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Biomedical subjects

R Herva

Publications and source records attributed to R Herva.

At least 19 recordsLinked to original sources
PubMed2002

Acute bilateral exercise-induced medial compartment syndrome of the thigh. Correlation of repeated MRI with clinicopathological findings.

We present a case report of acute bilateral excercise-induced compartment syndrome in the adductor longus muscles, which was treated with bilateral medial fasciotomies. Postoperatively, the healing process of the adductor muscles was followed up by repeated MR imagings over six months. Myonecrosis was found in peroperative muscle biopsies. Pain and muscle swelling subsided soon after the fasciotomy, correlating with the early postoperative MR findings. Four months postoperatively, the signal intensity of the adductor muscles was normal in T1- and T2-weighted images, but the normal fibre structure of the adductor muscles could only be seen 6 months postoperatively. At six month's control checkup there was no subjective weakness of the adductors, and hyperesthesia had disappeared and the patient was capable of normal activities.

Adult↗
PubMed2001

Extensive somatic microsatellite mutations in normal human tissue.

Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Inherited susceptibility to uterine leiomyomas and renal cell cancer.

Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.

Adult↗
PubMed2001

A novel mitochondrial DNA mutation and a mutation in the Notch3 gene in a patient with myopathy and CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral symptoms, but peripheral nerve or muscle involvement has not been reported. We describe a patient who had a stereotypic clinical presentation of CADASIL and, in addition, myopathy with ragged-red fibers, suggesting a mitochondrial disorder. Therefore we determined the nucleotide sequence in the entire coding region of the patient's mtDNA by conformation-sensitive gel electrophoresis and sequencing. Sequence of the exon 4 in the Notch3 gene was determined in a similar fashion. We found that the patient had myopathy with ragged-red fibers, and ultrastructural examination revealed mitochondrial aberrations. CADASIL was due to an R133C mutation in Notch3; in addition, we found a novel mutation 5650G>A in the tRNAAla gene in mtDNA. The mutation was heteroplasmic, with the proportions of the mutant genome being 99% in muscle, 96% in the buccal epithelium, 95% in the skin, and 65% in the blood. The absence of the mutation in a maternal cousin four times removed indicated that it was new in the pedigree. We suggest that the mtDNA mutation is pathogenic, as it was associated with a relevant clinical phenotype, it was not found among controls, and it altered a structurally important segment in the amino acid acceptor stem in the tRNAAla. Furthermore, its absence in nine patients from five families with R133C suggests that its relationship with the Notch3 mutation is coincidental.

Base Sequence↗
PubMed2001

Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.

Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.

Adult↗
PubMed2001

Human macrophage metalloelastase (MMP-12) expression is induced in chondrocytes during fetal development and malignant transformation.

Fetal development and tumor progression both require a complex system of extracellular matrix (ECM) synthesis and breakdown, which is mediated by, for instance, the matrix metalloproteinases (MMPs). Human metalloelastase (MMP-12) is an MMP, the expression of which has so far been documented in macrophages associated with atherosclerosis, wound repair, and certain cancers. In this study we first examined the expression of MMP-12 during human fetal development. By in situ hybridization MMP-12 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column, in ribs, and in extremities undergoing ossification, beginning at the gestational age of 8 weeks. Also, periosteal cells expressed MMP-12 at 11 weeks. No expression of MMP-12 mRNA could be noted in other fetal tissues, including the skin, lungs, intestine, kidney, and liver. Expression of MMP-12 mRNA could not be detected in adult normal cartilage or osteosarcomas, but in chondrosarcomas both macrophages (8 of 19 samples) (identified by CD68 immunostaining) and chondrosarcoma cells (8 of 19) were positive. MMP-12 was also demonstrated in the tumors by western blotting and it was expressed in the same regions as MMP-13 mRNA. By immunostaining, MMP-12 mRNA colocalized with the protein in both fetal and chondrosarcoma specimens. Unlike basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) induced MMP-12 mRNA production in chondrosarcoma-derived HTB-94 cells. Our results suggest that MMP-12 plays an important role in ECM remodeling during fetal bone development and is induced when chondrocytes undergo malignant transformation.

Bone Neoplasms↗
PubMed2001

Hippocampal lesions in the neuronal ceroid lipofuscinoses.

Epilepsy is a common manifestation in all childhood-onset forms of neuronal ceroid lipofuscinosis. In order to document hippocampal lesions and their relationship to epilepsy we studied autopsy specimens from the hippocampi of a series of patients with the infantile (CLN1), classic late infantile (CLN2), Finnish variant late infantile (CLN5), and juvenile (CLN3) neuronal ceroid-lipofuscinosis as well as Northern epilepsy (CLN8), using a battery of histological and immunocytochemical staining methods. Despite striking differences in the overall degree of neocortical neuronal storage and loss, these genetically heterogeneous forms of neuronal ceroid lipofuscinosis showed a common lesional pattern in the hippocampi: a relative sparing of the CA1 sector and severe involvement of the neighbouring CA2 sector, with intermediate degrees of involvement of the CA3 and CA4 sectors. These findings distinguish the hippocampal pathology associated with the neuronal ceroid lipofuscinoses from classical 'mesial temporal sclerosis' and show that the selective lesional pattern in the neuronal ceroid lipofuscinoses is not a secondary anoxic-ischaemic phenomenon. It is rather a consequence of the primary metabolic defects and may be directly involved in the causation of the epileptic discharges.

Child↗
PubMed2001

Second primary glioblastoma.

Although characterized by a highly variable phenotype and multiple genetic alterations, glioblastomas are considered monoclonal in origin. We here report on a 64-yr-old patient who developed a second glioblastoma in the left frontal lobe 10 yr after surgical resection of a glioblastoma of right frontal lobe. The first tumor contained 2 p53 mutations, in codon 213 (CGA-->TGA, Arg-->stop) and codon 306 (CGA-->TGA, Arg-->stop), further, 1 missense PTEN mutation (codon 257, TTC-->TTA, Phe-->Leu) and a silent PTEN mutation (codon 154, TTC-->TTT, Phe-->Phe). The second glioblastoma also contained multiple, but different mutations: p53 mutations in codons 158 (CGC-->CAC, Arg-->His) and 273 (CGT-->TGT, Arg-->Cys), and a PTEN mutation in codon 233 (CGA-->TGA, Arg-->Stop). Both neoplasms had a homozygous p16 deletion. The discordant pattern of mutations indicates that the second glioblastoma was not a recurrence but an independent second glioblastoma. The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome.

Chromosomes, Human, Pair 10↗
PubMed2001

Distribution and mRNA expression of tenascin-C in developing human lung.

Tenascin-C is an extracellular matrix glycoprotein that is spatially expressed during organogenesis, in inflammatory and fibrotic disorders, and in neoplasms. The aim of this study was to analyze its expression in developing human lung tissues during pseudoglandular, canalicular, saccular, and alveolar periods corresponding to Weeks 12 to 40. Lung tissues were obtained at autopsy from 34 nonmalformed cases. An immunohistochemical analysis and a messenger RNA (mRNA) in situ hybridization method combined with light microscopy were used. The extent of tenascin-C immunoreactivity was scored as absent, low, moderate, or strong in and around different types of pulmonary cells. The immunohistochemical expression for tenascin-C was strong beneath the airway epithelium, especially at the sites of airway subdivision during Weeks 12 to 23, whereas its expression was moderate or weak underneath alveolar and bronchiolar epithelia between Weeks 24 and 40. The expression for tenascin-C was strong in the intima of veins, especially in the canalicular period, i.e., Weeks 17 to 28. A moderate or strong immunoreactivity for tenascin-C was also observed around chondrocytes in every case studied during all periods. The increased expression of tenascin-C mRNA was most often seen in the cells below the airway epithelium. Taken together, tenascin-C is expressed in human lung during all developmental periods, and its expression is especially strong below the airway epithelium at the sites of airway subdivision.

Gestational Age↗
PubMed2001

Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4.

The majority of oocytes present in fetal ovaries are depleted before birth, and only about 400 will ovulate during the normal fertile life span. Studies on animals have shown that apoptosis is the mechanism behind oocyte depletion and follicular atresia. In the present study, we investigated the extent and localization of apoptosis in human fetal (aged 13-40 weeks) and adult ovaries. Furthermore, the expression of apoptosis-regulating proteins, bcl-2 and bax, and the relationship of transcription factor GATA-4 were studied. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14-28, decreasing thereafter toward term. Expression of bcl-2 was observed only in the youngest fetal ovaries (weeks 13-14), and bax was present in the ovaries throughout the entire fetal period. In adult ovaries, apoptosis was detected in granulosa cells of secondary and antral follicles, and Bcl-2 and bax were expressed from primary follicles onwards. During fetal ovarian development, GATA-4 messenger RNA and protein were localized to the granulosa cells, with expression being highest in the youngest ovaries and decreasing somewhat toward term. The expression pattern of GATA-4 suggests that it may be involved in the mechanisms protecting granulosa cells from apoptosis from fetal to adult life. The results indicate that depletion of ovarian follicles in the human fetus occurs through intrinsic mechanisms of apoptosis in oocytes, and later in adult life the survival of growing follicles may be primarily determined by granulosa cell apoptosis.

Aging↗
PubMed2000

Human herpesvirus-6 associated encephalitis with subsequent infantile spasms and cerebellar astrocytoma.

A 14-month-old girl presented after 3 days of fever, floppiness, and diffuse urticarial exanthem. She developed encephalitis and carditis and 1 week later, intractable seizures. Initial CT and MRI showed no changes in the brain parenchyma. On days 14 and 34 after the onset of symptoms, a human herpesvirus-6 (HHV-6) genome in cerebrospinal fluid was identified by polymerase chain reaction (PCR). Convulsions became more frequent and 11 weeks from the onset, they changed to typical infantile spasms with hypsarrhythmic electroencephalogram. She gradually lost her social contact and ability to walk and sit. Eleven months after the primary infection, a repeated MRI of the brain revealed a cystic tumour of 2 cm in diameter near the vermis. The tumour was surgically removed, and shown to be a pilocytic astrocytoma on histopathological examination. HHV-6 DNA was detected by PCR in new tumour tissue. This is the first reported case of HHV-6 encephalitis associated with carditis, infantile spasms, and a subsequent brain tumour containing the HHV-6 genome.

Astrocytoma↗
PubMed2000

Matrix metalloproteinase 2 (MMP-2) immunoreactive protein is associated with poor grade and survival in brain neoplasms.

UNLABELLED: Matrix metalloproteinases play an important role in the invasion of tumor cells and the progression of cancer. The 72 kDa type IV collagenase, a matrix metalloproteinase 2 (MMP-2) has been shown to contribute to the invasion and metastasis in diverse malignant neoplasms. OBJECT: To elaborate the potential role of MMP-2 in brain tumor invasion we studied the expression and localization of this enzyme protein in 101 brain tumors representing different types of brain neoplasms. For the first time, we also correlated the expression of MMP-2 protein to patient survival. METHODS: Using immunohistochemistry and a monoclonal antibody specific for MMP-2 we found that MMP-2 protein was primarily localized in tumor cells and vasculature cells as well as inflammatory cells. The expression of MMP-2 was absent or negligible in benign tumors (pilocytic astrocytoma and meningioma). Thirty-three percent (6/18) of astrocytomas, 38% (3/8) of anaplastic astrocytomas, 14% (1/7) of anaplastic oligodendrogliomas, 54% (19/35) of glioblastomas and 100% (6/6) of metastatic brain tumors were positive for MMP-2. A correlation between MMP-2 expression and survival was found in malignant brain tumors. The mean survival of patients with an MMP-2 negative tumor was 36 months, when it was only 7-14 months in patients with an MMP-2 positive tumor. CONCLUSIONS: Our data suggest that MMP-2 is associated with histological malignancy and poor survival in brain tumors.

Adult↗
PubMed2000

Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis.

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.

Adult↗
PubMed2000

Expression of transcription factor GATA-4 during human testicular development and disease.

GATA-4 is a highly conserved transcription factor that plays a critical role in regulating embryonic morphogenesis and cellular differentiation. Given the emerging role of GATA-4 in the development and function of murine gonads, we have now studied its role in human testis. We find that GATA-4 is expressed from early human fetal testicular development to adulthood. This transcription factor is evident in Sertoli cells through fetal and postnatal development. Expression of GATA-4 in Sertoli cells peaks at 19-22 weeks gestation at the time of high circulating fetal FSH. In Leydig cells, GATA-4 is expressed during fetal period and after puberty, coinciding with the periods of active androgen synthesis in the testis; this suggests a link between GATA-4 and steroidogenesis. Also, fetal germ cells and prepubertal spermatogonia express GATA-4, and it is down-regulated in these cells after puberty. As hormonal regulation of GATA-4 in human testis was not possible to study directly, we used testicular samples from patients who had endocrine abnormalities or were hormonally treated. Testicular expression of GATA-4 in hCG-treated cryptorchidism does not differ from that in controls. In androgen resistance, GATA-4 expression in Sertoli and germ cells is weak or totally absent. GATA-4 protein is abundantly present in Sertoli and Leydig cell tumors, suggesting a relationship to tumorigenesis or tumor progression in somatic cell-derived testicular neoplasms.

Adult↗
PubMed2000

Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders.

OBJECTIVES: To assess the frequency of mitochondrial abnormalities in muscle histology, defects in respiratory chain enzyme activities, and mutations in mitochondrial DNA (mtDNA) in children with unexplained psychomotor retardation in the population of Northern Finland. BACKGROUND: The frequency of mitochondrial diseases among patients with childhood encephalopathies and myopathies is not known. Frequencies are difficult to estimate because the clinical presentation of these disorders is variable. METHODS: A total of 116 consecutive patients with undefined encephalopathies and myopathies were enrolled during a 7-year period in a hospital serving as the only neurologic unit for a pediatric population of 97 609 and as the only tertiary level neurologic unit for a pediatric population of 48 873. Biochemical and morphologic investigations were performed on muscle biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, electron microscopy, and molecular analysis of mtDNA. RESULTS: Ultrastructural changes in the mitochondria were the most common finding in the muscle biopsies (71%). Ragged-red fibers were found in 4 cases. An oxidative phosphorylation defect was found in 26 children (28%), complex I (n = 15) and complex IV (n = 13) defects being the most common. Fifteen percent of patients (n = 17/116) with unexplained encephalomyopathy or myopathy had a probable mitochondrial disease. Common pathogenic mutations were found in the mtDNA of only 1 patient (.9%). CONCLUSIONS: The common known mutations in mtDNA are rarely causes of childhood encephalomyopathies, which is in contrast to the considerable frequency of the common MELAS mutation observed among adults in the same geographical area. Biochemically and morphologically verified mitochondrial disorders were nevertheless common among the children, making the analysis of a muscle biopsy very important for clinical diagnostic purposes.

Adolescent↗
PubMed1998

Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome.

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal-recessive disorder, characterized by massive proteinuria in utero and nephrosis at birth. In this study, the 150 kb critical region of NPHS1 was sequenced, revealing the presence of at least 11 genes, the structures of 5 of which were determined. Four different mutations segregating with the disease were found in one of the genes in NPHS1 patients. The NPHS1 gene product, termed nephrin, is a 1241-residue putative transmembrane protein of the immunoglobulin family of cell adhesion molecules, which by Northern and in situ hybridization was shown to be specifically expressed in renal glomeruli. The results demonstrate a crucial role for this protein in the development or function of the kidney filtration barrier.

Amino Acid Sequence↗
PubMed1998

Assignment of the disease locus for lethal congenital contracture syndrome to a restricted region of chromosome 9q34, by genome scan using five affected individuals.

Lethal congenital contracture syndrome (LCCS) is an autosomal recessive disease leading to death before the 32d gestational week. It is characterized by the fetal akinesia phenotype, with highly focused degeneration of motoneurons in the spinal cord as the main neuropathological finding. We report here the assignment of the LCCS locus to a defined region of chromosome 9q34, between markers D9S1825 and D9S1830. The initial genome scan was performed with the DNA samples of only five affected individuals from two unrelated LCCS families. The conventional linkage analysis performed with 20 affected individuals and their families was focused on those chromosomal regions in which the affected siblings were identical by descent in the initial scan. One core haplotype of 3 cM was observed in LCCS alleles, supporting the assumption of one major mutation underlying LCCS, and linkage disequilibrium analysis restricted the critical chromosomal region to <100 kb in the vicinity of marker D9S61. Two genes, NGAL (neutrophil gelatinase-associated lipocalin and NOTCH 1, were excluded as causative genes for LCCS

Chromosome Mapping↗