Regranulation of islets of Langerhans and normalization of in vivo insulin secretion in ob/ob mice treated with oxytetracycline.

Oxytetracycline (OTC) treatment was associated with regranulation of the islet cells and increased pancreatic insulin content in the ob/ob mouse. This was accompanied by an improvement of the in vivo insulin secretory response to glucose. Because of the wide-ranging effects of OTC on other membrane-related functions, it is postulated that this compound may exert ist effect by altering the composition of cellular membranes.

Malformations of the brain.

The purpose of this article is to provide a basic outline on which the reader can hold a more elaborate and detailed knowledge of malformations of the brain. The first half of the article consists of a general approach to brain malformations; the second, the shortest possible descriptions of the common brain malformations.

Sudden infant death syndrome: increased number of synapses in the hypoglossal nucleus.

The medulla was sampled from nine cases of sudden infant death syndrome (SIDS) and from six age-matched control cases without neurological disease. Morphometric analyses were performed on serial Nissl sections through the hypoglossal nucleus on the left side of the medulla. The total volume of the nucleus and both the numerical density (Nv, cells per mm3) and total number of neurons were measured. Tissue from the remaining hypoglossal nucleus was prepared for electron microscopy using the ethanolic phosphotungstic acid method to stain synaptic contacts. Stereological analyses were performed to determine the Nv and total number of synapses. Total volume of the hypoglossal nucleus was significantly greater (36%) in SIDS cases than in controls. The Nv of neurons was significantly less than in controls (28%), although the total number of neurons did not differ significantly. The mean profile area of motor neuron cell bodies was significantly greater (30%) in SIDS cases, with no differences in the mean profile areas for interneurons or glia. The Nv of synapses did not differ significantly between SIDS cases and controls, although the total number of synapses was greater (61%) in SIDS. These abnormalities in growth indicate a greater volume of neuropil in a hypoglossal nucleus containing a normal complement of neurons. The greater number of synapses in SIDS cases is consistent with a failure to eliminate normally extraneous synapses during early development.

Sudden infant death syndrome: increased synaptic density in the central reticular nucleus of the medulla.

The medulla was sampled from nine cases of sudden infant death syndrome (SIDS) and from six age-matched control cases without neurological disease. Morphometric analyses were performed on serial Nissl sections through the left half of each medulla to determine the total volume of the hemimedulla and the numerical density of neurons (Nv, neurons per mm3) in the central reticular nucleus. Blocks of tissue from the right half were prepared for electron microscopy using the ethanolic phosphotungstic acid (EPTA) method to stain synaptic contacts. Stereological analyses were performed to determine the Nv of synapses in the central reticular nucleus. Total volume of the hemimedulla did not differ significantly between SIDS cases and controls. However, in the central reticular nucleus of SIDS cases, the Nv of neurons was significantly less than in controls (30%), while the mean profile area of reticular neurons was significantly greater (39%). Synaptogenesis in control cases was characterized by a gradual decrease in the Nv of synapses from approximately 150 million at 40 postconceptional weeks to 110 million at 84 weeks. In SIDS cases the Nv of synapses was significantly greater (38%). These results demonstrate a disorder of synaptogenesis in the central reticular nucleus of SIDS cases. In view of previous reports of a persistence of dendritic spines on reticular neurons in SIDS, the results are consistent with a failure to eliminate normally extraneous synapses during early development.

The growth and development of microvasculature in human cerebral cortex.

Sections of the occipital cortex from 31 fetuses, infants and children, ranging in age from 15 weeks gestation to ten years postnatal, were stained to demonstrate alkaline phosphatase activity in intracortical vessels. At 15 weeks gestation intracortical positively staining vessels, assumed to be arterial precursors, were radially oriented, originating from leptomeningeal arteries. Most radial vessels coursed through the cerebral cortex without branching to vascularize the subcortical tissue. By 20 weeks gestation horizontal branches arose from radial vessels, most frequently in the lower half of the cortex. Occasionally, recurrent collaterals ascended from these horizontal branches to more superficial cortex. From 20-27 weeks gestation, the number of horizontal branches and recurrent collaterals increased in the lower half of the cortex, horizontal branches appeared in the upper half. From 27 weeks to term, shorter radial vessels, terminating in the more superficial cortical laminae increased in number. After birth a network of fine vessels, presumable precursors of capillaries, increased, particularly vascular layer 3 (neuronal lamina IV and Va). The number of radially oriented vessels per mm2 of pial surface (NA) decreased throughout development, with the most dramatic decrease occurring prenatally. In five cases of trisomy values of NA decreased less rapidly than in the normal.

Sudden infant death syndrome: postnatal changes in the numerical density and total number of neurons in the hypoglossal nucleus.

Tissue specimens from the medulla were sampled from 28 sudden infant death syndrome (SIDS) victims and from 15 control cases without neurological disease (36-95 postconceptional weeks). Morphometric analyses were performed on serial Nissl sections through the hypoglossal nucleus. The total volume of the hypoglossal nucleus, the numerical density (Nv, cells per mm3) and the total number of motor neurons, interneurons and glia were determined. Normal development was characterized by a linear increase in the volume of the hypoglossal nucleus during the first postnatal year. While the Nv of neurons decreased, the total number of neurons remained relatively constant at approximately 7,600 motor neurons and 3,100 interneurons. In SIDS cases the rate of increase in the volume of the hypoglossal nucleus was significantly greater than in controls (79%). The Nv of neurons was less than in controls (25-30%), although the total number of motor neurons and interneurons did not differ significantly. In SIDS cases the mean profile area of motor neuron cell bodies was significantly greater than in controls (29%), while the mean profile areas of interneurons and glia did not differ. These abnormalities in growth indicate a greater volume of neuropil in a hypoglossal nucleus containing a normal complement of neurons. The disproportionately rapid increase in volume of neuropil in the hypoglossal nucleus of SIDS cases may result from an increased arborization of dendrites on the motor neurons.

Sudden infant death syndrome: postnatal changes in the volumes of the pons, medulla and cervical spinal cord.

The brainstem and cervical spinal cord were sampled from 45 cases of sudden infant death syndrome (SIDS), from 17 control cases without neurological disease, and from three negative control cases with abnormal growth of the central nervous system (36-98 postconceptional weeks). Morphometric analyses were performed on serial Nissl sections to determine the total volumes of the pons, nucleus pontis, medulla and cervical spinal cord. Normal development was characterized by a linear increase in the volumes of these regions during the first postnatal year. Regression analysis revealed that in SIDS cases the rates of increase in the volumes of the pons and nucleus pontis were significantly greater than in controls (56% and 83%, respectively), while growth rates did not differ significantly for the medulla and cervical spinal cord. By direct comparison, there was a significant increase in the mean volumes of the pons (33%), nucleus pontis (38%) and medulla (19%) in SIDS cases when compared to controls. No evidence of excessive edema or gliosis was noted in the brainstem by light and electron microscopy to account for the increased volumes. Subtle morphological abnormalities in brainstem neurons from SIDS cases, including an increased size of Nissl bodies in the cytoplasm of large motor neurons and the presence of paranucleolar coiled bodies, were consistent with an increased synthesis and transport of ribosomal RNA, an increased synthesis of cellular proteins and neuronal hypertrophy.

Localization of tuberous sclerosis 2 mRNA and its protein product tuberin in normal human brain and in cerebral lesions of patients with tuberous sclerosis.

Tuberous sclerosis (TSC), an autosomal dominant disorder, is characterized by malformations, hamartomas and tumors in various organs including the brain. TSC is genetically linked to two loci: TSC1 on chromosome 9q34 and TSC2 on 16p13.3. TSC2 has been cloned, sequenced and encodes a protein (tuberin) which functions as a tumor suppressor. We have analyzed the distribution of TSC2 mRNA and tuberin in the brains of TSC patients and non-affected individuals using both autopsy and biopsy material. High levels of transcript and protein expression were observed in choroid plexus epithelium, ependymal cells, most brainstem and spinal cord motor neurons, Purkinje cells and the external granule cell layer of the cerebellum in both TSC and control cases. Individual balloon cells from TSC patients showed very faint expression while other glia showed no expression of either transcript or tuberin. Neocortical and hippocampal neurons expressed high levels of TSC2 transcript, but only modest levels of tuberin. The internal granule cell layer of the cerebellum expressed abundant transcript but low levels of tuberin. These observations suggest either that tuberin expression is controlled at the level of both transcription and translation or the antibody and in-situ hybridization recognize different splice variants of the TSC2 gene. In TSC patients, dysmorphic cytomegalic neurons expressed high levels of tuberin and transcript, particularly when in an 'ectopic' location. Individual cells within subependymal giant cell astrocytomas (SEGAs) and hamartomas from TSC patients expressed moderate to high levels of TSC2 transcript and tuberin. While the TSC2 transcript is widely expressed primarily within neurons, tuberin is demonstrable primarily within dysplastic/cytomegalic cells of the cortex and subependymal hamartomas/SEGAs. CNS expression of tuberin is unique in that primarily non-dividing cells express it in this location, whereas extra-CNS expression of tuberin is mainly found in actively proliferating cell types such as epithelium.

Centronuclear myopathy heterogeneity: distinction of clinical types by myosin isoform patterns.

We studied muscles from 3 patients with centronuclear myopathy (CNM) by immunocytochemistry using myosin heavy chain (MHC)-specific monoclonal antibodies to determine whether subtypes of CNM express prenatal MHC and to assess if there is an arrest in development of these muscles. Muscle from a woman with childhood-onset CNM did not express prenatal MHC, yet this prenatal MHC was strongly expressed in the muscle fibers of 2 brothers with X-linked CNM. This finding represents the 1st immunocytochemical evidence of the expression of a prenatal myosin isoform in nonregenerating postnatal human muscle and suggests that the X-linked form of CNM differs from the other types because of a true arrest in maturation of the muscle.

Bilateral dissecting aneurysms of the intracranial internal carotid arteries in an 8-year-old boy.

Nontraumatic intracranial dissecting aneurysms have rarely been reported as the cause of acute infantile and childhood hemiplegia. The present case is unique because dissecting aneurysms occurred bilaterally in two clinically distinct episodes. A recent dissecting aneurysm of the right intracranial internal carotid artery was present with a healed dissecting aneurysm of left internal carotid artery in an 8-year-old boy.

Nongerminomatous germ cell tumors of the brain.

PURPOSE: This analysis was performed to determine the clinical outcome of patients with primary nongerminomatous germ cell tumors of the brain. The efficacy of various treatment options was evaluated. METHODS AND MATERIALS: A total of 57 patients with primary nongerminomatous germ cell tumors of the brain were identified. Patient-related data were collected and analyzed retrospectively. Follow-up in surviving patients ranged from 3 to 243 months (median follow-up 36). Survival and failure rates were determined using the Kaplan-Meier method, and differences between the survival curves were evaluated using either the log rank test or the Wilcoxon test. RESULTS: The 3-year survival rate was 86% for patients with mature teratomas, 67% for patients with immature teratomas, 44% for patients with mixed germ cell tumors, and 13% for patients with the other histologic types (p = 0.02). The 3-year survival rate was 0% for patients having biopsies alone, 32% for patients having subtotal resections, and 73% for patients having gross total resections (p = 0.0001). Patients with tumors other than mature or immature teratomas were evaluated for possible relationships between the administration of chemotherapy or radiotherapy and survival. Patients who received chemotherapy had a 3-year survival rate of 56% compared to 8% for those patients who did not receive chemotherapy (p = 0.0001) Patients who received radiotherapy had a 3-year survival rate of 46% compared to 11% for those patients who did not receive radiotherapy (p = 0.0015). CONCLUSION: The survival of patients with primary nongerminomatous germ cell tumors of the brain is dependent on tumor histology and the extent of surgical resection. Patients with tumors other than mature or immature teratomas appear to benefit from the administration of chemotherapy and radiotherapy.

Lethal congenital muscular dystrophy with cataracts and a minor brain anomaly: new entity or variant of Walker-Warburg syndrome?

A term newborn male with severe hypotonia and contractures was found to have dense bilateral cataracts. He died at age 3 days of respiratory failure. Amino acidopathies and disorders of peroxisome function were excluded, and results of serologic studies and placental histopathology, specifically seeking evidence of intrauterine infection, were normal. Autopsy showed changes in the skeletal muscles consistent with congenital muscular dystrophy and a small focal anomaly of the cerebral cortex. These findings either represent a new syndrome or raise further questions about broadening the spectrum of known congenital muscular dystrophy syndromes with associated eye and brain anomalies.

Cytogenetic analysis of 109 pediatric central nervous system tumors.

Reports of cytogenetic abnormalities in pediatric central nervous system (CNS) tumors are important for collection and comparison of large numbers of karyotypes of primary CNS neoplasms to produce statistically significant correlations. We report cytogenetic results of 119 samples of pediatric CNS tumors from 109 patients. Tumors included 33 low-grade astrocytomas, 18 high-grade astrocytomas, 14 gangliogliomas, 13 ependymomas, 17 primitive neuroectodermal tumors (PNET), three choroid plexus papillomas and carcinomas, and a miscellaneous group of 20 rare primary CNS tumors and metastases. In each group, cytogenetic results were correlated with histologic subtype and survival. The study indicated specific chromosome abnormalities in different groups of tumors. Low-grade astrocytomas showed mostly numeric abnormalities with gains of chromosome 7, high-grade astrocytomas showed differences from karyotypic changes observed in adults in lacking double minutes (dmin) and monosomy 10. The ependymoma group showed the largest proportion of abnormal karyotypes with frequent involvement of chromosome 6 and 16. Chromosome 6 was the single most common abnormal chromosome in this study, closely followed by chromosomes 1 and 11. Pediatric CNS neoplasms differ from adult tumors cytogenetically as well as histologically and biologically.

Astrocytoma with a unique telomere association.

Many primary pediatric brain tumors are characterized by nonrandom cytogenetic abnormalities involving specific structural rearrangements and loss or gain of specific chromosomes. We describe a low-grade cerebellar astrocytoma with telomeric association of chromosomes 18 and 21 in a 7-year old girl. The nonrandom telomeric association of these chromosomes represents a unique cytogenetic finding in this type of pediatric brain tumor.

Multiple system atrophy with neuronal intranuclear hyaline inclusions. Report of a case and review of the literature.

A 31/2-year-old girl presented with frequent falls. She had an unsteady gait, delayed behavioural development absent tendon reflexes and in the legs decreased strength tone and equivocal plantar responses. She then developed ataxia, nystagmus, choreoathetosis, cranial nerve palsies, diminished strength and tone in the arms, sensory deficit in the limbs and autonomic nervous system dysfunction. She became progressively less responsive and succumbed at the age of 63/4 years. Examination of the central, peripheral and autonomic nervous system showed ubiquitous neuronal intranuclear hyaline inclusions and neuronal loss in several sites.

Primary Ewing's sarcoma of the base of the skull.

The authors report a case of primary Ewing's sarcoma of the petrous bone. The radiological features, including the computed tomographic scan and angiographic findings, are described in detail.

Unilateral cervical spinal cord lesion in a term newborn, associated with ipsilateral diaphragmatic atrophy and pulmonary hypoplasia.

Two major factors can interfere with normal development of the fetal lungs: mechanical constriction resulting in decreased intrathoracic space and reduced or absent fetal breathing movements. We report a unique case in which both factors contribute to the development of lethal pulmonary hypoplasia. This full-term neonate had an isolated unilateral lesion in the cervical spinal cord resulting in ipsilateral neurogenic atrophy of the diaphragm, bilateral pulmonary hypoplasia, and lung immaturity. Evenetration of the atrophied diaphragm decreased intrathoracic space, compromising fetal lung growth. This was compounded by impaired fetal respiration due to the diaphragmatic atrophy, further aggravating pulmonary hypoplasia on the affected side. The other lung was also hypoplastic, although to a lesser degree, suggesting that its growth was also affected by either or both of these factors.

Atelencephalic aprosencephaly.

Absence of the telencephalon and diencephalon characterizes the syndrome of aprosencephaly, while in atelencephaly, only the telencephalon is absent. Atelencephalic aprosencephaly is characterized by the presence of at least a rudimentary diencephalon. Embryologically, aprosencephaly is thought to occur after the optic vesicles form but before the cerebral vesicles appear. The syndrome is quite rare, with only 10 cases previously reported. We describe two fetuses with atelencephalic aprosencephaly. A 25-week estimated gestational age fetus was born to first-cousin parents and had a prenatal ultrasonographic diagnosis of anencephaly. The second, a 19-week estimated gestational age fetus, was thought to have semilobar holoprosencephaly by prenatal ultrasound. At autopsy, neuropathologic examination in both cases showed virtual absence of the cerebral hemispheres with an incomplete diencephalon. Microscopic examination in one case revealed disorganized neuropil with a proliferative vasculopathy. The optic globes were completely formed and attached to hypoplastic optic nerves, but retinal dysplasia was apparent histologically in both cases, and bilateral colobomata were present in one case. The findings in these cases demonstrate a spectrum of congenital variations that lie between the syndromes of atelencephaly and aprosencephaly, underscoring the complexity of the congenital anomalies.

Respiratory arrest and cervical spinal cord infarction following lumbar puncture in meningitis.

A 6-year-old child with meningitis had a respiratory arrest 20 minutes after a lumbar puncture. Thereafter she required maintenance on a ventilator, had a flaccid quadriplegia, and died 12 days later. Necropsy showed infarction of the central portion of the cord at the level of the decussation of the pyramids. The suggested mechanism of damage is compression of the arterial supply to the cord at the level of the foramen magnum by herniated cerebellar tonsils; concomitant hypotension may have contributed to production of the damage. Four similar cases, who survived with residual deficit, have also been reported. Other separate mechanisms by which the cord can be damaged in meningitis are vasculitis, thrombosis and arachnoiditis.

Bilateral encephaloclastic lesions in a 26 week gestation fetus: effect on neuroblast migration.

A 26 week gestation fetus with bilaterally symmetrical encephaloclastic lesions in the cerebral hemispheres is described. Information about gestation allows dating of the cerebral insult to the 3-4th fetal month. The history and morphology in this case suggest that insults occurring at or before the 3-4th fetal month interfere with normal neuroblast migration, producing a cerebral scar containing a band of neuroblasts arranged without order or lamination.