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Biomedical subjects

K E Wisniewski

Publications and source records attributed to K E Wisniewski.

At least 19 recordsLinked to original sources
PubMed1992

Altered protein patterns in brains of children with neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (NCL) are a group of inherited neurodegenerative diseases characterized by massive intralysosomal accumulation of storage materials. We have studied the protein patterns in 5 NCL, 5 control, and one Alzheimer disease brains. When protein patterns in NCL and control brain gray matter homogenates were examined by SDS-PAGE, NCL brains showed an absence or greatly reduced amounts of the Mr 160-180 kDa component and reduced amounts of the Mr 29-36 kDa component. Concomitantly, an increase in several components with Mrs of 45-50 kDa was noted. The 180 kDa polypeptide appears to be a glycoprotein because it was bound to the lectins concanavalin A and Ulex europaeus. Recently, the abnormal processing of amyloid protein precursor (APP) and its potential role in NCL have been suggested. Possible defects in tissue proteases and protease inhibitors may be considered responsible for the presence of these amyloid beta protein precursor fragments. To examine this possibility we are using polyclonal antibodies to the C terminal 672-695 (APP) and monoclonal antibodies to inter-alpha-trypsin inhibitor. Polypeptides with molecular weights of approximately 35-38 kDa were detected in the NCL brain, but not in controls in both cases. These findings suggest abnormal protein processing in NCL brain tissue, disturbances in protein and glycoconjugate metabolism, impaired lysosomal function (i.e., metabolic enzyme and/or proteases/proteinase inhibitor abnormalities), and the involvement of improperly processed APP.

Adolescent↗
PubMed1992

Head circumference of children with Down syndrome (0-36 months)

This study provides statistically appropriate head circumference reference curves for males and females with Down syndrome (DS) from birth to 36 months of age. A total of 239 males and 182 females from five study populations, yielding a combination of cross-sectional and longitudinal data, were used for the analysis. The method of least squares was used to test the fit of the growth model y = a+bx+c[log(x + 1)], where x is age in months. These standardized curves should provide information of value in the medical, physical, and developmental management of children with DS.

Biometry↗
PubMed1992

The adult and a new late adult forms of neuronal ceroid lipofuscinosis.

Three cases of the late adult form of neuronal ceroid lipofuscinosis (NCL) are reported. Two of these are siblings with a late clinical onset at ages 26 and 44 years. The third case, sporadic, has the oldest reported age for the onset of NCL, at 63 years and may be regarded as the first example of the "presenile" form of NCL. The clinical, morphological, histochemical, ultrastructural and genetic features of these three cases are discussed. The literature of the clinicopathological NCL cases with an onset at age of 25 and older is reviewed. The clinical and morphological differences between the late adult form and the presenile form of NCL as well as the difficulties in making the diagnosis are discussed.

Adult↗
PubMed1992

Glycoprotein metabolism in neuronal ceroid lipofuscinosis fibroblasts.

Human skin fibroblast lines of the infantile form of neuronal ceroid lipofuscinosis and control lines were cultured in the presence of [3H]glucosamine plus [3H]mannose and [35S]methionine. The labeled glycoconjugates were compared by quantitative polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The infantile form of the disease showed a 75% decrease of four glycoprotein components of M(r) 120-140 kDa. These components appeared to be N-linked glycoproteins as peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidase (PNGase F) released 86-96% of the labeled carbohydrate from the labeled protein. These results suggest that the infantile form of this disease may be characterized by abnormalities in glycoconjugate metabolism leading to reduction of specific glycoproteins.

Adolescent↗
PubMed1992

Growth hormone deficiency in Down's syndrome children.

Down's syndrome (DS) children have been reported to have severe postnatal growth arrest and microcephaly. To determine if growth hormone (GH) deficiency plays a role in growth retardation in DS, 20 children were studied. The subjects (13 boys, 7 girls) were aged between 15 months and 13.9 years, had a height SDS ranging from -1.19 to -5.48, weight SDS ranging from -0.21 to -4.58, head circumference SDS ranging from -0.40 to -6.6, and a skeletal age ranging from 0.9 to 4.6 SD below the mean for normal children of same age and sex. GH was evaluated by levodopa (125 mg up to 15 kg, and 250 mg between 15-30 kg), clonidine (0.15 mg m-2) stimulation tests and hGH secretory patterns by the integrated 24 h. GH concentration (IC-GH) using a constant withdrawal pump with continuous blood collection every 30 min. The serum concentrations were: TSH, 0.7-8.0 mIU ml-1 (0.2-5.5); T4, 6.6-14.3 micrograms dl-1 (5-12); T3, 95-254 ng dl-1 (85-185); LH, less than 2.0-8.3 mIU ml-1 (less than 3); FSH, less than 1.3-7.2 mIU ml-1 (less than 3); testosterone, less than 30 ng dl-1 (5-35); estradiol, less than 5 ng dl-1 (less than 5-25); prolactin, 35.7-2.9 (F: 5-25; m 5-15); and somatomedin-C (Sm-C), 0.14-1.98 U ml-1 (0.08-5.90) (normal values in brackets). Peak serum GH after levodopa and clonidine was found to be below 10 ng ml-1 for both stimulatory tests in seven out of the 20 children studied. Twelve children showed a disparity between levodopa and clonidine testing. Of the 12 children, peak serum GH after levodopa was found to be below 10 ng ml-1 in five children; and peak serum GH after clonidine was found to be below 10 ng ml-1 in six. One child had a clonidine peak increase in serum GH concentration exactly 10 ng ml-1, but had a 12 h IC-GH of 1.5 ng ml-1 (N greater than 3.2). Two children with peak GH after clonidine above 10 ng ml-1 had a 24 h IC-GH of 0.7 and 1.3 ng ml-1. A fourth child who had peak GH concentrations above 10 ng ml-1 with levodopa and clonidine had a 12 h IC-GH of 0.5 ng ml-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1992

Ageing in higher functioning adults with Down's syndrome: an interim report in a longitudinal study.

Mildly and moderately mentally retarded adults, who live in the community, were examined for global changes in mental status and specific changes in auditory and visual memory over a period of 3-5 years. Twenty-eight subjects with Down's syndrome (DS) between the ages of 27 and 55 years were compared to 18 subjects without DS who were of similar IQ and age. The evaluation of mental status consisted of testing orientation of person, place and time, object naming, visuomotor coordination, and concentration. Auditory memory was tested with an adapted version of the Buschke Memory test. Visual memory testing consisted of matching shapes which were presented simultaneously and after delays of 0, 5 and 10s on a computer-controlled screen. No changes were found in test scores between an initial testing and follow-up testing up to 5 years later, indicating that ageing processes were not having a major impact in the cognitive functioning of these subjects. Furthermore, there was no indication of any generalized decline in performance suggestive of early symptoms of dementia among the older subjects with DS.

Adult↗
PubMed1992

Reassessment of a chromosome 12q+ marker by fluorescent in situ hybridization (FISH).

We present a case previously described by Jenkins et al. (1983) as atypical Down syndrome (DS). The initial diagnosis was first made on the basis of phenotypic and cytogenetic data. This analysis was supported by studies of superoxide dismutase (SOD1) activity that maps to band 21q22.1. Results from phenotypic, chromosome banding and SOD1 studies suggested a karyotype of 46,XX,-12,+t(12pter to 12qter::21q21 to 21q22.?2). Using fluorescent in situ hybridization (FISH) for chromosome painting with DNA libraries derived from sorted human chromosomes to stain selectively the chromosomes No. 21 and No. 12, we demonstrate that the marker chromosome 12q+ has no chromosome 21 content but it is derived from chromosome 12.

Abnormalities, Multiple↗
PubMed1991

Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone.

The effect of recombinant human growth hormone on children with Down syndrome who had growth retardation and microcephaly was examined. Thirteen children with trisomy 21 without congenital heart disease who were short for age (-1.19 to -3.5 standard deviation score) and microcephalic (-1.58 to -6.60 standard deviation score) were given recombinant human growth hormone, 0.1 mg/kg subcutaneously, 3 days a week for 1 year. Before treatment, peak serum growth hormone concentrations were less than 10 micrograms/L after levodopa and clonidine stimulation tests in five patients, after clonidine in three patients, and after levodopa in three patients. Three patients had nocturnal integrated growth hormone concentrations of 0.5, 1.5 and 0.65 micrograms/L, respectively. The mean growth rate before treatment was 5.4 +/- 1.6 cm/yr and increased to 12.2 +/- 3.2 cm/yr (p less than 0.001) after 12 months of recombinant human growth hormone treatment. The mean head circumference standard deviation score before treatment was -3.1 +/- 1.3 and increased to -2.3 +/- 1.2 (p less than 0.001) at 12 months. Bone age before and 1 year after treatment increased in correspondence with chronologic age. Plasma hemoglobin A1c concentration was normal during treatment with recombinant human growth hormone. The mean plasma concentrations of insulin-like growth factor I at baseline and at 12 months were 0.54 +/- 0.19 U/ml and 1.25 +/- 0.97 U/ml, respectively (p less than 0.02). We conclude that recombinant human growth hormone therapy can result in a significant increase in annual growth rate and head circumference in children with Down syndrome, without significant side effects.

Age Determination by Skeleton↗
PubMed1991

Seizures in children with Down syndrome: etiology, characteristics and outcome.

Of 737 patients with Down syndrome, newborn to 22 years of age, 47 had a history of at least one seizure. Of those, 24 children had seizures with an identifiable etiology, usually related to a common medical complication of Down syndrome: neonatal hypoxia-ischemia, hypoxia from congenital heart disease, or infection. These acute medical illnesses may precipitate seizures in brains already predisposed to hyperexcitability because of abnormal neuronal development. It is recommended that all Down syndrome children with seizures undergo investigations to determine the etiology of the seizure.

Adolescent↗
PubMed1990

Altered amyloid beta-protein precursor processing in brains of patients with neuronal ceroid lipofuscinosis.

Our previous study disclosed strong immunostaining of brain tissue in neuronal ceroid lipofuscinosis (NCL) with antibodies against amyloid beta-protein and the presence of 31-kDa polypeptide in the storage material. In the present study, we investigated the immunoreactivity of the NCL brain tissue with anti-serum (anti-GID) raised against a synthetic peptide, based on the amyloid beta-protein precursor, with the 175-186 amino acid sequence. Immunocytochemistry was performed on autopsy brain material collected from 15 NCL cases, and from 8 age-matched normal controls. The results showed strong immunoreactivity of nerve cells in the NCL cases, which according to densitometry was 5 times more intense than in the control group (P less than 0.0001 by Student's t-test). Western blot analysis revealed that in protein fractions of NCL brain homogenates anti-GID recognized the protein band of 35 kDa. Thus our present and previously performed studies supplied for the first time data pointing to abnormal processing of amyloid beta-protein precursor in NCL. Moreover, the accumulation of both 31- and 35-kDa polypeptides that was demonstrated provides further support for postulated defective protein metabolism in this disorder.

Amyloid beta-Peptides↗
PubMed1990

Beta-protein immunoreactivity in brains of patients with neuronal ceroid lipofuscinosis: ultrastructural and biochemical demonstration.

The storage pigment in neuronal ceroid lipofuscinoses (NCL) has a close similarity to age pigment lipofuscin. We studied immunoreactivity of isolated neuronal pigments from the juvenile form of NCL and aging control, using monoclonal antibodies (mAbs) against amyloid beta-protein. Ultrastructural localization of the immunoreactivity demonstrated that in NCL the epitopes are distributed mainly in curvilinear multilamellar arrays of the storage pigments and less in fingerprint profiles, while in aging control they are more homogeneously distributed on age pigment lipofuscin. The different distribution of the epitopes may reflect some catabolic as well as morphologic differences in lysosomes. A unique 31-kDa polypeptide detected on Western blots in NCL possibly derives from the same precursor, amyloid beta-protein precursor (ABPP). ABPP processing may be aberrant in NCL brains, and this can be detected as a 31-kDa polypeptide reactive with the mAbs.

Adolescent↗
PubMed1990

Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis.

All Down syndrome (DS) children have different degrees of developmental disabilities, developmental delay, and developmental brain abnormalities associated with CNS maturation delay and cortical dysgenesis. We have examined 780 occipitofrontal circumferences (OFC), mean and +/- SD, of DS children from birth to age 5 years. Also, gross and microscopic neuropathological studies in the same age group were performed, with special attention to brain weight (BW), shape, myelin formation, cortical organization of 101 DS and 80 non-DS individuals; ultrastructural studies were also performed on selective cases (five DS and five non-DS). The OFC was plotted on Nellhause curves and showed microcranium after mid-infancy in most cases. Twenty percent of DS children had an OFC in the lower normal range. The brain shape in DS newborn infants was the same as in non-DS infants, but after 3-5 months of age in DS infants the antero-posterior diameter was found to be shorter than in non-DS infants. Narrowness of the superior temporal gyrus was noted in 34 of 101 (33%) of DS brains. Microscopic examination showed myelination delay in 22.5% DS and only in 6.8% non-DS children. Morphometric studies in DS cases from birth showed fewer neurons (20-50% less), lower neuronal densities, and neuronal distribution, especially of cortical layers II and IV. Ultrastructurally in DS, the synaptic density, synaptic length, and contact zones were found to be abnormal. The retardation of brain growth, maturation delay, and cortical dysgenesis present in DS children most likely are regulated by the extra chromosome 21, but the gene responsible for the abnormalities remains to be determined.

Brain↗
PubMed1990

Topographic heterogeneity of amyloid B-protein epitopes in brains with various forms of neuronal ceroid lipofuscinoses suggesting defective processing of amyloid precursor protein.

To verify our hypothesis of defective protease inhibitor domains that are encoded by abnormal processing of amyloid precursor protein (APP) in brains of patients with neuronal ceroid lipofuscinoses (NCL), immunohistochemical and cytochemical studies were performed with monoclonal antibodies (mAbs) directed against various domains of APP. For the studies, 22 autopsy brains were used: 12 with different forms of NCL, and 10 control brains. The staining procedure for the avidin-biotin complex (ABC) technique and the postembedding gold-labelled procedure for electron microscopy (EM) were employed. Of all mAbs used for the study, only mAbs generated against amyloid B-protein bound to neural tissue were affected with NCL. The strongest immunostaining of neurons and of some reactive glial cells was found in brains with the juvenile form of NCL. Only in the infantile form of the disease were some neurons overloaded with storage material weakly immunoreactive. In brains of patients with the adult form of NCL, immunoreactivity was found in affected neurons and in extracellularly deposited material of senile plaques. The results of EM study showed that the immunoreactivity was restricted to lysosomal cytosomes in neural tissue with any form of NCL selectively localized on the curvilinear and fingerprint proteinaceous component of ceroid lipofuscin. Studies performed on control aging brains and Alzheimer's disease (AD) brains confirmed previous observations of immunoreactivity being found diffusely in the protein component of some neurons containing lipopigment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Lectin histochemistry in brains with juvenile form of neuronal ceroid-lipofuscinosis (Batten disease).

Defective utilization of dolichols in the synthesis of glycoprotein leads to an accumulation of the storage, pigment "ceroid" lipofuscin, containing high-mannose-type glycoconjugates, in brains affected by neuronal ceroid-lipofuscinoses (NCL). We have employed lectin histochemistry to study the distribution of such compounds and the composition of other glycoconjugates in brains of patients with a juvenile form of the disease (JNCL). Concanavalin A detected the high-mannose glycoconjugates in all neurons of brains with JNCL, in lipofuscin-containing neurons of aging brains and in some neurons of age-matched control brains. Three other lectins (soybean agglutinin, Peanut agglutinin and Ulex europaeus agglutinin-I) recognized sugar moieties in neurons containing lipofuscin in patients only with JNCL and not in age-matched or aging brains. The results led to the conclusion, that the binding pattern of these three lectins may differentiate between storage materials of NCL and aging brains.

Adolescent↗
PubMed1990

Proteinase inhibitor alpha 1-antichymotrypsin has different expression in various forms of neuronal ceroid lipofuscinosis.

Defective proteolytic degradation is most widely maintained as the major pathogenetic factor in neuronal ceroid lipofuscinosis (NCL). The goal of the present study was to examine the expression in NCL brain tissue of one of the serine proteinase inhibitors, alpha 1-antichymotrypsin. Our study was based on previous findings of alpha 1-antichymotrypsin association with CNS amyloidoses related to amyloid beta protein deposits and our previous findings suggesting abnormal processing of amyloid beta-protein precursor (ABPP) in NCL brains. Immunocytochemical study was performed on formalin-fixed brain tissues collected from 15 NCL cases representing four different forms of the disorder and from 16 control cases comprising age-matched controls, older nondemented individuals, and Alzheimer disease cases. Our present study has shown that the expression of alpha 1-antichymotrypsin is generally higher in NCL cases than in control cases; however, it manifests in distinct variations of intensity and proportions of immunostained cells. The strongest immunoreactivity was found in the infantile form of NCL, which is characterized by a rapid clinical course and widespread tissue damage. We found no evidence of direct involvement of alpha 1-antichymotrypsin in either the ceroid lipopigment accumulation or the abnormal processing of ABPP in NCL. However, our findings may reflect the heterogeneity of the pathomechanism underlying this group of disorders and suggest that, similarly to blood circulation, alpha 1-antichymotrypsin can also represent an acute-phase protein in brain tissue.

Astrocytes↗