Distribution and fate of 54Mn in the monkey: studies of differnnt parts of the central nervous system and other organs.

The fate and distribution of isotopic manganese administered as a single carrier-free dose of 200 muCi of maleate-(54)Mn to 12 rhesus monkeys was studied at different time periods from the 6th hr to the 278th day. Whole-body activity was measured, and all body organs and tissues and different parts of the central nervous system (CNS) were evaluated for specific activity, exponential analysis, and relative retention. Exponential analysis revealed a pattern of discharge with a fast and a slow component for the whole body and for many of the viscera. All parts of the CNS and, to a lesser degree, the thyroid and muscle showed an almost steady state of activity after the initial uptake. While the whole body and most organs and tissues appeared to discharge their radioactivity with the passage of time, first rapidly and then gradually, the CNS, endocrine glands, and muscle tissues showed persistent levels of specific activity. All components of the brain exhibited increasing relative retention, the lentiform nucleus and the cerebellum showing this more. It is suggested that the selective vulnerability of the brain in manganese miners might result from this inability on the part of the CNS to discharge the (54)Mn with time. This investigation confirms and amplifies our earlier similar study on the rat.

Cerebral blood flow and metabolism in normal human aging, pathological aging, and senile dementia.

A review and a reappraisal are presented of earlier data on cerebral circulatory and metabolic studies in normal active elderly men (Group I) of mean age 71 years, compared with normal young subjects of mean age 21 years, conducted at the National Institutes of Health, Bethesda, MD, U.S.A., during 1956-1958. There was no significant difference in the mean CBF and cerebral metabolic rate for oxygen (CMRO2) values between the two populations; i.e., these important parameters did not fall with chronological aging per se. There was significant depression in the mean cerebral metabolic rate for glucose (CMRG) value (by approximately 23%) in the aged compared with the young. Newer methods using positron emission tomography and appropriate isotopes have confirmed these findings in normal aging in human subjects and experimental animals. As expected, MABP and cerebral vascular resistance (CVR) were significantly elevated in the normal aged. MABP was even more elevated in elderly hypertensive subjects, and the CVR more elevated in the subjects with arteriosclerosis (Group II), who also showed a small but significant fall in CBF and in internal jugular venous PO2. The CBF showed a more pronounced fall in senile aged patients with chronic brain syndrome (Group III), in whom the CMRO2 also showed a marked drop (by approximately 22%); the CMRG fell still further (approximately 40% of that in the young). Of the few aged subjects followed up after a lapse of 11 years by a repeat estimation of the same physiological and psychological parameters and of the EEG, most showed clear worsening, together with a fall in overall physical and intellectual performance, probably related to a rise in CVR and an increase in atherosclerosis with aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Interrelationships between the B-vitamins in B12-deficiency neuromyelopathy. A possible malabsorption-malnutrition syndrome.

Five patients presenting clinically with a form B12-deficiency neuromyelopathy, with cord involvement in all and proximal muscle weakness in two of them, were investigated for their neurologic, hematologic and vitamin status. Megaloblastosis and achlorhydria were present in all, and impaired absorption of 57Co vitamin B12 and of D-xylose was detected in four. Total cyanide extracted vitamin B12 (A) was lowered in all cases and noncyanide extractable (B) in four of the five, being zero in three. All five responded to injections of hydroxocobalamin. In two patients sequential estimations showed that both A and B, especially the latter, rose steeply initially, normalizing at 50% of A after some weeks. Moiety B is suggested to be physiologically the more active and dissociable form of vitamin B12. Markedly elevated initial serum folate levels, and their subsequent fall under treatment with B12, indicated the operation of the "methyltetrahydrofolate trap". Blood levels of thiamin, nicotinic acid and pantothenic acid were within normal limits. However, serum riboflavin (B2) total vitamin B6 and pyridoxal were reduced in all where tested. Vitamin B6 deficiency could have resulted from its own malabsorption and have contributed to be B12 deficiency. Vitamin B2 and B6 levels also corrected themselves on B12 therapy. The B-vitamin deficiencies in our patients probably resulted from intestinal malabsorption, with a possible factor of malnutrition consequent to their strictly vegetarian diet.

Light and electronmicroscopy of the bowel in an unusual form of Hirschsprung's disease.

In a histological and histochemical study of multiple biopsies of unaffected segments of the bowel from 15 patients with Hirschsprung's Disease (H.D.), the AChE or non-specific esterase and the NADPH tetrazolium reductase enzyme reactions proved to be useful in identification of myenteric plexus islands; and acid phosphatase for the delineation of individual neurones. In the affected segment (usually aganglionic), this myenteric plexus tissue was not reactive for esterase, but individual nerve fibres among muscle fibres of the two muscle coats showed the enzyme product in a third of the cases. Fine structural study of biopsies from a typical case of H.D., showed normal looking axons and Schwann cytoplasm with terminals bearing both andrenergic and cholinergic vesicles in the unaffected colon, smooth muscle fibres with normal fine structure in all parts of the bowel, and loss of neurons with myenteric plexus replaced by nerve fibre groups in the affected rectosigmoid. One patient clinically presenting as a case of severe H.D., with histologically and histochemically normal myenteric and submucous ganglion cells, and not responding to resection of the bowel, showed degeneration of the unmyelinated axons with prominent Schwann cytoplasm, depleted cholinergic but persistent adrenergic vesicles, and markedly thinned and degenerating smooth muscle fibres and myofilaments, suggesting either a primary disorder of muscle tissue of the colon or, less likely, a denervation atrophy with secondary degeneration of the smooth muscle fibres.

Isolated cysticercal infestation of extraocular muscles: CT and MR findings.

PURPOSE: We sought to document the appearance of isolated cysticercal infestation of single extraocular muscles on MR and CT studies, and to compare these findings with results of histopathologic examination. METHODS: Six MR and three CT examinations of the orbits of six patients were reviewed. Histopathologic confirmation of the diagnosis was available in three patients, and response to specific medical therapy was available in one. In all, the imaging findings were considered highly suggestive of cysticercal infestation. RESULTS: Typically, the affected extraocular muscle showed fusiform enlargement of its belly and contained a well-defined, spherical cyst with a nodule attached to its wall. The mural nodule was identified in all six cases with varying degrees of visibility. It was best seen on the CT examinations and in all cases in which contrast material had been administered. The nodule and the enlarged muscle showed intense enhancement on the contrast-enhanced studies. Imaging studies of the brain showed no evidence of cerebral cysticerci in any of the patients. CONCLUSION: The MR and CT appearance of isolated infestation of single extraocular muscles by the larva of the pork tapeworm Taenia solium is quite characteristic and often diagnostic of this condition.

Eales' disease with neurological involvement. Part 2. Pathology and pathogenesis.

Detailed neuropathologic examination was carried out on 1 case of Eales' disease with CNS involvement, in the form of retinal vasculopathy, followed first by signs of brain stem and cerebellar disease and then by a myelopathy, with death 4 years later from retinal infection. There was mild chronic inflammation in the retina, and sub-total demyelination of one optic nerve. The brain stem and cerebellum showed extensive vasculopathy, with various stages of venous change extending from proliferation and dilatation to haemorrhage, or to thickening with hyalinisation. The perivenular brain tissue, particularly of the cerebellum, often showed demyelination, with relative axon preservation, but no inflammation. Similar, but less pronounced venopathy was seen in the dorsal cord. There was ascending degeneration of Goll's columns and descending degeneration of the lateral columns.

Eales' disease with neurological involvement Part 1. Clinical features in 9 patients.

Nine patients with characteristic changes of Eales' disease in the eye in whom there was neurological involvement, have been described. The characteristic neurological picture comprised an acute or subacute myelopathy occurring at an interval of a few weeks to a few years after the eye episode; in only 1 patient was there cerebral involvement without any evidence of myelopathy. Besides the involvement of spinal cord at the dorsal level in the 8 patients, there was evidence of additional lesions in the brain stem in 1 patient and in the cervical cord in another.

Pleomorphism of fine structure of rabies virus in human and experimental brain.

Identification of the Negri bodies in the brain of an 8-year-old boy who died 8 days after a paralytic illness and 20 days after a dog bite, and who had received 9 injections of Semple's anti-rabies vaccine, provided evidence that he died of acute rabies encephalitis and not of post-vaccinal allergic encephalomyelitis. The Negri bodies in the human subject and those seen in the inoculated mouse differed in their morphological structure: the former consisted of a matrix of very fine granular material bearing larger granules or strands of higher electron-density resembling nucleic acids and representing products of host cell-virus interaction; and the latter showed better defined areas of granular matrix containing tubular, bullet-shaped and elongated forms of viral structures, and nucleocapsids or capsule-deficient cores, representing the virions, emerging from them. Fine structural examination of the patient's brain and of the inoculated mouse has provided evidence of the pleomorphism of the Negri bodies and the various stages of formation of viral material and virions in them, the animal alone showing the mature virions of rabies, and proving the infectivity of the Negri bodies of the human brain.

Histopathology and fine structure of the brain in six cases of Creutzfeldt-Jakob disease from western India.

Light and electronmicroscopic changes in 5 formalin-fixed brains, and one glutaraldehyde-fixed brain biopsy, from patients with Creutzfeldt-Jakob disease in the age range of 45 to 65 years, are described. These 6 patients (out of 7 reported clinically earlier and 2 unreported) had classical manifestations with progressive dementia, pyramidal signs and myoclonic jerks. Light microscopy showed neuronal and nerve fibre loss, moderate or severe spongiform change, astrocytic proliferation and absence of inflammatory reaction. Electronmicroscopy confirmed the characteristic membranous profiles of the 'cysts' and 'daughter cysts' constituting the spongiform change. The membranes were generally dark and thin, either concentrically arranged or splitting and with stray pale broad segments. The one glutaraldehyde-fixed brain biopsy specimen showed cisterns of RER in close proximity to these 'cysts', suggesting the source of proteinous material of these membranes. Though mainly in the neurones and dendrites of the cortex, at times they were seen in the myelinated fibres also, a few of which showed dystrophic axons bearing dense bodies. One of the 6 patients had cerebellar signs also, and a total duration of the neurological illness of 36 months, as against 2-8 months in the 5 other patients. The histopathological examination of her brain revealed less spongiform change, and many cerebral cortical glial whorls, the centre of which showed PAS-positive and congo-red-positive material representing amyloid. Fine structural examination confirmed the glial whorls, and the filamentous nature of amyloid in the plaques, which resembled Kuru plaques. All brains also showed more or less intraneuronal lipofuscin.

Von Recklinghausen's disease with a malignant meningeal, cerebral and optic nerve tumour and bilateral vagal schwannomas. Possible mesenchymal histogenesis on light and electron microscopy.

The clinical, histopathologic and fine structural features of multiple unusual tumours detected in a 20-year-old patient with von Recklinghausen's disease, who died within a year of onset of symptoms of a rapidly expanding intracranial tumour, are described. The tumour was found to involve the falx cerebri, the basal leptomeninges and dura mater, both olfactory and optic nerves, both frontal lobes, the right temporal lobe and middle cerebral peduncle, both middle cerebellar peduncles, and with a metastasis in a cervical node. On light and electron microscopy this tumour appeared to be a fibroblastic meningeal sarcoma with giant cells, mitotic figures, a rich reticulin matrix throughout, and tumour cells full of rough ER but without any glial filaments. Also very unusual was the involvement of both vagus nerves in their cervical and intrathoracic portions, by a schwannomatous benign tumour and with a non-chromaffin paraganglioma at its termination in the oesophagus. One of the few cutaneous "neurofibromas" was also schwannian, containing tumour cells with a basement membrane on electron microscopy. Most, if not all, of these tumours appeared mesenchymal in origin, more aggressive in behaviour and carrying a graver prognosis in von Recklinghausen's disease.

Pathology and pathogenetic mechanisms in neurotuberculosis.

The mechanisms and the changes described herein typically begin with a dense basal meningeal exudate often resulting from a "Rich focus" along the basal surface of the cerebrum or ventricular ependyma. In the interpeduncular fossa, when the exudate is copious, among other structures the proximal parts of the optic nerves and of the internal carotid arteries are seen surrounded and compressed by the exudate. This exudate is made up of small and large mononuclear cells, including epithelioid cells, which also act as macrophages and may fuse to form Langhans' giant cells. Further extension of this exudate along small proliferating blood vessels into the brain substance constitutes a border zone encephalitis with the development of focal and diffuse ischemic brain changes due to vasculitis. Entrapment and occasional arteritic occlusion of larger arteries, such as the middle cerebral in the Sylvian fissures, results in infarction. Blockage of the basal subarachnoid cisterns around the midbrain and pons by the dense basal exudate or narrowing of aqueduct and third ventricle by a small tuberculoma causes consequent hydrocephalus. Development of many or one large focal granuloma (i.e., tuberculoma) occurs in the cerebrum, cerebellum, and/or brain stem. Similar pathogenetic mechanisms produce tuberculous spinal meningitis myeloradiculopathy that may be secondary to or occur before cranial tuberculous meningitis. More extensive damage to the white matter may occur together with the infrequent onset of perivascular demyelination on the basis of a hypersensitivity reaction to tuberculoprotein (i.e., "allergic tuberculous encephalopathy"). Finally, there may be a part played by NO in the production of the vascular and perivascular inflammatory central nervous system changes and a role for the the potential beneficial action of corticosteroids, especially in cases of tuberculous encephalopathy.

Dual infections of mice: visceral larva migrans and sublethal infection with Japanese encephalitis virus.

Experiments in 3 weeks old albino mice with Toxocara canis and sublethal infection with JE virus established a marked synergestic effect in dually infected mice. The results are discussed to indicate the possible role of visceral larva migrans in creating exploxive outbreaks of "acute encephalopathy syndrome" in individuals having simultaneous infection with a virus (es) which, alone, might produce only mild illness. The nature of the possible mechanisms involved yet remains to be understood.

Atherogenic markers in the offspring vis-à-vis family history of coronary heart disease.

The object of the study was to determine if atherogenic markers in the offspring reflected family history of coronary heart disease (CHD). Two hundred and four male subjects aged 9-18 years, mean age 13.3 +/- 1.7 (S.D.) years, and apparently healthy and normolipidemic, were selected for the study. Information on their family history of fatal or non-fatal heart attack or stroke was obtained on a questionnaire, and a scoring system was devised to grade the positivity of family history. The boys having the highest decile values of triglyceride, ratios of LDL/HDL-cholesterol, total/HDL-cholesterol and apolipoprotein B/A-I, and cumulative skin-fold thickness, a marker of obesity, had higher family history scores and increased occurrence of myocardial infarction in their families than the boys with the lowest decile values of these variables. The reverse was true with variables such as HDL-cholesterol and apolipoprotein A-I, high levels of which are known to be cardioprotective by virtue of controlling reverse cholesterol transport. The mean values of triglyceride and total/HDL-cholesterol ratio were significantly elevated in the boys with positive parental history of CHD as compared with those with negative parental history. Thus, although the boys were normolipidemic, their lipoprotein markers and an obesity marker exhibited a variation which in turn reflected family history of CHD.

Fine structure of cellular and vascular reaction in brain tuberculomas: a model for phagocytosis in the CNS.

The fine structure of cells of the mononuclear phagocyte series (MPS) and a few other cells with phagocytic capacity, has been critically evaluated, mainly from an electronmicroscopic examination of the reactive border zone of 11 human brain tuberculomas, which provide ideal material for the study of macrophages. Most of them appeared to be blood monocyte-derived epithelioid cells of various forms and stages. The cytoplasm of these cells showed either more rough ER representing protein synthesising activity; or more frequently, phagosomes, phagolysosomes, dense bodies or empty vacuoles, representing various stages of ingestion and digestion of necrotic material. Often such material, which was more or less osmiophilic, was seen abundantly between the cells. These actively phagocytic cells occasionally undergoing, mitosis, are referred to as "epithelioid macrophages" and were morphologically similar to the "activated microglia" described in other conditions. They also showed a tendency to be closely adjacent to each other and occasionally fuse to form giant cells. There were also a number of lymphocytes and plasma cells. The latter showed various stages of active and granular or depleted and distended rough ER tubules, phagocytic activity and tendency to fuse. Expected vasculitis and small vessel necrosis formed part of this granulomatous reaction. Constituents of oedematous or necrosed brain tissue were seen immediately around the reactive zone of these tuberculomas, the most frequent being reactive astrocytes, many of which showed membrane-bound vacuoles. It is conceivable that the excessive pleomorphic cellular, vascular and necrotic reaction in these brain tuberculomas could have resulted from a delayed type of hypersensitivity to a very small quentity of antigenic tuberculoprotein, which probably initiates the chain of immunologic responses.

Changes in atrial biopsies in chronic rheumatic heart disease. I: Cellulo-vascular and mesenchymal reaction.

The cellular, vascular and connective tissue changes were studied in 32 atrial biopsy specimens from patients with chronic rheumatic heart disease (RHD). 15 of these 32 specimens showed some inflammatory reaction, 7 with small mononuclear cells only and 8 with macrophage reaction amidst increased but necrotic collagen, especially in the subepicardial and subendocardial regions. Most cellulonecrotic foci were histologically consistent with a stage of Aschoff nodule. Acid phosphatase activity in frozen sections was seen in the cytoplasm of the macrophages. Fine structural examination showed membrane-bound vacuoles and lipofuscin bodies rather than ingested material in the macrophages. By light and electronmicroscopy, these macrophages were not different from those encountered in other granulomatous or necrotic conditions. There was moderate proliferation of blood vessels, with prominence of endothelial cells and pinocytotic vesicles, or fibrosis of media, or proliferation of basal laminae. The presence of Aschoff nodules in the right atrium, the least affected chamber in RHD, suggests a diffuse and smouldering pathology on the basis of a persistent subclinical cell-mediated immune (CMI) reaction.

Changes in atrial biopsies in chronic rheumatic heart disease. II: Muscle fibre reaction.

Myocardial fibres were studied in the right atrial biopsies from 32 patients with chronic rheumatic heart disease (RHD). Paraffin and, particularly, araldite sections showed many muscle fibres well preserved, and others with large hyperchromatic nuclei, or with depleted myofibrils and increased mitochondria. With the SDH and ATPase reactions, there was no type difference in the myocardial fibres, and the former showed the reaction predominantly in the centre while the latter showed it mainly at the periphery of the fibres. At electronmicroscopy, fibres with intact myofibrils were found close to "degenerating" fibres with variable degrees of myofibrillar and myofilament disorganisation and loss, mitochondrial proliferation, occasionally with degeneration of cristae, and accumulation of lipofuscin in varying amounts, and irregularly tortuous or loosened intercellular junctions. This study has revealed more severe muscle changes than expected, even in the clinically less affected right atrial chamber in chronic RHD. It is speculated that this might be due to subclinical involvement of the tricuspid valve, known to be frequent in Indian patients, and the resulting "back pressure" on the right atrium might lead to changes in its myofibres.

Neuropathology & pathogenesis of experimental fenfluramine toxicity in young rodents.

The anorectic compound fenfluramine hydrochloride was injected into young Holtzman strain rats (from days 6 to 40 of life), at the dose of 75 mg/kg body weight. Intralysosomal lamellar bodies (LBs) were seen in the endothelial cells, pericytes, the perivascular astrocyte processes and occasionally in the lumen. The pathology of myelinated fibres varied from thinning of myelin to complete demyelination and, at times, presence of dense bodies in the axons, the changes perhaps being a result of the oligodendroglia damage. A small group of adult mice was administered three oral doses each of Ponderax equivalent to 5 mg of fenfluramine. The brain stem and cerebellar neurons of these mice showed abnormal dark cytoplasm, without lamellar bodies. Even in this short-term experiment, there was formation of a few LBs in the neuropil, the prominence of dark glial cells, probably oligodendroglia, and some perivascular intracytoplasmic oedema. The earliest detection of dense bodies in the undistended astrocyte processes before they were observed in the cell perikarya, both in the younger rats and the adult mice, suggested the perivascular astrocyte to be the first CNS constituent to come in contact with the toxic agent as it passes the blood-brain barrier. On the basis of our observations, it also appears that the 'myelinosomes' or lamellar phagolysosomes developing due to failure of degradation of drug-phospholipid interaction product, accumulate in different cells of the CNS.

Megacystis, microcolon, intestinal hypoperistalsis syndrome: possible pathogenesis.

Two cases of "Megacystis-microcolon-intestinal hypoperistalsis syndrome" are described. These appear to be the seventh and eighth cases in published literature. Consistent with the two published reports, both our patients were newborn female infants who manifested a large bladder, associated with unused colon and functional intestinal obstruction. While the earlier published reports mention a full complement of normal mature ganglion cells in all parts of the bowel, the two cases described here showed " dysganglionosis " to some extent, in the form of fewer and shrunken neurones along with other mature-looking neurones in some parts of the bowel. The bladder was available for histologic examination only in the second case and showed apparently normal innervation. Hence, it is felt that the intestinal obstruction in these cases could have been due to a disturbance in bowel innervation.

Ultrastructural changes in medullomyoblastoma. Similarities with foetal rhabdomyoma.

The light and electronmicroscopic changes are described in two cases of medullomyoblastoma, and compared with the changes seen in a case of foetal rhabdomyoma. The medullomyoblastomas in two children aged 8 and 5 years, consisted predominantly of classical type of medulloblastoma cells, along with few to many 'strap cells' or 'myoid cells' which, on closer examination, showed clear cross striations, consistent with muscle fibres or myofibrils. The primitive myoid cells were similar to those encountered in larger numbers in a post-auricular rhabdomyoma, possibly of foetal origin in a 40 day old infant. The four pathogenetic mechanisms i.e. (i) an embryonal stage of myofibrillar differentiation; (ii) a malformative factor; (iii) a teratoid factor on account of the presence of mesenchyme derived striated muscle tissue in the obviously predominant ectodermal medulloblastoma; and (iv) metaplasia of the vascular smooth muscle cells in the medullomyoblastoma, are discussed.

Pituitary tuberculoma--a case report.

Pituitary tuberculomas, mimicking adenomas are very unusual. We describe a rare case of a patient with an exclusively intrasellar mass, and who presented with severe headaches and loss of libido. The lesion was approached trans-sphenoidally and pathological examination revealed a tuberculoma. Complete removal was achieved and the patient followed on anti-tuberculous therapy.