band on chromosome 19 is a mutation specific for myotonic dystrophy. To examine the correlation between clinical expression and CTG trinucleotide repeat length, we carried out Southern blot analysis in a family with myotonic dystrophy. In this pedigree, the expanded CTG repeats were transmitted maternally. The mother had three female children. The mother had about 200 CTG repeats, and the number of repeats for each child was about 800, 1500 and 1600 in birth order. The mother and the patient with 800 repeats were unaware of muscle weakness or myotonia. Symptoms were present from age 3 years in the patient with 1500 repeats and from birth in the one with 1600 repeats. Although the mother menstruated regularly, the patients with 800 and 1500 repeats both menstruated irregularly, and the one with 1600 repeats has never menstruated. The age of onset and severity of the disease were correlated with the size of the expanded repeats. Endocrinological studies revealed that the basal levels of the gonadotropins, PRL and E2 were within normal range, and a pituitary response to LHRH was observed. These data suggest that the amenorrhea and menstrual irregularities were caused by a suprahypophyseal dysfunction. When expanded CTG repeats are transmitted maternally, abnormal products resulting from the metabolic disturbance in the affected mother may harm the fetus in utero. A heterozygous fetus, who has more CTG repeats, may be unable to metabolize the pathologic products sufficiently and therefore may become more severely affected. This may explain the exclusive maternal transmission of congenital myotonic dystrophy.

Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome.

Localized proton magnetic resonance spectroscopy (MRS) was performed to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T-->G point mutation at nt 8993 of mitochondrial DNA. In this patient, sodium dichloroacetate therapy normalized the lactate and pyruvate levels in both blood and cerebrospinal fluid (CSF). However, his psychomotor retardation did not improve and magnetic resonance imaging showed progressive cerebral atrophy. In the patient's spectra, elevation of brain lactate was observed throughout the brain with regional variations, predominantly in the basal ganglia and brainstem with an abnormal MRI appearance. Although the lactate/creatine ratio observed on proton-MRS was related to the CSF lactate level, the ratio did not completely parallel the CSF lactate level, i.e. brain lactate was detected even when the CSF lactate level had become normalized. Furthermore, proton-MRS revealed a decrease in the N-acetylaspartate/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. The clinical and MRI findings were well related to the changes in spectroscopically determined brain metabolites. These results indicate that the brain metabolites observed on proton-MRS are useful indicators of a response to therapy and prognosis in Leigh syndrome.

Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome.

We studied the circadian rhythm of serum melatonin levels in two patients with classical Rett syndrome having severe sleep disorders; serum melatonin levels were measured before and during melatonin treatment using radioimmunoassay. Patient 1 had a free-running rhythm of sleep-wake cycle from 3 years of age. At the age of 4 years, the peak time of melatonin was delayed 6 h compared to normal control and the peak value was at the lower limit. Patient 2 had a fragmented sleep pattern accompanied by night screaming from 1 year and 6 months of age. At the age of 10 years, the peak time of melatonin secretion was normal but the peak value was at the lower limit. These patients were given 5 mg melatonin orally prior to bedtime. Exogenous melatonin dramatically improved the sleep-wake cycle in patient 1. In patient 2, exogenous melatonin showed a hypnotic effect but early morning awakenings occurred occasionally. When melatonin treatment was stopped, the sleep disorders recurred and re-administration of 3 mg melatonin was effective in both patients. The effect was maintained over 2 years without any adverse effects. These findings suggests that sleep disorders in patients with Rett syndrome may relate with an impaired secretion of melatonin.

L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling.

Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.

Effects of neonatal hypoxia on brainstem cholinergic neurons-pedunculopontine nucleus and laterodorsal tegmental nucleus.

Hypoxic changes in the cholinergic neurons of the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) were studied morphologically using immunohistochemistry for choline acetyltransferase (ChAT). Fifty-three postnatal day (PND) 7 Sprague-Dawley rats were subjected to a hypoxic load of 8% oxygen for 5 h. The rats which survived were later sacrificed at PND 14 or 28 for histological analysis. The results were compared with those obtained from control rats. Three weeks after hypoxic load, a decrease in the number of ChAT immunoreactive cells, especially in the caudal PPN, was found, although no remarkable changes were detected in cell morphology. Since several studies support the possibility that the cholinergic system from PPN/LDT is responsible for both REM generation and the general motor inhibition during REM sleep, our results may account, in part, for the clinical features of hypoxic brain damage such as sleep disorders and abnormal muscle tonus.

Cyclic vomiting and elevation of creatine kinase associated with bitemporal hypoperfusion and EEG abnormalities: a migraine equivalent?

A 13-year-old mentally retarded boy suffered from repeated vomiting attacks since infancy. Each episode lasted 2 to 10 days, and was precipitated by respiratory infection, exercise or stress. During an attack he became irritated, agitated and amnesic, but did not have headaches or seizures. Associated findings were transient elevation of serum creatine kinase (CK) (331-3381 IU/l), and of plasma ACTH and cortisol. The raised CK level was the result of muscle hypertonicity. Ictal EEGs showed delta activity in the front-temporal areas, and inter-ictal IMP-SPECT revealed hypoperfusion in both temporal regions. Unlike the periodic ACTH-ADH discharge syndrome, neither hypertension nor depression developed. These attacks were diagnosed as a migraine equivalent and were suppressed with phenytoin. From the EEG and SPECT findings, we concluded that the vomiting and behavioural changes were related to the paroxysmal vascular abnormality in the temporal regions, but it was not easy to make the distinction between migraine and focal epilepsy. Before a diagnosis of the periodic ACTH-ADH discharge syndrome is made, the possibility of migraine equivalent should be considered.

Hypocalcemic focal seizures in a one-month-old infant of a mother with a low circulating level of vitamin D.

We present a case of a one-month-old infant with hypocalcemia and rickets, with symptoms of focal seizures. The ictal EEG showed left occipital spikes spreading over all of the left hemisphere. From the laboratory studies, we concluded that a low maternal circulating level of vitamin D would cause infantile hypocalcemia and rickets, while immature renal response to parathyroid hormone and transient hypoparathyroidism in infancy would induce hyperphosphatemia. Hypocalcemia may be an important factor in the cause of focal seizures which start even after the age of one month. Further, investigation of maternal vitamin D levels should be done in infantile hypocalcemia.

Beta-2-microglobulin and ferritin in cerebrospinal fluid for evaluation of patients with meningitis of different etiologies.

To determine whether or not the beta-2-microglobulin (beta2-m) and/or ferritin levels in cerebrospinal fluid (CSF) can be used as markers for the differential diagnosis of meningitis and determination of the response to treatment, 122 subjects with etiologically well-characterized diagnoses were classified into three groups: bacterial meningitis (n = 5; mean age +/- SD. 1.0+/-1.0 year), viral meningitis (n = 39; 5.9+/-3.8 years), and a non-meningitis group (n = 78; 5.2+/-4.9 years). The levels of beta2-m and ferritin in CSF were determined by means of a latex photometric immunoassay. The statistical significance of the data was analyzed with the Mann Whitney U-test. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of each prediction marker. This study indicated that (1) the levels of beta2-m and ferritin in CSF were related with age in the non-meningitis group: subjects of up to 5 months of age exhibited higher concentrations of these proteins than ones of above 6 months of age (beta2-m, 1.89+/-1.13 vs. 0.84+/-0.65 mg/l. P < 0.01; ferritin, 2.97+/-2.04 vs. 1.81+/-1.34 microg/l, P = 0.09); (2) the beta2-m level was significantly higher in the CSF of patients with viral meningitis than in ones without meningitis (2.41+/-1.23 vs. 0.84+/-0.65 mg/l, P < 0.01): the best cut-off value was 1.2 mg/l (3) the ferritin level was significantly higher in the CSF of patients with bacterial meningitis than in ones with viral meningitis (43.24+/-39.49 vs. 6.81+/-7.41 microg/l, P < (.01): the best cut-off value was 7.5 microg/l; and (4) sequential measurement of the CSF ferritin level was of value for determination of the response to antibiotic treatment for bacterial meningitis. These results only apply to patients of greater than 6 months of age. beta2-m and ferritin in the CSF can be used as an ancillary tool for diagnostic guidance in the acute phase of meningitis and determination of the response to treatment for bacterial meningitis.

The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome.

A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur.

Theophylline-induced seizures in a 6-month-old girl. Serum and cerebrospinal fluid levels.

The case is presented of a 6-month-old girl with theophylline-induced focal seizures associated with tachycardia, tremor and irritability. The serum level of theophylline was 20.0 micrograms/ml 30 min after the onset of seizures, and declined to half this level at 19 h. The ratio of the concentration in cerebrospinal fluid (CSF; 8.9 micrograms/ml) to serum (16.4 micrograms/ml) was 0.54 at 4.5 h after the onset. Despite the cessation of seizures, the EEG showed periodic high voltage delta waves over the right hemisphere and left-sided flatness. Since theophylline diffuses easily through the blood-brain barrier in infancy, serum levels should be maintained below 15 micrograms/ml unless severe bronchial asthma occurs.

Serial neuroimages of acute necrotizing encephalopathy associated with human herpesvirus 6 infection.

A previously healthy 8-month-old girl developed exanthem subitum and acute encephalopathy with status epilepticus, quadriplegia and bilateral abducens nerve palsies. Human herpesvirus-6 DNA was found in the cerebrospinal fluid by the polymerase chain reaction at the acute stage. Cranial computed tomography showed low density areas in the thalami and in the cerebellar and abducens nuclei. The distribution of the lesions was consistent with acute necrotizing encephalopathy. As for the thalamic lesions, a T2 weighted magnetic resonance image on the 24th day of the illness demonstrated low signal intensity surrounded by high intensity; 99mTc-ECD SPECT showed hypoperfusion, which suggested irreversible tissue damage. The patient is now 1 year 6 months old and has spastic quadriparesis with mental retardation and abducens nerve palsies.

Development of spinal motoneurons in rats after a neonatal hypoxic insult.

To determine the developmental changes of cervical and lumbar motoneurons (MNs) during normal development and after a neonatal hypoxic insult, cervical and lumbar MNs were studied in rats of various postnatal ages using a retrograde neurotracing technique combined with immunohistochemistry. The results regarding normal development could be summarized as follows: (1) the dendrites elongated mainly during the first 5 postnatal days (PNDs), being longer and more extensive in cervical MNs than in lumbar MNs; (2) the average cell body area increased from PND 5 to 14; and (3) the distribution of cell body areas changed from a unimodal to a bimodal pattern between PND 5 and 14. The temporal differences in morphologic development between cervical and lumbar MNs may influence the motor development in a rostrocaudal manner. The dendrites of lumbar MNs were shorter and less extensive in rats with a neonatal hypoxic insult than in rats without one; no significant difference was observed in cervical MNs between the two groups. The developmental difference between cervical and lumbar MNs after a neonatal hypoxic insult may contribute to motor deficits, with greater effect on the lower than the upper limbs.

Cognitive deterioration associated with focal cortical dysplasia.

Surgery for an area of focal cortical dysplasia in a critical region is reported in a right-handed female manifesting intractable focal epilepsy and verbal cognitive deterioration. She developed the first seizure at 2 years of age and was treated with phenytoin and zonisamide, with good control until 10 years of age. Although seizures did not occur at 9 years of age, she manifested dyscalculia, right-left disorientation, and finger agnosia, and N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (SPECT) revealed focal hypoperfusion in the left parietal lobe. At 11 years of age, she developed regular nocturnal seizures and gradually lost the ability to understand the meaning of sentences. Verbal IQ declined from 94 to 63, and the area of hypoperfusion detected by interictal N-isopropyl-p-iodoamphetamine SPECT spread over the left parietotemporal lobes. Magnetic resonance imaging revealed focal cortical dysplasia mainly in the left parietal lobe, and ictal technetium-99m-ethyl cysteinate dimer SPECT images demonstrated an area of hyperperfusion around the focal cortical dysplasia, including the left precentral gyrus. Because of the overlap between the epileptogenic and functional cortex, the authors concluded that cortical resection, including focal cortical dysplasia, was inappropriate in this patient.

Cerebellar hypoperfusion and developmental dysphasia in a male.

A male with developmental dysphasia is documented with fine motor dysfunction whose improvement in expressive language was associated with increased cerebellar perfusion, as detected by serial N-isopropyl-p-[iodine-123] iodoamphetamine single photon emission computed tomography (SPECT). His expressive language has been improving since 6 years, 8 months of age, and his verbal intelligence quotient improved from less than 45 at 5 years of age to 80 at 8 years of age. Compared with the SPECT findings at 4 years of age, the ratio of the average pixel values of the cerebellum to the frontal cortices increased at 9 years of age (from 0.81 to 1.03-1.09 in the hemisphere and from 0.66 to 0.98 in the vermis). However, he was not able to understand stories presented orally even at 9 years, 4 months of age. These results suggest that developmental dysphasia, which mostly involves expressive impairment, in this patient could have been the result of delayed maturation of cerebellar function, mainly that of the vermis.

Alobar holoprosencephaly with diabetes insipidus and neuronal migration disorder.

A 2-year-old girl with alobar holoprosencephaly associated with facial abnormalities, central diabetes insipidus, and a neuronal migration disorder is reported. The diagnosis of diabetes insipidus was based on low urine osmolality and low plasma ADH concentration during a water deprivation test, and clinical and biochemical improvement after desmopressin acetate administration. Because the posterior portion of the pituitary was located in the sella turcica and the hypothalamo-pituitary stalk was intact, the diabetes insipidus was presumed to have been caused by hypothalamic osmoreceptor dysfunction. MRI findings were compatible with alobar holoprosencephaly. In addition, heterotopic gray matter was recognized as a continuous band over a single ventricle. Defective cleavage of the prosencephalon associated with a neuronal migration disorder is characteristic of alobar holoprosencephaly.

Developmental changes in the noradrenergic innervations of spinal motoneurons in neonatal rats.

Developmental changes in the noradrenergic innervations of spinal motoneurons in both the cervical and lumbar cords were studied in neonatal rats. The labeling of motoneurons was done using choleratoxin B subunit as a retrograde neurotracer. The noradrenergic fibers were detected by immunohistochemistry for tyrosine hydroxylase. At postnatal day 1, tyrosine hydroxylase immunoreactive fibers were evident in the entire ventral horn, including the triceps brachii motoneuron pools at the cervical level. In contrast, they were observed only in that portion of the ventral horn medial to the quadriceps femoris motoneuron pools at the lumbar level. Subsequently, tyrosine hydroxylase immunoreactive fibers increased at both levels, and they were distributed in most of the gray matter at postnatal day 14. At this age, the distribution pattern of tyrosine hydroxylase immunoreactive fibers in the lumbar level was almost identical to that of the cervical level. The number of closely apposed tyrosine hydroxylase immunoreactive varicosities on motoneurons (close appositions) increased continuously from postnatal day 1 to 14 at both the cervical and lumbar levels. At postnatal day 1, triceps brachii motoneurons had more close appositions than quadriceps femoris motoneurons in number and, after postnatal day 7, there was no difference in the number of close appositions between triceps brachii motoneurons and quadriceps femoris motoneurons. Based on these results, we discuss the significance of monoaminergic influences on the postnatal development of spinal motoneurons and of motor behavior with a rostrocaudal gradient.