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Biomedical subjects

J Rapola

Publications and source records attributed to J Rapola.

At least 37 records · Page 2Linked to original sources
PubMed1997

Hypoparathyroidism in a patient with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation.

Mitochondrial trifunctional protein (MTP), an enzyme complex participating in fatty acid beta-oxidation, is the potential site of two documented defects: long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) and MTP deficiencies. LCHAD deficiency usually manifests as hypoglycemia, with hepatopathy, hypotonia, cardiomyopathy, and retinopathy. Hypoparathyroidism has been detected in a patient with MTP deficiency. We now report on a patient with LCHAD deficiency and hypoparathyroidism, evidenced by hypocalcemia, hyperphosphatemia, and a low level of parathyroid hormone, in whom the parathyroid glands could not be located after death.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1996

Prenatal diagnosis of Batten's disease.

BACKGROUND: Batten's disease is the most common progressive encephalopathy of childhood in Western countries. The major mutation is a 1kb deletion, which is carried by 81% of Batten's disease patients. We report on the use of direct gene analysis in the prenatal diagnosis of this disease. METHODS AND FINDINGS: A Finnish woman with a son with Batten's disease came for genetic counselling for her current pregnancy. Electron microscopy of a chorionic villus sample gave suggestive findings. We used PCR to look for the intragenic microsatellite marker D16S298; 96% of Finnish Batten's disease patients carry allele 6 at this marker. The fetus and the affected son both carried the same high-risk genotype, 6/6. Both were homozygous for the 1 kb deletion. The pregnancy was terminated. Electron microscopy of the fetus showed typical Batten's disease changes. INTERPRETATION: We have successfully used direct gene analysis in the prenatal diagnosis of Batten's disease.

Base Sequence↗
PubMed1996

Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation.

Lactic acidosis and mitochondrial abnormalities have been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We studied muscle morphology and the respiratory chain function in ten patients with LCHAD deficiency and the G1528C mutation. In eight cases the light microscopy of muscle specimens showed fatty infiltration and fibre degeneration. The degenerated fibres appeared as ragged red fibres in four cases. Electron microscopy revealed enlarged mitochondria often with swollen appearance in four out of seven patients. The number of mitochondria had also increased. Complex I associated enzyme activities in muscle mitochondria were decreased in five out of seven patients, and in three of them Complex II or II + III associated activities were also affected. We suggest that the reason for respiratory chain dysfunction and structural changes of mitochondria is the accumulation of toxic intermediates of fatty acid beta-oxidation in mitochondria. Because these changes may confound the differential diagnostics between LCHAD deficiency and respiratory chain defects, awareness of their frequency is important.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1996

Treatment with human chorionic gonadotrophin for cryptorchidism: clinical and histological effects.

The efficacy of hCG treatment was studied in 182 cryptorchid patients. The efficacy of the treatment correlated with the initial position of the testis. None of the abdominal testes reached a normal position, whereas 90% of high scrotal testes descended during the treatment. Fifty-four boys who were treated unsuccessfully with hCG and 29 untreated boys were biopsied. The biopsies were performed on 32 scrotal and 87 maldescended testes to examine the state of the organ and the effects of hCG treatment. In biopsies, the volume densities of seminiferous tubules, interstitial tissue and blood vessels were counted, and the sections screened for interstitial bleeding. Significant differences between scrotal and maldescended testes were found in all of the volume densities measured. Interstitial bleeding occurred rarely in scrotal testes, whereas in maldescended testes it was frequently apparent. hCG treatment induced a significant increase in the volume density of both interstitial tissue and blood vessels. Even though the hCG treatment induced measurable, possibly harmful, changes both in scrotal and maldescended testes, our data do not prove that hCG treatment causes permanent damage to the testis.

Adolescent↗
PubMed1996

Postmarathon paradox: insulin resistance in the face of glycogen depletion.

Acute physical exercise enhances insulin sensitivity in healthy subjects. We examined the effect of a 42-km marathon run on insulin sensitivity and lipid oxidation in 19 male runners. In the morning after the marathon run, basal serum free fatty acid concentration was 2.2-fold higher, muscle glycogen content 37% lower (P < 0.01), glycogen synthase fractional activity 56% greater (P < 0.01), and glucose oxidation reduced by 43% (P < 0.01), whereas lipid oxidation was increased by 55% (P < 0.02) compared with the control study. During euglycemic-hyperinsulinemic clamp, whole body glucose disposal was decreased by 12% (P < 0.01) because of a 36% lower glucose oxidation rate (P < 0.05), whereas the rate of lipid oxidation was 10-fold greater (P < 0.02) than in the control study. After the marathon, muscle glycogen content correlated positively with lipid oxidation (r = 0.60, P < 0.05) and maximal aerobic power (Vo2peak; r = 0.61, P < 0.05). Vo2peak correlated positively with basal lipid oxidation (r = 0.57, P < 0.05). In conclusion, 1) after the marathon run, probably because of increased lipid oxidation, the insulin-stimulated glucose disposal is decreased despite muscle glycogen depletion and the activation of glycogen synthase; 2) the contribution of lipid oxidation in energy expenditure is increased in proportion to physical fitness; 3) these adaptations of fuel homeostasis may contribute to the maintenance of physical performance after prolonged exercise.

Adult↗
PubMed1996

In vivo purging of bone marrow in children with poor-risk neuroblastoma for marrow collection and autologous bone marrow transplantation.

PURPOSE: To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used. PATIENTS AND METHODS: Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT. RESULTS: Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease. CONCLUSION: In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Adolescent↗
PubMed1996

Apoptotic cell death in the normal and cryptorchid human testis: the effect of human chorionic gonadotropin on testicular cell survival.

Cryptorchidism is associated with histologic changes in the human testis apparent by 2 y of age. The mechanism accounting for these changes is still unknown. To clarify whether apoptosis plays a role in human cryptorchidism, we evaluated its occurrence in cryptorchid testes of 73 prepubertal boys, 43 of whom had received human chorionic gonadotropin (hCG) treatment. The histologic samples in our study included both scrotal and inguinal testes. Using an in situ apoptosis detection method, we were able to demonstrate that both interstitial cells and germ cells were affected and that the specific germ cells undergoing apoptosis were exclusively spermatogonia. Apoptosis in situ was further seen in both scrotal and inguinal tests; in scrotal testes the numbers of apoptotic spermatogonia were 170% of those seen in the cryptorchid testes (p < 0.05). Analysis of apoptotic DNA fragmentation from isolated DNA of a few selected biopsy samples served to validate our in situ findings. The amount of germ cell apoptosis analyzed during the 1st mo after hCG treatment was increased in both scrotal and inguinal testes compared with the amount before treatment (p < 0.001). But after the 1st mo it returned to the initial level, suggesting that hCG (and/or androgen) withdrawal increases germ cell apoptosis in the human testis. Our findings lead to the conclusion that apoptosis is a hormonally controlled, normal phenomenon in a human prepubertal testis and that cryptorchidism decreases its occurrence by reducing the number of germ cells capable of undergoing apoptosis.

Apoptosis↗
PubMed1995

Evolution of glomerular basement membrane changes in chronic rejection.

We have investigated the evolution of chronic glomerular changes in the absence of the recurrence of original disease in an experimental rat model of chronic renal allograft rejection. Using serial graft needle biopsies and serum creatinine levels, we were able to focus on early glomerular changes that are associated with good graft function. The recipient rats were divided into 5 groups, 2 with allogeneic (DA to WF) transplants and 3 with syngeneic (DA to DA) transplants. In the first 2 allogeneic groups, one group received cyclosporine (CsA) for 2 weeks (n = 7) and the other received CsA for 12 weeks (n = 5). In the 2-week treatment group, all allografts developed chronic rejection, compared with none in the 12-week group. Syngeneic controls received CsA for 2 (n = 3) and 12 weeks (n = 3), or no immunosuppression (n = 2) in order to exclude the effects of CsA. The first detectable ultrastructural event was slight deposition of electron lucent material in the glomerular basement membrane. Contrary to previous morphological studies, the initial deposition was not subendothelial, but was within the lamina densa itself. Examination of allogeneic grafts with good graft function and syngeneic grafts showed glomerular alterations that were similar to the early changes preceding chronic rejection. The intensity of changes in optimally immunosuppressed allografts was mild, and they were arrested early in the evolving stage of glomerular basement membrane changes. In the suboptimally immunosuppressed allografts with chronic rejection, the glomerular basement membrane changes became more pronounced and extensive in subsequent biopsies. Thus, all recipients in different groups showed similar glomerular alterations, but to different intensities. These results suggest a common pathogenetic mechanism which might be endothelial damage. In chronic rejection, the endothelial damage might be immunologically mediated by rejection episodes and progressive, whereas in syngeneic grafts and in allografts without chronic rejection, perioperative trauma, ischemia, and graft reperfusion may be responsible for the self-limiting glomerular changes.

Animals↗
PubMed1995

Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCL) represent a group of common progressive encephalopathies of children which have a global incidence of 1 in 12,500. These severe brain diseases are divided into three autosomal recessive subtypes, assigned to different chromosomal loci. The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy. The molecular pathogenesis underlying the selective loss of neurons of neocortical origin has remained unknown. Here we report the identification, by positional candidate methods, of defects in the palmitoyl-protein thioesterase gene in all 42 Finnish INCL patients and several non-Finnish patients. The most common mutation results in intracellular accumulation of the polypeptide and undetectable enzyme activity in the brain of patients.

Amino Acid Sequence↗
PubMed1995

Diagnosis of fatal infantile defects of the mitochondrial respiratory chain: age dependence and postmortem analysis of enzyme activities.

We studied two diagnostic aspects of fatal infantile defects of the mitochondrial respiratory chain: the age dependence of muscle mitochondrial enzyme activities and the reliability of diagnosis from autopsy samples. In morphologically normal quadriceps muscle samples of 46 children between the ages of 3 days and 15 years, activities of complex I plus III (NADH:cytochrome c oxidoreductase) and complex II plus III (succinate:cytochrome c oxidoreductase) increased 2-fold during the first three years of life, while that of complex II (succinate dehydrogenase), complex IV (cytochrome c oxidase), and citrate synthase did not show significant correlation with age. We suggest that these changes are related to age and stress the importance of strictly age-matched controls when diagnosing a mitochondrial disease of early childhood. The value of autopsy samples in diagnostic studies was evaluated by comparing mitochondrial enzyme activities in quadriceps muscle from autopsies and from surgical biopsies. In quadriceps muscle mitochondria, all the enzyme activities studied remained stable for at least 3 h after death. Using age-matched controls and autopsy samples, we diagnosed a respiratory chain enzyme deficiency in two infants, and the defects were confirmed in cultured skin fibroblasts.

Adolescent↗
PubMed1995

Alpha-actinin in nemaline bodies in congenital nemaline myopathy: immunological confirmation by light and electron microscopy.

To elucidate the protein composition of the nemaline bodies present in the muscle fibres of patients with congenital nemaline myopathy (CNM), we studied muscle biopsies with monoclonal antibodies against alpha-actinin and desmin in combination with a modified Gomori trichrome method. Electron microscopy of immunolabelled resin embedded sections was used for cytochemical localisation of alpha-actinin and desmin. Light microscopy of sections immunolabelled for alpha-actinin showed a cross-striation of the muscle fibres corresponding to the Z band pattern, focal thickening of the Z bands and additional reactivity with a granular pattern corresponding to the presence of nemaline bodies. Labelling of desmin did not show a similar pattern. Electron microscopy confirmed the presence of alpha-actinin in the nemaline bodies and Z bands, whereas desmin was only found in intermediate filaments around the Z bands. Western blots showed single, sharp alpha-actinin bands indistinguishable from normal. Our results provide direct evidence for the presence of alpha-actinin in nemaline bodies and a lack of quantitative or qualitative differences between the alpha-actinin of normal and CNM muscle.

Actinin↗
PubMed1995

Osteitis caused by bacille Calmette-Guérin vaccination: a retrospective analysis of 222 cases.

To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by bacille Calmette-Guérin (BCG) vaccination, medical records from Finnish children based on nationwide registration from 1960 to 1988 were retrospectively analyzed. During the study period, three different BCG vaccine preparations were used. In 222 children, diagnostic criteria of BCG osteitis were fulfilled. The age at onset of BCG osteitis varied from 0.25 to 5.7 years. The most common sites of osteitis were metaphyses of the long bones. The lower extremity (58%) was affected more often than the upper (14%). Osteitis was situated in the sternum in 36 patients (15%) and in the ribs in 27 (11%). The frequency of BCG osteitis, but not the clinical parameters, was closely associated with the vaccine preparation used. Only 6 children were left with some sequelae. With adequate treatment, the prognosis for children vaccinated with BCG is good.

BCG Vaccine↗
PubMed1995

Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome.

We describe a four-generation family with a maternally inherited mitochondrial disorder. The symptoms were restricted to the CNS and muscle, the most common features being subacute necrotizing encephalomyopathy, cognitive impairment, ataxia, retinitis pigmentosa, infantile spasms, and optic atrophy. A point mutation at the nucleotide 8993 of the gene encoding subunit 6 of the ATP synthase, associated with the neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP) syndrome, was shown to be inherited maternally in this family, and a clear correlation was found between the clinical severity of the disease and the proportion of mutant mtDNA. Analysis of oxidative phosphorylation in mitochondria carrying 80% mutant mitochondrial DNA showed a reduction of the ATP generation rate coupled to substrate oxidation.

Adolescent↗
PubMed1995

Glomerular anionic charge in congenital nephrotic syndrome of the Finnish type.

Decrease of the anionic charge of the glomerular basement membrane and especially the reduced amount of heparan sulphate proteoglycan in the lamina rara externa has been suggested to be the basic pathogenetic defect in congenital nephrotic syndrome. In the present study the anionic charge of glomeruli was examined in the congenital nephrotic syndrome of the Finnish type and in controls using cationic stains (polyethyleneimine, Ruthenium Red) in electron microscopy. Chondroitinase and heparinase treatments were used to characterize further the anionic elements detected. Scanning electron microscopy (SEM) was used in addition to transmission electron microscopy (TEM) to examine the tridimensional structure and secondary changes of podocytes in this syndrome. The number (mean +/- SD) of polyethyleneimine granules per 1 micron length of lamina rara externa of the glomerular basement membrane was 24.9 +/- 4.5 in control and 23.2 +/- 4.3 [corrected] in congenital nephrotic syndrome subjects. The Ruthenium Red staining pattern was closely similar in syndrome and control kidneys. The granules evident after staining with either cationic stain were seen after chondroitinase but not after heparinase treatment in control as well as in syndrome patient kidney samples. No denuded areas of basement membrane in 42 glomeruli from four syndrome patients were found in SEM. In conclusion, the amount of anionic sites in the lamina rara externa as detected by either cationic stain was comparable to controls. These results do not support the hypothesis of decreased anionic sites in the lamina rara externa of the glomerular basement membrane in congenital nephrotic syndrome of the Finnish type.

Anions↗
PubMed1994

Sensory neuropathy in infantile onset spinocerebellar ataxia (IOSCA).

Infantile onset spinocerebellar ataxia with sensory neuropathy is a new, inherited multisystem disorder discovered in 19 Finnish patients. In order to define the neuropathy of the disease, we measured sensory nerve action potentials and nerve conduction velocities in 18 patients, and recorded somatosensory evoked potentials (SEP) in 10 patients and performed a sural nerve biopsy in 13 patients. The fixed and teased nerve fascicles were examined by light and electron microscopy, and the whole transverse section of a nerve fascicle was photographed and enlarged for morphometric measurements. Our investigation revealed an early onset, rapidly progressive axonal neuropathy: the sensory action potentials were decreased after the age of 2 and a severe loss of mainly large myelinated fibers was found.

Adolescent↗
PubMed1994

Lysosomal storage diseases in adults.

Most lysosomal storage disorders are known as pediatric diseases. In recent years late onset and adult forms of these disorders have been recognized. The adult form of a given lysosomal storage disorder differs from the childhood disease in several respects. Adult disorders are, with some exceptions, less common than the childhood diseases. The clinical picture is not only less severe, but often shows quite different clinical signs and symptoms than the early onset form. Metachromatic leucodystrophy, GM1 and GM2 gangliosidoses, Gaucher disease and aspartylglucosaminuria are presented as examples of lysosomal storage disorders manifesting as adult diseases. The differences of the early and late onset disorders are discussed in the light of recent results of molecular genetics, residual enzyme activity and pseudodeficiency.

Acetylglucosamine↗
PubMed1994

Pathology of renal arteries of dyslipidemic children with congenital nephrosis.

Congenital nephrotic syndrome of the Finnish type (CNF) is well characterized in infants and associated with major lipid risk factors for atherosclerosis. This study was undertaken to investigate if any arterial pathology is present in children with CNF and, if so, to describe its nature in renal arteries collected at nephrectomy at a mean age of 12.5 +/- 4.4 months. Denuded endothelial injury and intimal thickening were seen in 9 out of 10 patient specimens of renal arteries. Intimal thickening contained loose abundant extracellular matrix with a few smooth muscle or myofibroblastoid cells. Only a few Sudan black- or oil red O-positive lipid droplets were found in six and seven samples, respectively. Areas immunoreactive with antibodies against apoprotein B were seen in only two specimens. Immunohistochemistry did not reveal any activated T or B cells, or any expression of IL-1 or IL-2 receptors. Macrophages were present in only two specimens. No foam cells were seen. We conclude that the vascular pathology together with altered lipoprotein metabolism indicates that children with CNF might be at risk for early atherosclerotic arterial disease, particularly if their hyperlipidemia persists.

Apolipoproteins B↗