Exercise capacity, daily activity, and severity of fatigue in term born young adults after neonatal respiratory failure.

Little is known about long-term effects of neonatal intensive care on exercise capacity, physical activity, and fatigue in term borns. We determined these outcomes in 57 young adults, treated for neonatal respiratory failure; 27 of them had congenital diaphragmatic hernia with lung hypoplasia (group 1) and 30 had normal lung development (group 2). Patients in group 2 were age-matched, with similar gestational age and birth weight, and similar neonatal intensive care treatment as patients in group 1. All patients were born before the era of extracorporeal membrane oxygenation, nitric oxide administration, and high frequency ventilation. Exercise capacity was measured by cycle ergometry, daily physical activity with an accelerometry-based activity monitor, and fatigue by the fatigue severity scale. Median (range) VO2peak in mL/kg/min was 35.4 (19.6-55.0) in group 1 and 37.6 (15.7-52.7) in group 2. There was a between-group P-value of 0.65 for exercise capacity. Daily activity and fatigue were also similar in both groups. So, residual lung hypoplasia did not play an important role in this cohort. There were no significant associations between exercise capacity and perinatal characteristics. Future studies need to elucidate whether exercise capacity is impaired in patients with more severe lung hypoplasia who nowadays survive.

Biological and karyotypic characterization of a new cell line derived from human gliosarcoma.

A cell line (NCE-G28) was established from the biopsy material of a human gliosarcoma of low histological differentiation. The initial cultures showed a mixed population of cells which in later stages became more uniform due to loss of slower growing constituents. The cells have been growing steadily for 20 months. A suspension of NCE-G28 cells injected s.c. as well as i.p. into nude mice produced solid tumors in all cases. Histologically these tumors closely resembled the original tumor. The original tumor, the nude mouse tumor, and NCE-G28 cells were immunochemically positive for glial fibrillary acidic protein as well as for neural plasma membrane antigen A2B5 expression. Two cell strains, 9B2C and 9B2E, were obtained by cloning of the initial cultures and another strain, NCE-G28T, was derived after explantation of a mouse heterotransplant. The two subclones were negative for glial fibrillary acidic protein expression but stained for cell surface fibronectin. NCE-G28T cells initially were positive for glial fibrillary acidic protein but lost this property within 8 months of cultivation. Karyotype analysis of NCE-G28 and the three strains revealed hyperdiploidy and six structurally altered marker chromosomes five of which were shared by nearly all cells. Receptors for epidermal growth factor were detected in all cell lines with the highest levels (about 300,000 receptors/cell) in the parental cell line. The epidermal growth factor receptors had an affinity of 2.5 nM (Kd) and by affinity cross-linking analysis a molecular weight of 170,000 was found. Initially, NCE-G28 cells responded to epidermal growth factor as well as fibroblast growth factor with increased rates of proliferation, while platelet derived growth factor had no effect. In higher passages the growth factor sensitivity was reduced. Using antibodies directed against synthetic protooncogene peptides the production of c-sis immunoreactive material was detected. NCE-G28 cells produce an autocrine factor which stimulated proliferation. This factor is present in conditioned medium and is active on cultured meningiomas and other glioma cell lines. NCE-G28 cells can be maintained in serum-free defined medium on plastic coated with fibronectin or an extracellular matrix from bovine corneal endothelial cells. The NCE-G28 cell line with its strains provide an in vitro model system in which the complexity of gliosarcoma cell populations and the interaction of the cloned cellular constituents can be studied.

Demonstration of p53 protein and TP53 gene mutations in oligodendrogliomas.

Paraffin embedded tissue of 84 oligodendrogliomas (63 primary tumours, 21 recurrences), 21 glioblastomas with oligodendroglial growth pattern (15 primaries, 6 recurrences) and 17 mixed gliomas was investigated for the presence of mutations in exons 5-9 by means of single stranded conformation polymorphism (SCCP), temperature gradient gel electrophoresis (TGGE) and direct DNA sequencing. In parallel, p53 protein accumulation was determined by means of immunohistochemistry. The percentage of mutations was found to be higher than previously reported (6 of 44 grade II oligodendrogliomas, 4 of 19 grade III oligodendrogliomas, 4 of 15 glioblastomas). In 4 cases, the mutations lead to distinct changes in the primary or secondary structure of the protein (cysteine-->tyrosine, proline-->leucine) and were associated with marked accumulation of p53 protein. A significant correlation between p53 protein accumulation and TP53 gene aberrations was found (P < 0.001), although p53 protein accumulation was detected more often than TP53 gene anomalies, indicating that factors other than TP53 gene mutation may also lead to a p53 protein accumulation in the tumour cells. A significant correlation was found for p53 protein accumulation and tumour grade but not TP53 gene mutations. In conclusion, evaluation of p53 protein accumulation reflected the clinical course of oligodendrogliomas better than the mere presence of TP53 gene mutations.

Agnathia, holoprosencephaly, and situs inversus: a third report.

We report on a male infant with cyclopia, agnathia, and situs inversus. In addition, anal atresia and horseshoe-kidneys were present. To our knowledge, this is the third published case of the "agnathia-holoprosencephaly-further midline defects association."

Comparison of 4 proliferation markers and their significance for evaluation of tumor dignity in intracranial tumors.

The proliferation indices of immunohistochemically detected bromodeoxyuridine, Ki-67 antigen (antibodies Ki-67 and MIB 1), and proliferating cell nuclear antigen were determined manually and with computer assisted morphometry in 38 gliomas, 29 meningeomas, 9 metastases, and 16 other tumors. Comparing the markers among one another the highest correlation coefficient was found for bromodeoxyuridine and MIB 1 (0.9). The proliferation indices of all markers correlated significantly with the tumor grading. The highest correlation coefficient for proliferation index and grading (0.7) was calculated for the MIB 1 index determined in one high power field (0.0153 mm(2)) in the tissue area with the highest proliferative activity. Concerning applicability and correlation with tumor dignity MIB 1 was superior to the other three antibodies investigated.

Common variable immunodeficiency (CVID) and inclusion body myositis (IBM).

A case of a 38-year old man with a common variable immunodeficiency syndrome (CVID) is demonstrated who suffered at the same time from a histologically proven inclusion body myositis (IBM). The myositis did not resolve after institution of regular intravenous IgG infusions. This case demonstrates a very long lasting benign course of IBM. The occurrence with CVID may be a clinical hint for a viral pathogenesis of IBM. So far only two similar cases are reported in the literature.

Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas.

Meningiomas are usually benign tumors; however, they can recur after surgical resection and occasionally show histological progression to a higher malignancy grade. Five such rare cases of aggressively recurring meningiomas were present in our departmental cohort of 923 primary meningeal neoplasms operated over a 17-year period. Four other aggressively recurring meningeal tumors with a very similar clinical and histomorphological appearance (three undifferentiated meningeal sarcomas, one hemangiopericytoma) was also included in this study. We investigated whether disease progression can be traced by genetic alterations and whether a pattern of genetic alterations is specific for meningiomas. A total of 40 specimens from primary tumors and multiple recurrences of the nine patients were analyzed with 26 polymorphic allelic markers for deletions on 1p, 1q, 9q, 10q, 14q, and 22q. Loss of heterozygosity (LOH) at 22q was observed in all meningiomas cases at the earliest time point analyzed. Allelic loss at 1p was seen in the original tumor in two cases and upon meningioma recurrence in two others. Deletion on 10q occurred during tumor progression in two cases, and on 9q and 14q in one case. While allelic loss at 22q appears to be an early event in aggressive meningioma disease, there is a clear correlation of further deletions on chromosome arms 1p, 9q, 10q, and 14q with histopathological and clinical progression, as shown in these intraindividual trackings. None of these genetic findings were present in the non-meningiomatous meningeal tumors, indicating that meningothelial cells have their own lineage-specific genetic pathways towards clinical malignancy.

Treatment of nongerminomatous germ-cell tumors of the pineal region.

Germ-cell tumors can be subdivided into germinoma, embryonal carcinoma, choriocarcinoma, endodermal sinus tumor (yolk-sac tumor), and teratoma. They are also distinguished by their production of secreted markers such as alpha-fetoprotein produced in endodermal sinus tumors and embryonal carcinoma or beta-human chorionic gonadotropin, produced by choriocarcinoma and embryonal carcinoma. Germinoma and teratoma produce none of the markers. Because it has been proposed that teratomas may differentiate from multipotent stem cells contained in embryonal carcinoma and are thus lineage related, the presence of markers indicates the presence of a nongerminomatous germ-cell tumor. Nongerminomatous germ-cell tumors are an invariably fatal subgroup within the pediatric pineal region germ-cell tumors. There is no effective, established therapeutic regimen. We report the treatment regimen for three children diagnosed with this highly aggressive tumor entity. The children were first given a course of chemotherapy with bleomycin, etoposide, and cisplatin. This resulted in the normalization of markers and the shrinkage of tumors. These were then removed by the infratentorial supracerebellar approach. Removal was followed by a second course of chemotherapy with vinblastine, ifosfamide, and cisplatin; after which the children underwent radiotherapy. All three children are well and without evidence of residual or recurrent disease 20, 30, and 32 months after surgery, respectively. We propose this therapy regimen for children in whom the markers are positive.

Duration versus degree of hypotension as critical conditions of brain infarction in the albino rat.

In 41 anesthetized, spontaneously breathing male adult albino rats, cerebral hypotension of precisely defined duration and magnitude was induced by means of controlled arterial hemorrhage. One common carotid artery was occluded throughout the hypotensive period, and the target pressure was monitored in the ipsilateral internal carotid artery. Regional brain infarcts developed in all 16 animals with a target pressure of 14 mm Hg maintained for 90 minutes and in all five animals with a target pressure of 12 mm Hg maintained for 70 minutes. However, the brains of all 10 rats with a target pressure of 17 mm Hg maintained for 80 minutes remained intact. In two further groups of five animals each with target pressures of 15 mm Hg for 80 minutes and 16 mm Hg for 90 minutes the incidence of infarct was about 30%. There were no marked differences between the five groups of rats in body weight, body temperature, heart rate, respiratory rate, PaO2, PaCO2, arterial pH, or hematocrit. The data suggest that, in the rat, the clear-cut threshold for the induction of brain infarcts is a function of the severity and duration of arterial hypotension. Evidence is presented indicating that this function is distinctly species-dependent, due to species differences in the dilatory capacity of the arteries supplying the brain rather than species differences in brain vulnerability.

Hormone production in pituitary adenomas following external irradiation: an experimental study in rats.

INTRODUCTION: The aim of this study was to investigate the hormone production in pituitary gland tumors following fractionated external irradiation in rats. MATERIALS AND METHODS: Sixty female Wistar rats 3 to 4 month of age at the beginning of the experiments, were subjected to fractionated roentgen-rays exposure, 2 Grays (Gy) daily, either up to 20, 40 or 60 Gy. The animals were sacrificed either 6 month or 1 year after completion of the randomly assigned irradiation protocol. RESULTS: We found 9 pituitary tumors in 60 irradiated rats (15%). All tumors proved to be adenomas. Immunohistochemical analysis of hormone production in remnants of the normal adenohypophysis revealed immunoreactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH). In adenomas, 4 cases were immunoreactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The tumors were not reactive with anti-ACTH and anti-LH (luteinizing hormone). DISCUSSION: We concluded that irradiation accelerates the development of pituitary gland adenomas. In our series these tumors were predominantly incidental findings at necropsies after pre-termed follow-up, with a variety of hormone producing tumor cells. However, 4 of 9 tumors in our study were not producing hormones.

The carbohydrate epitope 3-fucosyl-N-acetyllactosamine is developmentally regulated in the human cerebellum.

The carbohydrate epitope 3-fucosyl-N-acetyl-lactosamine (CD15) is involved, as a constituent of glycoconjugates, in cell-cell interactions and cell sorting during rodent CNS morphogenesis. The present study was designed to test whether CD15 is also involved in the development of the human CNS. Human cerebellar hemispheres and vermes from the 24th week of gestation (wg) to the 26th postnatal month (pnm) and from adults were investigated for CD15 immunoreactivity, using the monoclonal antibody MMA. Our findings establish that the carbohydrate moiety is developmentally regulated in neuronal and glial cells during their differentiation. First, the parallel fibers of granule cells are CD15+ during the epoch of synaptogenesis with Purkinje cell dendrites. Second, a subpopulation of neurons from the dentate nucleus is transiently CD15+ from the 32nd wg until the 15th pnm. Third, at the onset of myelination (around the 35th wg), CD15 immunoreactivity is discernible in the cytoplasm of young oligodendrocytes. Immunoreactivity on protoplasmic astrocytes of the inner granular layer and on fibrous astrocytes of the white matter progressively increases during fetal development. In addition, the CD15 epitope is persistently present on Bergmann glial processes and ependymal cells. Within the three subdivisions of the cerebellum, i.e., hemispheres, vermis, and flocculonodular lobe, the CD15 expression follows a different timing of morphogenesis. For example, diminution of immunoreactivity in the parallel fibers occurs first in the phylogenetically older flocculonodular lobe and vermis, and later in the phylogenetically younger hemispheres. This study shows that in the human cerebellum the distribution of CD15 undergoes marked developmental changes. This epitope may also act in cell-to-cell recognition, and perhaps could play a role in controlling CNS development.

Xanthogranuloma and xanthoma of the choroid plexus: evidence for different etiology and pathogenesis.

Xanthogranulomas of the choroid plexus (XGCP) and xanthomas of the choroid plexus (XCP) are generally held to be closely related to each other. Obtained by autopsy 17 cases with XGCP and 21 cases with XCP were investigated. Foamy cells were confirmed to be constitutional for both lesions. Immunohistochemically their antigen profile was shown to be of histiocytic type. A dense siderosis emerged as a consistent feature of XGCP but not of XCP. In no case both tumors were found associated. Analysis of clinical data revealed hyperlipidemia in 15 out of 17 cases with XCP but in only 3 out of 13 cases with XGCP (p < 0.01; in 4 cases of each sample pertinent data were pending). The male-to-female ratio was 14:3 in cases with XGCP and 13:8 in cases with XCP; when combined with data of other authors the male preponderance in XGCP became statistically significant. In conclusion, XGCP and XCP emerged as different independent lesions. XCP appeared to be closely related for example to tendon xanthomas of the skin which are well established as being diagnostic of hyperlipidemia. XGCP, on the other hand, are most likely to correspond to cholesterol granulomas of extracranial provenance. Thus, the data presented strongly recommend the replacement of the term "xanthogranuloma of choroid plexus" with the term "cholesterol granuloma of choroid plexus".

Hypoxia-ischemia and thiamine deficiency.

In order to test the hypothesis that Wernicke's encephalopathy is of topographic rather than of pathogenetic specificity we examined the brains of 49 patients without any evidence of chronic alcoholism. They had died at least four days after an event of severe hypoxia-ischemia. They all showed extensive lesions in the cortex, in the thalamus and in other regions. In 19 of them there was additional necrosis in the mamillary bodies which apparently was of the same age as the associated cortical and thalamic lesions and which could not be distinguished from Wernicke's encephalopathy. In three of the 19 cases there was a total necrosis within the mamillary bodies. By re-examining the mamillary bodies of 12 known alcoholics without any evidence for an ischemic impact we could affirm that total necrosis may fit into the spectrum of Wernicke's encephalopathy. Our findings demonstrate that the morphological changes in the mamillary bodies due to thiamine deficiency and those due to hypoxia-ischemia may be identical.

Comparative brain pathology of HIV-seronegative and HIV-infected drug addicts.

Early stages of infection with human immunodeficiency virus (HIV) were studied in HIV-seropositive drug addicts. Since heroin users are immunocompromized even in the absence of HIV infection, the aim of the present study was to compare the morphological alterations present in HIV-seronegative and HIV-seropositive drug addicts. A total of 60 cases (32 HIV-seronegative subjects, 21 HIV-seropositive patients without signs of acquired immunodeficiency syndrome (AIDS), and 7 HIV-seropositive patients with signs of AIDS) were investigated macroscopically, histologically, and immunohistochemically HIV-seronegative patients presented more frequently with acute drug intoxication, died at a significantly younger age than HIV-seropositive patients, and were found to suffer more frequently from alcohol-related changes. These results indicated that HIV-seronegative and HIV-seropositive patients differed possibly in their drug consumption and also in their general conditions of life. In accordance with previous reports activated microglia and a diffuse astrogliosis in the white matter were detected at a significantly higher frequency and found to be more severe in HIV-seropositive subjects than in HIV-seronegative addicts. A lymphocytic meningitis was present in 6 of 21 HIV-seropositive patients but in none of the HIV-seronegative patients. Perivascular infiltrates consisting of lymphocytes and macrophages were detected at similar frequencies in HIV-seronegative and HIV-seropositive patients but were significantly more severe in patients suffering from lymphocytic meningitis or purulent encephalitis. Opportunistic infections were only demonstrated in 2 AIDS cases. In 10 of the HIV-seronegative patients and in 3 of the HIV-seropositive patients CD68-and Ham56-positive multinucleated cells were detected scattered in the subarachnoidal space exclusively over the frontal cortex.

Prognostic relevance of TP53 mutations, p53 protein, Ki-67 index and conventional histological grading in oligodendrogliomas.

The prognostic value of tumour grading according to WHO, Ki-67 proliferation index, p53 labelling index and TP53 gene mutations was assessed in 59 patients (33 oligodendrogliomas WHO grade II, 15 anaplastic oligodendrogliomas, 11 glioblastomas with oligodendroglial growth pattern). The minimal observation period was 5 years after operation. According to multivariate correlation and regression tree (CART) analysis grading was the prime prognostic factor (grade II vs. anaplastic tumours, p < 0.00001). Grade II oligodendrogliomas were further divided into tumours with and without TP53 mutations (p < 0.05) whereas anaplastic tumours were subdivided according to age (p < 0.05, cut off at 57 years) and p53 protein accumulation (p < 0.05, cut off at 2%, age 57 years). Ki-67 labelling index correlated highly significantly with grading but had no independent prognostic relevance in CART analysis. Accumulation of wild-type p53 protein was not related to bcl-2 expression, a co-expression of p53 and bcl-2 was found at similar frequencies in tumours with or without TP53 mutations (4/12 vs. 3/11). Since accumulation of wild-type and mutant p53 are both associated with a poor prognosis, it is suggested to include immunohistochemical evaluation of p53 protein in routine diagnostics of oligodendrogliomas.

Microgastria-hypoplastic upper limb association: a severe expression including microphthalmia, single nostril and arhinencephaly.

Report on a female infant with iris coloboma on the right and microphthalmia/orbital cyst on the left, single nostril, radial defectis, abnormal lung lobation, congenital heart defect, hypoplastic spleen, absent gallbladder, microgastria, unilateral renal aplasia, arhinencephaly and fused thalami. This case represents an unusually severe expression of a probably rare association recently reviewed by Lueder et al. (1989).

Cerebellar atrophy following mild head injury in a 4-year-old girl.

Cerebellar atrophy following severe head injury in infants has been described in imaging studies. We report the case of a 4-year-old girl who died of accidental hypothermia. Three weeks before, she had sustained head injury after falling on the back of her head with linear fracture of the occipital bone. Neuropathological examination of the girl's brain revealed cerebellar atrophy with specific loss of Purkinje cells. We present findings of detailed neuropathological studies and discuss possible mechanisms of posttraumatic cerebellar atrophy. To the best of our knowledge, cerebellar atrophy following mild head injury in man has not been described morphologically so far.

Common carotid artery stump pressure in the gerbil stroke model.

In 106 slightly anaesthetised adult mongolian gerbils one common carotid artery (CCA) was ligated and the blood pressure in the distal and in the proximal stump was monitored for 8 minutes. The mean distal CCA stump pressure of the 39 nonsurvivors was 15 (+/- 6) mm Hg, that of the 25 survivors with retinocerebral infarcts was 25 (+/- 6) mm Hg, and that of the 42 intact survivors was 31 (+/- 7) mm Hg. The corresponding mean arterial blood pressures (MABP), as measured in the proximal CCA stump, were 81 (+/- 12) mm Hg, 84 (+/- 13) mm Hg, and 87 (+/- 11) mm Hg, respectively. There were no differences between the samples concerning sex, body weight, rectal temperature, arterial blood gases, arterial pH, and haematocrit. Measurements in a second series of 10 awake gerbils showed that the mean values of MABP, heart rate, and respiratory rate of the nonsurvivors were less than those of the survivors during 90 minutes after CCA ligation. It is inferred that in the mongolian gerbil the lower threshold of the arterial blood pressure for the development of brain infarcts ranges within 22 and 25 mm Hg, that is, within the values found in monkeys and cats. The longlasting depression of respiration and circulation in the nonsurvivors is considered to be related to the phenomenon of diaschisis .