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.

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.

[Immunohistochemical detection of hormones in hypophyseal adenomas of the rat after fractionated irradiation]. / Immunhistochemischer Nachweis von Hormonen in Hypophysenadenomen der Ratte nach fraktionierter Bestrahlung.

BACKGROUND: The aim of this study was to determine the hormones produced in pituitary gland tumours (TM) following fractionated external irradiation in rats. The TM arose in the course of studies on other questions of radiation effects. METHODS: The left neck and skull base of sixty female Wistar rats, 3 to 4 months of age at the beginning of the external irradiation, were subjected to roentgen rays exposure, fractionated to 2 Grays daily, either up to 20, 40 or 60 Gy. The midline of the neck and skull was always inside the radiation field. The animals were sacrificed either 6 months or 12 months after completion of the randomly assigned irradiation protocol. Five non-irradiated rats served as controls. RESULTS: No TM developed in the non-irradiated animals. Out of 60 irradiated rats 9 developed a pituitary TM (15%). In remnants of the normal adenohypophysis we revealed immunohistochemical reactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid stimulating hormone (TSH), and follicle stimulating hormone (FSH). In the radiation-induced adenomas, 4 TM were immuno-reactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The TM did not react with anti-ACTH and anti-LH (luteinizing hormone) anti-sera. CONCLUSIONS: Obviously, irradiation accelerates the development of pituitary gland adenomas. In this series the TM were predominantly incidental findings at necropsies after pretermed follow-up intervals with a variety of hormone-producing cells. On the other hand, four of nine TM were null adenomas. Necropsies of the brain should be carried out routinely in irradiation studies of the skull.

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.

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.

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.

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.

Increased proliferative activity due to necroses induced by pre-operative embolization in benign meningiomas.

The proliferative behaviour of 35 benign intracranial meningiomas was investigated which were embolized for devascularization 3 to 268 hours prior to surgical exstirpation. The nuclear proliferation antigen Ki-67 was visualized by means of the monoclonal antibody MIB1 on formalin fixed and paraffin embedded tissue. Tumor cells and inflammatory reactions were recognized by means of conventional staining procedures and by immunohistochemical detection of HAM56, LCA, HLA-DR, CD15-epitope and vimentin. Extravasation and proliferation of granulocytes, macrophages, lymphocytes and the degree of expression of MHCII antigens was estimated according to a 7-point ordinal scale. Confirming preliminary observations of others the proliferation index within the perinecrotic tumor rim (PIperinec) exceeded that of intact tissue highly significantly. PIperinec peaked at the third to fourth day after embolization and kept this level until the seventh day. The time course of PIperinec was paralleled by that of macrophages, whereas--expectedly--granulocytes occured earlier and lymphocytes and HLA-DR-positivity somewhat later. The timely relationships suggested that the perinecrotic increase in tumor cell proliferation was mainly due to macrophage-born mitogens. Perinecrotic proliferative activity in embolized meningiomas does not reflect genuine tumor proliferation and should not be used for assessment of the presence or degree of malignancy in a given tumor.

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".

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.

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.

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.

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.

Hirano bodies and chronic alcoholism.

Experiments on rodents have shown convincingly that chronic ethanol ingestion may damage the hippocampal formation. Nevertheless this region has, hitherto, not been considered as a target for alcoholism-induced brain lesions in man. Guided by the observation of increased numbers of Hirano bodies (HB) in the hippocampus of chronic alcoholics, this study determines the maximum number of HB per high power field (HPF: 0.19 mm2) in the stratum pyramidale (HBpyr) and in the stratum lacunosum (HBlac) of Ammon's horn in 123 chronic alcoholics and in 197 controls. The average count of HBlac found in alcoholics was 14.4 (SD = 17.7) compared with 4.2 (SD = 7.4) in non-alcoholics (P < 0.001). Counts of more than 19 HBlac per HPF were revealed as highly indicative of chronic alcoholism being observed in 33 (27%) alcoholics and in six (3%) non-alcoholics (P < 0.001). An increased number of HBlac was the most frequent of the neuropathological findings in the alcoholics. Affirming observations of others, the count of HBlac peaked during middle age and declined thereafter. The maximum count of HBpyr, in contrast, increased with age and was independent of alcoholism. It is proposed that increased numbers of HBlac indicate alterations of the apical dendrites of the pyramidal neurons of the CA1 field of Ammon's horn which probably are due to direct neurotoxic effects of ethanol and which may be reversible in nature.

The direct carotid cavernous fistula: a clinical, pathoanatomical, and physical study.

In order to further elucidate the pathogenesis of the direct carotid cavernous fistulas (dCCF) clinical, patho-anatomical, and physico-mechanical studies were performed. In 27 of 42 patients the dCCF were found to be localized in the segment C4 (according to Teufel, 12), in 13 patients in segment C2 and in only 2 patients in segment C3. The patients with dCCF in segment C4 were significantly younger than those with dCCF in the segments C2 or C3. In none of the patients fractures of the bony walls of the cavernous part of the internal carotid artery (ICA) could be ascertained. On human cadavers it was affirmed that the cavernous branches of the ICA arise nearly exclusively from the top of segment C3 and from the lateral wall of segment C2. The strength of the wall of the cavernous part of the ICA was shown to decline with age as revealed by means of a tensile machine. There were no significant differences between the four segments investigated. As revealed by roentgenograms the distensibility of the ICA within its coverings was shown to be greatest in the segments C2 and C4 and lowest in segment C3. A sudden increase of the intraluminal pressure ruptured the ICA exclusively in the segments C2 and C4. Histological preparations revealed that the trabeculae of the cavernous sinus insert tangentially into the adventitia of the ICA. Taken together these findings strongly support the view that the dCCF are mainly due to a sudden increase of the intraluminal pressure of the ICA.

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.

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.

Haemorrhagic thiamine deficient encephalopathy following prolonged parenteral nutrition.

Neuropathological examination of three patients who were maintained on parenteral nutrition without substitution of thiamine demonstrated an acute haemorrhagic encephalopathy. The lesions differed substantially from the classic features of thiamine deficient encephalopathy regarding the histopathological alterations and the topographical distribution. The extreme rapidity of thiamine deprivation may have been responsible for the abrupt clinical onset of the disease and the intensity of the morphological alterations.

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).