Marcia E. Cornford

Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain.

Neuronal changes in the brain of a Rett syndrome patient were examined in a frontal lobe biopsy performed at age 3 years and in the postmortem brain at age 15 years. In the brain biopsy, frontal cortex contained numerous scattered pyramidal neurons with cytoplasmic vacuolation and increased cytoplasmic density, with no neuronophagia or inflammation detected; electron microscopy showed these neurons to have large, lucent-appearing mitochondria, very abundant ribosomal content, and some lipofuscin granules. Postmortem brain 12 years later showed scattered neurons in frontal cortex, substantia nigra, and cerebellar folia, with increased electron density of the cytoplasm, stacks of ribosomal endoplasmic reticulum, and large amounts of disorganized membranous material, including autophagic-type organelles. Mitochondria of these neurons contained electron-dense, finely granular matrix inclusions; in the substantia nigra, some spherical mitochondrial inclusions completely filled the matrix space. Golgi preparations of (autopsy) frontal cortex and cerebellar folia showed truncation and thickening of dendrites and a degenerate appearance of cortical pyramidal neurons, similar to changes found in aged brain. Synaptophysin immunohistochemistry indicated that the density of synapses was not greatly altered compared to controls in frontal cortex and cerebellum. The patient also had a second genetic defect, severe combined immunodeficiency with thymic aplasia, which may be X-linked. (J Child Neurol 1994;9:424-431).

Greatly increased numbers of histamine cells in human narcolepsy with cataplexy.

To determine whether histamine cells are altered in human narcolepsy with cataplexy and in animal models of this disease.

Concurrent Cerebral American Trypanosomiasis and Toxoplasmosis in a Patient with AIDS

We report a case of concurrent cerebral infection with Trypanosoma cruzi and Toxoplasma gondii in a patient with acquired immunodeficiency syndrome (AIDS). A 22-year-old El Salvadoran man initially improved during receipt of antitoxoplasmosis therapy, but he had rapidly progressive hemiplegia. Magnetic resonance imaging showed an abnormal finding in the left internal capsule, and cytological analysis of cerebrospinal fluid revealed T. cruzi trypomastigotes. Despite prompt therapy with nifurtimox, the patients mental status declined, and he died of nosocomial complications. Although infrequent, T. cruzi infection should be considered in the differential diagnosis of brain lesions in patients with AIDS from regions of endemicity.

Intrachromosomal triplication of 2q11.2-q21 in a severely malformed infant: case report and review of triplications and their possible mechanism.

A female fetus with brain malformations, multicystic kidneys, absence of the right thumb, and a posterior cleft of palate was delivered at 32 weeks of gestation. Cytogenetic studies including FISH showed a novel intrachromosomal triplication of the proximal long arm of chromosome 2 (q11.2-q21), resulting in tetrasomy for this segment. The middle repeat was inverted. At least 11 patients with intrachromosomal triplications have been reported, mostly involving chromosome 15q. The mechanism involved in formation of these rearrangements is compatible with U-type exchange events among three chromatids.

Responses of nitric oxide synthase expression in the gracile nucleus to sciatic nerve injury in young and aged rats.

Neuronal nitric oxide synthase (nNOS) is induced in dorsal root ganglion neurons following axotomy in young rats, and is also increased in the gracile nucleus neurons of intact aged rats. The present study examined the influence of sciatic nerve axotomy on nNOS expression in the gracile nucleus in young compared to aged rats. The unilateral transection of the sciatic nerve was performed in young (4 months) and old (24 months) Fischer rats. Sections of rat medulla obtained 14 days after axotomy were immunolabelled using a polyclonal antibody directed against nNOS and stained by nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry, a marker of nNOS activity. In young rats, unilateral axotomy produced increased NADPHd containing neurons in the rostral region and the caudal region of the ipsilateral gracile nucleus compared to the side with intact sciatic nerve. In old rats, the NADPHd containing neurons in the ipsilateral gracile nucleus were moderately increased by axotomy over the age changes seen in the contralateral side. Similar results were obtained with nNOS immunoreactivity in young rats, but more cells were seen with NADPHd staining compared to nNOS immunostaining in old rats. The results suggest that unilateral sciatic axotomy causes an increase in nNOS expression in the ipsilateral gracile nucleus of young rats, which is still seen in old rats as an increase over normal aging changes.

Coincident choroid plexus carcinoma and adrenocortical carcinoma with elevated p53 expression: a case report of an 18-month-old boy with no family history of cancer.

We describe a young patient with no known family history of cancer who presented at 18 months with 2 advanced primary tumors, choroid plexus carcinoma and adrenal cortical carcinoma. Immunohistochemical studies demonstrated high levels of nuclear p53 protein expression in both tumors, as well as in the adjacent normal-appearing adrenal cortical cell nuclei of the adrenal gland. The immunohistologic distribution of elevated p53 expression suggests that this individual has a de novo germline mutation affecting p53 gene expression.

A Single Glucose Transporter Configuration in Normal Primate Brain Endothelium: Comparison with Resected Human Brain

Cellular distribution of the Glutl glucose transporter in normal primate brains was analyzed by immunogold electron microscopy. Two configurations of endothelial Glutl glucose transporter (high and low density capillaries) have been found in resections of traumatically injured and epileptogenic human brain; the objective of the present study was to ascertain whether these same 2 capillary populations, expressing high and low glucose transporter densities, were the common configuration in normal brain. The relative numbers of Glutl glucose transporter- associated gold particles on luminal and abluminal endothelial cell membranes were determined within the cerebral cortex of several normal, nonhuman primates. Low Glutl densities were seen in brain endothelia of both the rhesus and squirrel monkey cortex, with slightly greater quantities of Glutl in vervet monkey cortices. The Glutl transporter was most highly expressed in the baboon cortex, approaching the concentrations seen in human brains. In the rhesus, squirrel, and vervet monkeys, Glutl concentrations were greater on the abluminal than luminal capillary membranes. In contrast, mean luminal membrane Glutl concentrations were greater in baboons, resembling the distribution seen in the human brain. Brain regional differences in transporter concentration were seen in comparing membrane densities in the baboon cortex (˜15 Glutl-gold particles per (µ meter), hippocampus (˜12 Glutl gold particles per µ meter), cerebellum (˜6 Glutl-gold particles per µ, meter), and retinal microvasculature (˜20 Glutl-gold particles per µ, meter). We conclude that a single, uniform Glutl distribution characterizes brain capillaries of normal nonhuman primates, and hypothesize that the presence of high and low density glucose transporter endothelial cells (seen in human traumatic injury and seizure resections) represents a pathologic response to brain insult.

Sclerosing hyaline necrosis of the liver in Bloom syndrome.

Bloom syndrome is a rare autosomal recessive disorder characterized by normally proportioned but strikingly small body size, a characteristic facies and photosensitive facial skin lesion, immunodeficiency, and a marked predisposition to development of a variety of cancers. We describe here, we believe for the first time, pronounced sclerosing hyaline necrosis with Mallory bodies in the liver of a patient with Bloom syndrome. Mallory bodies are cytoplasmic eosinophilic inclusions, which are more common in visibly damaged, swollen hepatocytes in various liver diseases but are never found in normal liver. The possible pathogenesis of this finding in Bloom syndrome is discussed.

Sudden unexpected death associated with HHV-6 in an adolescent with tuberous sclerosis

A 14-year-old female with tuberous sclerosis and history of seizures was found dead in bed at home 3 days after she had been assessed as doing well at a routine neurology clinic appointment. She had been treated with an antiepileptic drug, felbamate, for 36 months and had been seizure-free except for one seizure episode 5 months before death. Postmortem examination revealed cerebral edema, with uncal and tonsillar herniation, and pulmonary edema, consistent with seizure-induced apnea. Multiple microglial nodules with mature perivascular lymphocytic cuffing and diffuse infiltrates were identified around subependymal tuberous sclerosis giant cell nodules. Immunostaining and electron microscopy revealed human herpesvirus-6-infected macrophages, astrocytes, lymphocytes, and endothelial cells in the subependymal tuberous sclerosis lesions and choroid plexus. Subacute human herpesvirus-6 encephalitis is postulated to have precipitated a seizure and thus sudden unexpected death in epilepsy in this otherwise stable adolescent patient.

Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

Heroin addiction is accompanied by an increase in detected hypocretin (orexin) neurons, and in narcoleptic mice deficient in these neurons, morphine can reverse cataplexy. Opiate addiction and narcolepsy: Opposite sides of the same coin? The neurological mechanisms that maintain opiate addiction and prevent long-term withdrawal are not well understood. In a new study, Thannickal et al. found that human heroin addicts have, on average, 54% more hypocretin-producing neurons than do neurologically normal control individuals. They show that a similar increase in hypocretin-producing neurons could be induced in mice through long-term morphine administration. This long-lasting increase in hypocretin neurons may be responsible for maintaining addiction. Narcolepsy is caused by a loss of hypocretin-producing neurons. Morphine administration restored the population of hypocretin neurons in hypocretin cell–depleted mice back to normal numbers and decreased cataplexy in narcoleptic animals. Induction of specific long-term changes in neuropeptide production, outlasting the half-life of the administered drugs, may be useful in treating diseases characterized by loss of neurons producing these neuropeptides. The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.