Polymorphisms in the 5'-upstream region of the PKCbeta gene in Japanese patients with Type 2 diabetes.

AIMS: Protein kinase C (PKC), a serine/threonine kinase, is known to be activated in various tissues under hyperglycaemic conditions. Notably, PKCbeta, a member of the conventional PKC group, is the predominant isoform detected in vascular tissues and could be involved in the development of diabetic vascular complications. In the present study, we investigated genetic variations in the 5'-upstream region of the PKCbeta gene to assess their possible relation to vascular complications in diabetic patients. METHODS: Variations upstream from the PKCbeta gene (-1066/+256) were examined in 60 Type 2 diabetic patients using a cycle sequencing method. Screening of detected variations was performed in 204 Type 2 diabetic patients and 160 healthy controls. RESULTS: Five single nucleotide polymorphisms; C(-238)G, C(-287)T, A(-348)G, C(-546)G, and C(-853)T, were identified in the upstream region. The C(-287)T and A(-348)G polymorphisms were in perfect linkage disequilibrium. There were no significant differences in genotype or allele frequencies of the five polymorphisms among the diabetic patients and healthy subjects. However, both -238GG and -287CC (-348GG) homozygotes showed significantly higher frequencies of macrovascular disease compared with patients with other genotypes. Further, an electrophoretic mobility shift assay revealed that the -238G fragment had a five-fold higher affinity for transcription factor Sp1 when compared with -238C. CONCLUSIONS: The C(-238)G and C(-287)T-A(-348)G polymorphisms in the 5'-upstream region of the PKCbeta gene may have an effect on the susceptibility of diabetic vascular complications through an alteration of tissue PKCbeta density or function.

A polymorphism in the promoter region of the glucocorticoid receptor gene is associated with its transcriptional activity.

Since glucocorticoid exerts its biological effects by binding to its receptor, the expression efficiency of the glucocorticoid receptor (GR) gene could influence glucocorticoid sensitivity. We found a polymorphism of cytosine/adenine (-22 C/A) in the upstream region of the GR gene. There was no difference in the allelic frequency between normal and type 2 diabetic subjects. The promoter activity determined by luciferase assay was significantly lower in the -22 A allele than in the -22 C allele in both HepG2 (A allele, 4.19 +/- 0.15; C allele, 6.07 +/- 0.27, p < 0.001) and human embryonic kidney 293 cell lines (A allele, 0.93 +/- 0.16; C allele, 1.51 +/- 0.32, p < 0.001). This polymorphism is associated with transcription of the CR gene, which could be related to glucocorticoid sensitivity through an alteration in tissue GR number.

[Brain MRI and single photon emission computed tomography in severe athetotic cerebral palsy: a comparative study with mental and motor disorders].

Single photon emission computed tomography (SPECT) using N-isopropyl-p-[123I]-iodoamphetamine(123I-IMP) was performed in twelve patients with severe athetotic cerebral palsy (Ath; 5 males and 7 females) who had both motor delay (unable to move) and mental retardation (I.Q, or D.Q, below 30). The neuroimaging findings of those patients were compared with those of patients mental and motor disorders. In five cases suffering from neonatal asphyxia, SPECT demonstrated a decreased regional cerebral blood flow (rCBF) in corpus striatum, thalamus, orbitofrontal areas, pericentral gyrus areas, prefrontal areas and medial temporal areas. In seven cases suffering from neonatal jaundice, SPECT demonstrated a decreased rCBF in orbito-frontal areas, prefrontal areas and medial temporal areas. SPECT showed hypoperfusion of peri-central gyrus areas in cases with complications of spastic palsy. The decreased rCBF in medial temporal areas mostly corresponded to an alteration in hippocampal formation as assessed by magnetic resonance imaging (MRI). Cases with hypoperfusion of bilateral medial temporal areas showed a lower score of language understanding than those with the unilateral damage. In cases with hypofusion of bilateral prefrontal areas and bilateral medial temporal areas, the grade of understanding of language was almost below 12 months. In cases with hypoperfusion of orbitofrontal areas, psychomotor hypersensitivity had been observed. Those results suggest that IMP-SPECT and MRI of the brain is useful tool for neurological assessment in handicapped patients with athetotic cerebral palsy.

[Pattern of the brain damages and its developmental mechanisms in monozygotic twins].

Neurologic morbidity is observed more frequently in twins than in singletons. Low birthweight and premature birth are observed more frequently in twins but cannot always explain the cause of cerebral palsy, although circumstances related to twinning may cause brain damage. We attempted to select the patients whose brain damages might be caused by circumstances related to twinning and discussed the developmental mechanisms of their brain damages. We divided the cases into 3 groups. One comprised the monozygotic (MZ) twins whose co-twins had died. The second comprised the MZ twins with the complication of the twin-twin transfusion syndrome or discordant twins. The third comprised the MZ twins with concordant co-twins. We postulated that group I and II had complication of the disturbance of fetal circulation, but group III did not. Hydranencephaly (group I) and polymicrogyria (group II) might develop when the disruption occurs at an intermediate stage of morphogenesis (before the 6th month of gestation). In the cases with cerebral infarction (group I), the distribution of the lesions were related to the main vascular territories of the mature form, might be caused by occlusion of blood vessels associated with intrauterine disseminated intravascular coagulation. In the cases of MCE (group I), multiple cavities are present mainly in the white matter, the gray matter having a tendency to be spared. As the distribution of the cavities is not related to the main vascular territories, it was less likely that the lesions was produced by occluded vessels. The death of one fetus might cause severe blood deprivation, leading to hypoxic-ischemic brain insults in the surviving fetus.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle and intramuscular nerve pathology in congenital hypomyelination neuropathy.

Two patients had delayed development and generalized muscle hypotonia and weakness since early infancy. Their muscle biopsies showed slight variation in fiber size without group atrophy, and no clear evidence of an active demyelinating process in the intramuscular nerves. The most striking finding by light microscopy was the absence of myelinated fibers in the intramuscular nerve bundles. Ultrastructurally, the axons were devoid of myelin sheath or had very thin myelin sheaths, and the axons were surrounded by multilayered basal lamina forming an atypical onion bulb with no suggestions of myelin destruction. A sural nerve biopsy from one of the patients showed similar findings. Unlike the Déjèrine-Sottas type of hereditary motor and sensory neuropathy, there was no evidence of demyelination and remyelination in the muscle pathology, suggesting that the poor myelination in congenital hypomyelination neuropathy is due to a true "hypo"-myelination and not the result of demyelination.

[Epilepsy in patient with structural autosomal abnormality].

Few cases have been reported on the structural autosomal abnormality (SAA) focusing on epilepsy excluding those of Down syndrome and Klinefelter syndrome. We investigated patients who had SAA with special reference to epilepsy. Various types of epilepsy were observed in its severity in our cases as well as previously reported cases. There was no correlation between the degree of mental retardation, motor dysfunction, brain damage on CT scan, and severity of epilepsy. Some cases had brain dysplasia, such as agenesis of corpus callosum, pachygyria, and mega cisterna magna. No correlation was found between these brain dysplasia and severity of epilepsy. It is important for a pediatrician to find a common epileptic syndrome or EEG abnormality in a SAA. An observation of symptoms in patients with the same chromosomal deletion or duplication will lead to identification of responsible gene for an epileptic symptom.

[Clinical consideration of patients with neonatal bilateral basal ganglia-thalamic lesion due to hypoxic ischemic encephalopathy].

We describe herein the clinical symptoms, clinical course and results of investigation of 7 patients with bilateral basal ganglia-thalamic lesions (BBTL). All patients had spastic quadriplegia with rigidity. They were unable to sit and turn over. They could follow objects, turn head towards a sound and recognize parents to some degree. They were all evaluated as having the most severe degree of disability (Oshima's classification 1). They all had dysphagia and 2 patients had a episode of bradycardia and hypothermia, which might be evidences of brain stem disorders. Muscle hypertonia, vomiting, hematemesis and obstructive respiration, which were the major complications for the patients, worsened with age. High percentage of histories of birth asphyxia and poor feeding in the neonatal period suggested that perinatal brain insults might be one of the important factors for developing BBTL. It seemed to be difficult to explain that such diffuse brain injuries in our cases were caused by only the insults during parturition. Brain insults during parturition as well as prenatal factors probably participate in developing BBTL. Although the cerebrum of the patients seem to be relatively preserved in the images of head CT-scan, MRI of the patients revealed diffuse brain lesions. All of five patients tested had an abnormal auditory brain stem response (ABR). These investigations demonstrated that patients with BBTL have diffuse brain damage including brain stem. Further observation is needed to verify the mechanisms of development and the time of onset of BBTL.

[Two cases of myocarditis appearing during ACTH therapy for infantile spasms].

We experienced two cases of myocarditis occurring during ACTH therapy for infantile spasms. Myocarditis cases occurred during the reduction of ACTH doses, and viral infection was suspected. Steroid replacement therapy was effective in the both cases. It is important to consider that ACTH therapy for infantile spasms could sometimes lead to severe myocarditis.