False-negative prenatal diagnosis of restrictive dermopathy.

Restrictive dermopathy is a rare autosomal recessive lethal skin dysplasia. It has been assumed that the characteristic morphologic abnormalities should allow a reliable prenatal diagnosis on fetal skin biopsies at about 20 weeks pregnancy. We report on a false-negative prenatal diagnosis.

Are thrombocyte membranes altered in Alzheimer's disease? A morphometric and biochemical study.

Morphometric analysis of thrombocytes from patients with Alzheimer's disease, from patients with multi-infarct dementia, and from young and age-matched healthy control donors, did not reveal any Alzheimer-related increase in internal membranes. Biochemical analysis showed a reduced cholesterol content of thrombocyte membrane preparations from Alzheimer patients relative to age-matched controls, but not relative to multi-infarct dementia patients. Overall distribution of protein kinase C activity (PKC) between cytosol and membrane, in resting as well as in activated thrombocytes from Alzheimer patients, was similar to that in the control groups. However, both Alzheimer and multi-infarct dementia patients had lower cytosolic levels of basal kinase and PKC activities than age-matched controls, while only Alzheimer patients had lower cytoskeletal PKC activity than controls.

Restrictive dermopathy in two brothers.

BACKGROUND: Restrictive dermopathy is an autosomal recessive phenotype characterized by universal tautness of skin resulting in fetal akinesia and death during the neonatal period. The clinical signs and symptoms of this uncommon disease are described in two brothers, and evidence is provided that fetal biopsy specimens obtained during the 20th week of gestational age are nondiagnostic. OBSERVATIONS: The first patient was a growth-retarded preterm boy suffering from generalized desquamation, marked joint contractures, and facial hypoplasia. Prominent light microscopic findings were hyperorthokeratosis intermingled with parakeratosis and absence of the elastic fibers in a thinned dermis. Electron microscopic examination of the epidermis revealed a lack of keratin filaments and an abnormal globular shape of the keratohyalin granules. The child died 4 days after birth. A following pregnancy resulted in birth of a preterm boy who died of the same disease within 2 hours. In the 20th week of gestational age, fetal biopsy specimens were obtained, but light and electron microscopy failed to reveal any abnormalities. CONCLUSIONS: Restrictive dermopathy is a genuine skin disease resulting in fetal akinesia that precludes a normal intrauterine development. The clinical features of this disorder are so distinctive that an on-the-spot diagnosis can be established. In view of the data obtained in this case, the feasibility of prenatal diagnosis should be regarded with great caution.

Experimental autoimmune retinitis in the rat induced by immunization with rhodopsin: an ultrastructural study.

Experimental autoimmune retinitis induced by immunization with rhodopsin was investigated in the Lewis rat using transmission electron microscopy and light microscopy. The first signs of retinitis consisted of scattered infiltrations of lymphocytes and other mononuclear cells, predominantly in the inner nuclear layer and outer plexiform layer. Occasionally, some macrophages were detected in the photoreceptor cell layer. Eyes exhibiting a clinically moderate or severe inflammation contained areas of normal retina coexistent with mildly to severely inflamed foci. The central retina was more frequently affected than the peripheral area. In moderately inflamed foci, macrophages infiltrated the photoreceptor cell layer, damaging and eliminating its structures. Inflammatory cells penetrated the photoreceptor outer segment layer which remained unaltered so far in spite of a high serum anti-(rhod)opsin antibody titer. In stages of severe inflammation, massive infiltrations of macrophages and polymorphonuclear cells destroyed the photoreceptor cells focally, leaving the retinal pigment epithelium virtually unaffected. Adjacent to these foci the pigment epithelial cells sometimes exhibited increased numbers of phagosomes and swelling. The locations of the cell infiltrations and lesions in progressive stages of development suggest that the rod outer segments are the target for the autoimmune damage. The described patterns of inflammation were compared with those of previous studies using other animal species and inciting antigens. Especially in rhodopsin-induced retinitis, the blood-retina barrier at the level of the Bruch's membrane/pigment epithelium appears to be highly resistant to cytotoxic cells. The present observations are in agreement with the concept that the cellular immune response plays a major role in the pathogenesis of (rhod)opsin-induced retinitis.

Exogenous aluminum accumulates in the lysosomes of cultured rat cortical neurons.

In order to study the intracellular localization of aluminum, 0.01% AlCl3 was added to rat cerebral organotypic cultures following 14 days incubation in a standard medium. The cultures were maintained in the aluminum (Al)-containing medium for 1 or 3 days. Subsequently, electron probe X-ray micro-analysis (EPXMA), was used to localize aluminum in the neurons. The Al was found in the cells as early as after 1 day of AlCl3 exposure. The Al was detected exclusively in the neuronal lysosomes, in 66% (1 day exposure) and 97% (3 days) of the measured lysosomes. This localization was confirmed by laser microprobe mass analysis (LAMMA) measurements. Our results demonstrate an Al localization in the neurons, exposed to exogenous Al, different from that in the brains of patients with Alzheimer's disease.

Renal biopsy and family studies in 65 children with isolated hematuria.

We have investigated 65 children with isolated hematuria persisting for at least a year. Renal biopsy specimens were studied by light microscopy, electron microscopy and immunofluorescence with antisera specific against basement membrane components. The majority of the biopsies (62/65) showed variable histologic abnormalities. Four categories could be distinguished on combined histological and clinical criteria: Alport syndrome (n = 8), benign hematuria (n = 33, familial in 23), IgA nephropathy (n = 16) and increase in mesangial cells and matrix (n = 5). On the basis of our results, we suggest that a renal biopsy can establish diagnosis and prognosis in those children with isolated hematuria where the family history is negative. If the family has adult male individuals with isolated hematuria, a biopsy can usually be avoided, since this family history effectively excludes Alport syndrome. The use of antisera against basement membrane components did not allow a differentiation between Alport syndrome and benign hematuria. Goodpasture serum immunofluorescence was variable in the former and normally present in the latter.

Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ.

To assess the potential of breast-conserving treatment for ductal carcinoma in situ (DCIS), 82 mastectomy specimens were studied by Egan's serial subgross method. 42 (51%) of the tumours were larger than 50 mm and only 12 (15%) were smaller than 20 mm; the size distribution was not affected by the mode of detection (mammography 52 cases, clinical examination 30). All but 1 case showed only 1 region of tumour. 66% of tumours involved one breast quadrant, 23% extended over more than one quadrant, and 11% were centrally located. Mammographic estimates, based on the extent of microcalcifications, frequently underestimated the histological size of tumours, the extent of the discrepancy being related to the histological type--8/50 predominantly micropapillary/cribriform. In view of the frequently large size, adequate excision of many DCIS will require a wide excision involving up to a whole quadrant.

Ichthyosis bullosa of Siemens: further delineation of the phenotype.

We report a third family affected with ichthyosis bullosa of Siemens, and we further delineate the clinical spectrum of this mild type of epidermolytic hyperkeratosis. Erythroderma had never been present in any of the affected individuals. All of them exhibited a brownish, rimpled hyperkeratosis, the main characteristic sites being the joints, the shins and the periumbilical region. Blistering occurred after slight mechanical trauma and even after sweating, resulting in superficially denuded areas. Two affected family members also suffered from chronic, relapsing pustular eruptions surrounded by a transient erythematous flare. Light- and electron-microscopic examination revealed epidermolytic hyperkeratosis limited to the upper part of the epidermis. The pustular lesions were found to be subcorneal blisters filled with neutrophils. Ichthyosis bullosa of Siemens can be clearly distinguished from bullous ichthyosiform erythroderma. The observation of subcorneal pustular dermatosis occurring in this phenotype provides further evidence for the genetic heterogeneity of epidermolytic hyperkeratosis.

Phenotypic expression in mucopolysaccharidosis VII.

beta-glucuronidase deficiency is an extremely rare disorder which is known to have a considerable phenotypic variation. A survey of the clinical findings in 19 previously reported patients with mucopolysaccharidosis VII is presented together with the results of clinical and biochemical studies in two further patients. Because a similar clinical picture is present in a heterozygotic sister it is doubted whether all signs and symptoms can be attributed to the beta-glucuronidase deficiency. The probability of a concomitant disorder is discussed. Diagnosis was made both by demonstration of the deficiency in plasma and leucocytes, and by means of hair root analysis. The phenotypic variation and the fact that increased levels of glycosaminoglycans were not found in the urine of the two patients lead to the suggestion that in certain cases a correct diagnosis may be missed if the beta-glucuronidase activity in plasma and leucocytes is not determined and only routine urine investigation is performed as a screening for a mucopolysaccharidosis. Hair root analysis may be a useful method to measure the beta-glucuronidase activity.

Early infantile form of neuronal ceroid lipofuscinosis. Four Dutch cases and review of the literature.

In this paper four Dutch cases of early infantile neuronal ceroid lipofuscinosis (NCL) are described, all being boys. NCL is a group of diseases morphologically characterized by accumulation of autofluorescent ceroid lipofuscin-like pigment. Psychomotor deterioration, impairment of vision, and epileptic manifestations are the major clinical features. Onset in early infantile age is rare. We reviewed 71 cases reported in the literature, and compared the symptoms and signs with the findings in our patients. Psychomotor deterioration, visual impairment and myoclonic jerks are often observed early in the disease. Eventually, every patient shows psychomotor deterioration. The outcome is always lethal, usually within a few years. Special attention is paid to diagnostic procedures.

Acute generalized microvascular injury by activated complement and hypoxia: the basis of the adult respiratory distress syndrome and multiple organ failure?

It has been suggested that generalized endothelial damage and permeability changes, induced by prolonged activation of the complement system and ensuing release of lysosomal enzymes, prostaglandins and toxic oxygen products, underlie the genesis of the Adult Respiratory Distress Syndrome (ARDS) and Multiple Organ Failure (MOF). The effects in New Zealand white rabbits were investigated of a 4 h infusion of activated complement and its combination with a short hypoxic episode on respiratory function, leukocyte count, platelet count and morphology of the lungs, heart, liver, kidney and spleen. Prolonged activation of the complement system induced hyperventilation with respiratory alkalosis and hypocapnia, depletion of granulocytes (PMN), and a variable accumulation PMN in the capillaries of all organs examined, in combination with interstitial, and, in the liver, cellular oedema. Electron microscopy of the lungs revealed degranulation of PMN, endothelial swelling and widening of the alveolar septa. The combination of hypoxia and systemic complement activation appeared to aggravate this microvascular injury with the occurrence of protein rich alveolar oedema and haemorrhage in the lungs and accumulation of PMN debris containing macrophages in the spleen. The alterations in respiratory function and pulmonary morphology in these rabbits, imitate the clinical and morphological characteristics of the early phase of ARDS. The inflammatory reaction, found in all other organs examined, might represent the early phase of MOF. If so, ARDS and MOF -- clinically closely interconnected syndromes -- might be interpreted as manifestations of the same syndrome and as the clinical expression of an uncontrolled whole body inflammation.

Morphology and incidence of the "posttherapeutic lymphoid cell" in the bone marrow of children with acute lymphoblastic leukemia.

In the posttherapeutic bone marrow of a group of 30 children with acute lymphoblastic leukemia (ALL), small numbers of a particular lymphoid cell with a comparatively large size and large dark nucleus were found. This cell was called the "posttherapeutic lymphoid cell." This type of cell is easily distinguishable in the May-Grünwald-Giemsa-stained smears as well as in semi- and ultrathin Epon sections. Immunoelectron-microscopically it proved to be positive for common ALL. It is hypothesized that the cell might be characteristic for ALL. However, it appeared that this cell could equally be found in non-Hodgkin's malignant lymphoma after a treatment comparable to that in ALL. Furthermore, the cell could be detected in the posttherapeutic bone marrow of children with nonlymphoid malignancies as well as the marrow of very young children (under 2 years of age) with nonmalignant diseases. The results showed that the cell in question is not associated with a particular disease but, rather, represents a special type of lymphoid cell in the regenerating or actively proliferating bone marrow.

Nuclear pockets and clefts in the lymphoid cell population of bone marrow and blood of children with acute lymphoblastic leukemia.

Ultrastructural investigation of the nuclei of the lymphoid cell population of bone marrow and blood of children with acute lymphoblastic leukemia regularly shows the presence of two types of nuclear pockets and nuclear clefts. The incidences of these nuclear features decrease significantly during cytostatic therapy. The pockets consist of either a cytoplasmic segment enclosed by a nuclear heterochromatin bridge or a nuclear segment enclosed by an intranuclear cleft. One type of nuclear cleft is, for its greater part of whole length, situated just under the nuclear surface. The other type of cleft is oriented more or less perpendicular to the nuclear surface. It is proposed that these four types be designated as nuclear pockets and nuclear clefts "Type 1" and "Type 2."

The usefulness of an endomyocardial biopsy in heart disease of unknown etiology.

Light-, electron microscopic and enzyme histochemical examinations (phosphorylase, LDH, NADH:TR, SDH and 3-HBDH) were performed on endomyocardial biopsies of 26 patients with heart diseases of unknown etiology. On the basis of the clinical findings the patients were grouped into hypertrophic cardiomyopathy patients), dilated-congestive cardiomyopathy (8 patients), latent cardiomyopathy and small vessel disease (11 patients) and myocarditis (4 patients). Morphologic changes which might characterize the pathogenesis, were found in 7 patients: small vessel disease in 3 patients, nonspecific myocarditis in 1, iron storage disease in 1, adriamycin cardiomyopathy in 1 and cardiomyopathy with inclusions typical of Fabry's disease in 1 patient. In the other patients the morphologic changes were not sufficiently characteristic to be indicative of an etiopathogenesis. Several pathologic alterations did, nonetheless, appear to have a certain prognostic value such as endocardial and interstitial fibrosis, myofibrillolysis, myolysis, mitochondrial degeneration and increased lipid content in the muscle fibers. The frequency of these changes was evaluated partly semiquantitatively, partly by means of the point-counting method and graded with 1-3 points. Three patients with congestive cardiomyopathy scored at least 7 points. Two of them died within 8 weeks, 1 patient with adriamycin cardiomyopathy recovered after discontinuation of the therapy but he died 4 years after the biopsy. Six to 50 months after the biopsy (mean 31.5, median 6.5) the score was less than 7 in the other patients and all these patients were still alive. The histochemical changes manifested as an increase and/or a decrease of the enzymatic activities, involving scattered muscle fibers or their segments. A decrease of the activities of all dehydrogenases examined appeared to be prognostically ominous, correlating with a score of 7 or higher. A decrease of SDH activity in 7 cases, in combination with a decrease of the HBDH activity in 4 of them, was indicative of a disturbance in the Krebs cycle and lipid metabolism in the absence of ischemic damage. The alterations in the phosphorylase activity did not, however, appear to have a prognostic significance. Normal activity of the phosphorylase seemed to be prognostically favorable.

Abnormal wall movements of the right ventricle and both atria in patients with pericardial effusion as indicators of cardiac tamponade.

A retrospective study on 126 patients with pericardial effusion showed cardiac tamponade to be present in 39 patients and absent in 87. We evaluated the distribution of the pericardial effusion as well as the effect of hydrodynamic compression on the different heart chambers. Small to large volumes of pericardial fluid were found in both groups of patients. Abnormal wall movements were only present if pericardial effusion was adjacent. Hydrodynamic compression signs consisted of abnormal wall movements of both atria at end-diastole continuing into systole, and of the right ventricle in early- and mid-diastole. Most of the patients with cardiac tamponade showed an abnormal motion pattern of both right atrium and ventricle (13 patients) or of the right atrial wall alone (12 patients). Abnormal motion of the right ventricle alone was seen in 6 patients, of both atria and right ventricle in 4 and of the left atrium alone in 1 patient. False-negative diagnoses of cardiac tamponade occurred in 3 of the 39 patients and false-positives in 2 of the 87 (sensitivity 92%, specificity 98%). Measurements of the duration of the inversion of both atria increased the specificity of these abnormal wall movements to 100%. Echocardiography can help to identify those patients who are clinically at risk and need pericardial drainage.

Ultrastructural study of the vacuoles in the peripheral lymphocytes in juvenile amaurotic idiocy. Juvenile form of generalized ceroid lipofuscinosis.

Lymphocytes of the peripheral blood of 31 patients with juvenile amaurotic idiocy (juvenile form of ceroid lipofuscinosis) were examined with the electron microscope. In all cases, intracytoplasmic clear vacuoles were present, containing round hollow, fingerprint and highly electron dense structures. The combination of these structures, not necessarily in one and the same vacuole, was considered to be highly indicative for the diagnosis of juvenile amaurotic idiocy. In addition to these three structures, parallel tubular inclusion bodies, rectilinear profiles and rod-shaped structures were found but in a number of the cases. The parallel tubular inclusion bodies were not regarded as having any diagnostic significance.

Ultrastructural study of so-called curvilinear bodies and fingerprint structures in lymphocytes in late-infantile amaurotic idiocy.

Peripheral lymphocytes of 6 patients with late-infantile amaurotic idiocy were examined with the electron microscope for the occurrence of curvilinear bodies and fingerprint structures. In 3 of the patients predominantly curvilinear bodies were found; in 1 case they contained some fingerprint profiles. In the remaining 3 patients curvilinear bodies were relatively scarce, whereas fingerprint structures prevailed. Moreover, pleomorphic bodies with rectilinear profiles and parallel tubular inclusion bodies were present. No lymphocytes with vacuoles were observed in any of the patients. The sural nerve biopsies of all patients revealed curvilinear bodies. This tissue consequently may be considered to give more reliable information in comparison with the lymphocyte. The likelihood of transition of one type inclusion body into another, the specificity of the curvilinear body and, to our mind, the rigid classification of the amaurotic idiocy into a curvilinear and a fingerprint type, are discussed.

Intracytoplasmic granule-lamella structures in visceral epithelial cells of human glomeruli.

A description is given of the rare occurrence of peculiar oblong structures having a maximal length of about 4.5 micron and a width of 0.5 micron, in the visceral epithelial cells of human glomeruli. These inclusions are marked by regular arrangement of parallel lamellae which are either in parts or over their whole surface associated with ribosome-like particles. Besides speculations on their origin and nature, some literature data come up for discussion.