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Chronic ethanol consumption reduces delta-and mu-opioid receptor-stimulated G-protein coupling in rat brain.

BACKGROUND: Ethanol consumption is thought to enhance the release of endogenous opioids acting at opioid receptors (ORs) in the central nervous system. Prior studies have shown that chronic ethanol consumption in alcohol-preferring rats uncouples mu-ORs from Gi proteins. The purpose of this study was to investigate the potential for uncoupling of the delta- and the mu-OR after chronic ethanol consumption in a nonpreferring rat strain. METHODS: We used radiohistochemical methods to study mu- and delta-OR-stimulated G-protein coupling in brain tissue of rats ingesting liquid diets containing 6.7% ethanol (v/v) for 16 days, as compared with 0% ethanol pair-fed control rats. Sections of brain from pair-fed and ethanol-treated rats were incubated with guanylyl 5'-[gamma-[35S]-thio]-triphosphate ([35S]-GTPgammaS) in the absence and presence of d-Pen2,d-Pen5 enkephalin (DPDPE), a delta-OR agonist, or Tyr-d-Ala-Gly-N(me)Phe-Gly-ol-enkephalin (DAMGO), a mu-OR agonist. RESULTS: DPDPE significantly stimulated [35S]-GTPgammaS binding in the hippocampal dentate gyrus (DG), CA1, cerebellum, and inferior colliculus of untreated pair-fed controls. By contrast, DPDPE-stimulated [35S]-GTPgammaS binding was reduced significantly in those brain regions in the ethanol-consuming group. DAMGO stimulated [35S]-GTPgammaS binding in cortex, caudate, nucleus accumbens, DG, CA1, and superior and inferior colliculi, whereas the DG, CA1, and colliculi showed a significant reduction of binding after chronic ethanol. Basal [35S]-GTPgammaS binding was not different between the two diet groups. CONCLUSIONS These data are the first to demonstrate functional uncoupling of delta-ORs from G proteins after chronic ethanol consumption. Uncoupling may result from modulation of receptors, possibly by internalization or phosphorylation. Alterations in functional coupling of both delta- and mu-ORs and subsequent effects may contribute to continued ethanol consumption.

Alcohol Drinking↗

Localization of nitric oxide synthase in the adult rat brain.

The distribution of the immunoreactivity to nitric oxide synthase has been examined from rostral to caudal areas of the rat central nervous system using light microscopy. Endogenous nitric oxide synthase was located using a specific polyclonal antiserum, produced against affinity purified nitric oxide synthase from whole rat brain, following the avidin-biotin peroxidase procedure. Immunoreactive cell bodies and processes showed a widespread distribution in the brain. In the telencephalon, immunoreactive structures were distributed in all areas of the cerebral cortex, the ventral endopiriform nucleus and claustrum, the main and accessory olfactory bulb, the anterior and posterior olfactory nuclei, the precommisural hippocampus, the taenia tecta, the nucleus accumbens, the stria terminalis, the caudate putamen, the olfactory tubercle and islands of Calleja, septum, globus pallidus and substantia innominata, hippocampus and amygdala. In the diencephalon, the immunoreactivity was largely found in both the hypothalamus and thalamus. In the hypothalamus, immunoreactive cell bodies were characteristically located in the perivascular-neurosecretory systems and mamillary bodies. In addition, immunoreactive nerve fibres were detected in the median eminence of the infundibular stem. The mesencephalon showed nitric oxide synthase immunoreactivity in the ventral tegmental area, the interpeduncular nucleus, the rostral linear nucleus of the raphe and the dorsal raphe nucleus. Immunoreactive structures were also found in the nuclei of the central grey, the peripeduncular nucleus and substantia nigra pars lateralis, the geniculate nucleus and in the superior and inferior colliculi. The pons displayed immunoreactive structures principally in the pedunculopontine and laterodorsal tegmental nuclei, the ventral tegmental nucleus, the reticulotegmental pontine nucleus, the parabrachial nucleus and locus coeruleus. In the medulla oblongata, immunoreactive neurons and processes were detected in the principal sensory trigeminal nucleus, the trapezoid body, the raphe magnus, the pontine reticular nuclei, the supragenual nucleus, the prepositus hypoglossal nucleus, the medial and spinal vestibular nuclei, the dorsal cochlear nucleus, the medullary reticular field, the nucleus of the solitary tract, the gracile and cuneate nuclei, the dorsal nucleus of the vagus nerve and the oral, interpolar and caudal parts of the spinal trigeminal nucleus. In the cerebellum, the stellate and basket cells showed immunoreactivity, which was also seen in the basket terminal fibres of the Purkinje cell layer. Isolated immunoreactive Purkinje cells were found in the vermis and parafloccular regions of the cerebellum. In the granular layer of the cerebellum, the granular cells and glomeruli were also immunoreactive. Numerous positive varicose nerve fibres and occasional neurons were also found in the lateral and interposed cerebellar nuclei.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Oxidoreductases↗

1,3-Dinitrobenzene-induced encephalopathy in rats.

Exposure to 1,3-dinitrobenzene (1,3-DNB) in humans induces methaemoglobinaemia, nausea and nervous symptoms. When given to conventional rats, twice-daily oral doses of 10 mg kg-1 1,3-DNB produce methaemoglobinaemia and frequently ataxia after four or five doses. In germ free rats given only a single oral dose of 20 mg kg-1, similar symptoms occur but are of more rapid onset. Light and electron microscope examinations reveal an acute thiamine deficiency-like lesion in the brain stems of both ataxic and apparently normal rats. Bilaterally symmetrical vacuolated lesions involve cerebellar roof, vestibular and superior olivary nuclei and the inferior colliculi. Frequent petechial haemorrhages are associated with these lesions, the erythrocytes usually being limited to enlarged Virchow-Robin spaces but sometimes spreading more widely. The primary cellular targets appear to be astrocytes, oligodendrocytes and vascular elements with secondary neuronal involvement. It is suggested that 1,3-DNB interferes with intracellular redox mechanisms resulting in impaired glucose oxidation.

Animals↗

The neurotoxicity of alpha-chlorohydrin in rats and mice: II. Lesion topography and factors in selective vulnerability in acute energy deprivation syndromes.

Mice and rats have been found almost equally susceptible to (R, S)-alpha-chlorohydrin neurotoxicity, but in rats the distribution of lesions in the neuraxis is less widespread. The topography of the brain lesions shows an incomplete relationship to the regional hierarchy of local glucose utilization in rats and local cerebral blood flow in mice, suggesting that other, unknown, factors also play roles in determining this. Evidence suggesting progressive tonotopic selective vulnerability was found in inferior colliculi in rats given five doses of 50 mg/kg/day. Distinct differences in the patterns of damage to brain stem centres found with chlorohydrin by comparison with other acute energy deprivation syndromes, despite the proximity of the metabolic lesions along the energy generation pathway, suggests there are other unrecognized factors that play a role in determining whether a neuronal centre is at risk or not.

Animals↗

Saccade deficits after a unilateral lesion affecting the superior colliculus.

A 70 year old patient with a small haematoma largely restricted to the area of the right superior and inferior colliculi is reported. Eye movements were electro-oculographically recorded 17 and 80 days after the onset of the haematoma. At the first examination, latency of lateral reflexive visually-guided saccades was asymmetrical, both in the gap task (central fixation point switched off 200 ms before the onset of the lateral target) and in the overlap task (central fixation point remaining switched on). Furthermore, latency of leftward saccades in the overlap task was increased, and accuracy of these saccades was impaired, at both examinations. In the immobility task (fixation straight ahead while lateral targets suddenly occurred) and in the anti-saccade task (saccade made away from the lateral target), the percentages of errors (saccades made to the target) were high at the first examination, and noticeably lower at the second. These results suggest that the superior colliculus plays an important role both in the triggering and inhibition of reflexive visually-guided saccades.

Aged↗

Synaptic inputs to stellate cells in the ventral cochlear nucleus.

Auditory information is carried from the cochlear nuclei to the inferior colliculi through six parallel ascending pathways, one of which is through stellate cells of the ventral cochlear nuclei (VCN) through the trapezoid body. To characterize and identify the synaptic influences on T stellate cells, intracellular recordings were made from anatomically identified stellate cells in parasagittal slices of murine cochlear nuclei. Shocks to the auditory nerve consistently evoked five types of synaptic responses in T stellate cells, which reflect sources intrinsic to the cochlear nuclear complex. 1) Monosynaptic excitatory postsynaptic potentials (EPSPs) that were blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, probably reflected activation by auditory nerve fibers. Electrophysiological estimates indicate that about five auditory nerve fibers converge on one T stellate cell. 2) Disynaptic, glycinergic inhibitory postsynaptic potentials (IPSPs) arise through inhibitory interneurons in the VCN or in the dorsal cochlear nucleus (DCN). 3) Slow depolarizations, the source of which has not been identified, that lasted between 0.2 and 1 s and were blocked by -2-amino-5-phosphonovaleric acid (APV), the N-methyl-D-aspartate (NMDA) receptor antagonist. 4) Rapid, late glutamatergic EPSPs are polysynaptic and may arise from other T stellate cells. 5) Trains of late glycinergic IPSPs after single or repetitive shocks match the responses of D stellate cells, showing that D stellate cells are one source of glycinergic inhibition to T stellate cells. The source of late, polysynaptic EPSPs and IPSPs was assessed electrophysiologically and pharmacologically. Late synaptic responses in T stellate cells were enhanced by repetitive stimulation, indicating that the interneurons from which they arose should fire trains of action potentials in responses to trains of shocks. Late EPSPs and late IPSPs were blocked by APV and enhanced by the removal of Mg2+, indicating that the interneurons were driven at least in part through NMDA receptors. Bicuculline, a gamma-aminobutyric acid-A (GABAA) receptor antagonist, enhanced the late PSPs, indicating that GABAergic inhibition suppresses both the glycinergic interneurons responsible for the trains of IPSPs in T-stellate cells and the interneuron responsible for late EPSPs in T stellate cells. The glycinergic interneurons that mediate the series of IPSPs are intrinsic to the ventral cochlear nucleus because long series of IPSPs were recorded from T stellate cells in slices in which the DCN was removed. These experiments indicate that T stellate cells are a potential source of late EPSPs and that D stellate cells are a potential source for trains of late IPSPs.

Action Potentials↗

Analysis of angiotensin II receptor subtypes in individual rat brain nuclei.

Previous studies have used new angiotensin II (AII) receptor subtype selective compounds to localize AII receptor subtypes within discrete rat brain nuclei. The purpose of this autoradiographic study was to extend these preliminary findings and provide a comprehensive analysis of AII binding sites in 22 rat brain nuclei and the anterior pituitary, to include estimates of the binding affinity for 125I sar1 ile8 AII (125I SIAII) at each nucleus, and determine the fractional distribution of each subtype at each nucleus. Estimates of KD in separate experiments revealed that AT1 nuclei had a consistently higher affinity for 125I SIAII than AT2 nuclei (0.66 vs. 2.55 nM). Displacement of subsaturating concentrations of 125I SIAII by 10(-8)-10(-4) M DuP753 (selective for the AT1 subtype) or PD123177 (selective for the AT2 subtype) indicated that approximately half of the brain regions surveyed contained predominantly AT1 sites and half contained predominantly AT2 sites. Binding was partially displaced by both compounds in several regions and two site analyses were performed to estimate the distribution of subtypes within each nucleus. The data were then corrected for differential occupancy by 125I SIAII. Brain nuclei associated with cardiovascular or dipsogenic actions of AII, e.g., subfornical organ, organum vasculosum of the lamina terminalis, median preoptic nucleus, nucleus of the solitary tract and area postrema, contained pure, or almost pure, populations of AT1 receptors. The functions of AII in brain regions containing predominantly AT2 binding sites, e.g., thalamus, colliculi, inferior olive and locus ceruleus, remain undefined. Thus, AII binding sites in the rat brain have been differentiated into two subtypes with similar characteristics to those reported in peripheral tissues. However, the unexpected finding that they can be differentiated on the basis of their affinity for 125I SIAII raises questions concerning their coidentity with peripheral receptor subtypes.

1-Sarcosine-8-Isoleucine Angiotensin II↗

1,3,5-Trinitrobenzene-induced encephalopathy in male Fischer-344 rats.

Administration of 1,3,5-trinitrobenzene (TNB) to male Fischer-344 rats produced ataxia after 6 or 7 oral doses (71 mg/kg). Light microscopic examination after 10 days revealed petechial hemorrhages in the brain stem and cerebellum and bilaterally symmetric degeneration and necrosis (malacia) with reactive gliosis in the cerebellar peduncles. The malacia was dorsal and lateral to the fourth ventricle involving the cerebellar nuclei, medial and lateral vestibular nuclei, and inferior colliculi. Blood vessels associated with the lesion had widened Virchow-Robin spaces, occasionally with extravasated erythrocytes. Rats administered daily oral doses of 35.5 mg/kg of TNB for 10 days and 35.5 and 71 mg/kg of TNB for 1 or 4 days did not have brain lesions.

Administration, Oral↗

Fkh5-deficient mice show dysgenesis in the caudal midbrain and hypothalamic mammillary body.

The murine winged helix gene Fkh5 is specifically expressed in the developing central nervous system (CNS). Early embryonic Fkh5 expression is restricted to the mammiliary body region of the caudal hypothalamus, midbrain, hindbrain and spinal cord. Postnatally, signals persist in specific nuclei of the mammillary body and in the midbrain. We generated Fkh5 deficient mice by homologous recombination to assess its in vivo function. At birth, Fkh5-deficient mice are viable and indistinguishable from wild-type and Fkh5 heterozygous littermates. However, about one third die within the first two days and another fifth before weaning. Surviving Fkh5-deficient mice become growth retarded within the first week and remain smaller throughout their whole life span. Fkh5-deficient females on 129Sv x C57BL/6 genetic background are fertile, but do not nurture their pups. More detailed analysis of Fkh5-deficient brains reveals distinct alterations in the CNS. In the midbrain, mutant mice exhibit reduced inferior colliculi and an overgrown anterior cerebellum. Furthermore, the hypothalamic mammillary body of Fkh5-deficient brains lacks the medial mammillary nucleus. These results suggest that Fkh5 plays a major role during CNS development.

Animals↗

[The central neural mechanism of the gastric motility in the dog's medulla oblongata on the vagal inhibitory and excitatory reflexes (author's transl)].

The influences of the vagal inhibitory and excitatory reflexes on the gastric motor centers in the dog's medulla oblongata were investigated. Dogs were anaesthetized with Nembutal, and supplemented Gallamine at need. The brain stem was transected on the level of inferior colliculi of midbrain, the spinal cord transected on the level of between C1 and C2. Bilateral splanchnic nerves were also severed. Electrical activities from the inhibitory and excitatory areas in medulla oblongata were recorded by using a concentric circle electrode which was inserted into medulla oblongata from the dorsal surface of it. Following results were obtaind. 1) Electrical activities of the gastric inhibitory areas were classifed into three types (see Table 1). Type I: The augmentation of electrical activities of the gastric inhibitory areas during theinhibitory reflex were associated with the diminution of them during the exictatory reflex. Type II: Although electrical activities of the gastric inhibitory areas were augmented during the inhibitory reflex, any changes of them were not obtained during the excitatory reflex. Type III: Any changes of electrical activities of the gastric inhibitory areas were not obtained during both inhibitory and excitatory reflexes. 2) Electrical activities of the gastric excitatory areas were classified into two types (see Table 2). Type I: The diminution of electrical activites of the gastric excitatory areas during the inhibitory reflex were associated with the augmentation of them during the excitatory reflex. Type II: Although any changes of electrical activities of the gastric excitatory areas were not observed during the inhibitory reflex, they were augmented during the excitatory reflex.

Animals↗

Effects of age and interstimulus interval on the brainstem auditory evoked potential.

Brainstem auditory evoked potentials (BAEPs) were studied in young (mean age 25 years; n = 8) and very healthy elderly women (mean age 71.2 years; n = 8) in order to evaluate the effects of age on transmission time over the brainstem auditory afferent pathway. Peak latencies, interwave latencies (ILs) and response amplitudes were determined at interstimulus intervals (ISIs) of 100, 50, 20 and 10 msec. Four repeated measures were obtained at each ISI in order to assess response variability as a function of age. While the elderly group had delayed peak latencies for all BAEP components, ILs were equivalent in the two age groups. Response amplitude tended to be reduced in the elderly compared to the young group and this effect was dependent upon ISI. Latency values (both peak and ILs) increased with decreasing ISI but there was no age-ISI interaction. Response variability did not change with age. The peak latency increases observed in the elderly were shown to be due to peripheral processes (mild presbycusis). The lack of an age effect for ILs and the lack of an ISI-age interaction indicate no age related slowing of central transmission time in the afferent auditory system at least to the region of the superior olivary complex and inferior colliculi.

Acoustic Stimulation↗

Bilateral trochlear nerve palsies. A clinicoanatomic correlate.

A patient with bilateral trochlear nerve palsies is presented. Computed tomographic (CT) brain scan localized an anterior cerebellar vermis lesion compressing the area caudal to the inferior colliculi where the fourth nerves decussate and exit the dorsal brain stem. This lesion was probably responsible for the bilateral trochlear nerve dysfunction. Pertinent anatomy and pathologic involvement are discussed.

Adenocarcinoma↗

The use of neural transplantation for suppression of seizure activity in genetically epilepsy-prone rats.

The possibility of correcting seizure activity with neural transplantation was studied in Wistar rats with audiogenic seizures and in Krushinskii-Molodkina rats with high level of audiogenic seizures. In Wistar rats seizures were absent during 24 weeks after combined bilateral transplantation of striatal and cerebellar tissue from newborn rats into the parietal cortex. The same transplantation performed in Krushinskii--Molodkina rats increased the latency of audiogenic seizures. In some rats the intensity of seizures decreased, but they did not completely disappeared. Suppression of seizure activity in Krushinskii-Molodkina rats was observed after transplantation of striatal and cerebellar tissue simultaneously into the parietal cortex and inferior colliculi.

Animals↗

[A case of chronic methyl bromide intoxication showing symmetrical lesions in the basal ganglia and brain stem on magnetic resonance imaging].

A 30-year-old man developed paresthesia in the feet, unstable gait and blepharoptosis subsequent to pharyngeal pain while working in a warehouse of imported fruit and vegetable fumigated with methyl bromide and cyanate. Neurological examination showed bilateral blepharoptosis, diplopia, ataxic gait and paresthesia below the inguinal region. The serum concentration of thiociane, a metabolite of cyanide, was within normal limits, but that of bromide was elevated (43.7 mg/l, normal: 3.7-8.6). Thus we diagnosed the patient as intoxication of methyl bromide. Magnetic resonance imaging of the brain (MRI) revealed bilateral symmetrical lesions of high signal intensity in the posterior region of the putamen, the subthalamic nuclei, the dorsal medulla oblongata corresponding to inferior cerebellar peduncles and vestibular nuclei, the inferior colliculi and the periaqueductal gray matter surrounding the oculomotor nucleus of the midbrain. As far as we know, this is the first report of MRI detected cerebral lesions in a case with intoxication of methyl bromide.

Adult↗

[Methyl bromide poisoning. 3 cases, 1 fatal. Neruopathological study of one case of coma with myoclonus followed for 5 years].

Three new cases of methyl bromide poisoning (leakage from a fire extinguisher) are reported. Two of these were characterized, after an initial period of coma and myoclonic status, by an action myoclonus. Electrical data are presented. A follow up of 4 and 8 years allowed to study the effect of drugs, two of which (clonazepam and baclofene) being pecularly contributive. The third patient outlived for 5 years in a stuporous state with myoclonus. The anatomical findings consisted mainly of a necrosis of both inferior colliculi with gliosis in the upper brain stem reticular formation and moderate changes in the dentate and pontine nuclei. Their significance is discussed in view of physiological and experimental knowledge.

Adolescent↗

MR imaging assessment of myelination in the very preterm brain.

BACKGROUND AND PURPOSE: MR imaging was performed in very preterm infants by using an MR imager in the neonatal intensive care unit. The aims of this study were to assess the development of myelination in the preterm brain based on MR imaging findings and to compare the ability of T1-weighted conventional spin-echo, inversion recovery fast spin-echo, and T2-weighted fast spin-echo MR imaging to show myelination in these infants. METHODS: MR imaging was performed for 26 preterm infants with a median gestational age of 28 weeks who had normal neurodevelopmental outcomes at 2 years corrected age. RESULTS: Myelin was evident in the gracile and cuneate nuclei and fasciculi, vestibular nuclei, cerebellar vermis, inferior and superior cerebellar peduncles, dentate nucleus, medial longitudinal fasciculus, medial geniculate bodies, subthalamic nuclei, inferior olivary nuclei, ventrolateral nuclei of the thalamus, decussation of the superior cerebellar peduncles, medial lemnisci, lateral lemnisci, and inferior colliculi at < or = 28 weeks gestational age. From this gestational age, myelination was not visualized at any new site until 36 weeks gestational age, when myelin was visualized in the corona radiata, posterior limb of the internal capsule, corticospinal tracts of the precentral and postcentral gyri, and lateral geniculate bodies. T2-weighted fast spin-echo MR imaging showed myelin in gray matter nuclei at an earlier gestational age than did T1-weighted conventional spin-echo or inversion recovery fast spin-echo MR imaging. T1-weighted conventional spin-echo MR imaging showed myelin earlier in some white matter tracts in the preterm brain. CONCLUSION: Myelination was evident in numerous gray and white matter structures in the very preterm brain. A knowledge of myelination milestones will allow delays to be detected at an early stage.

Brain↗

[Symmetrical necrosis in the gray matter of the brainstem and spinal cord. Two adult cases of anoxic encephalopathy].

We describe distinctive necrosis in the brainstem of two adult patients of anoxic encephalopathy. The patients were a 75-year-old man and an 82-year-old woman, who were resuscitated after cardiac arrest that lasted about 20 minutes and artificially ventilated. The first patient remained comatose without recovery of brainstem reflexes and had persistent hypotension requiring continuous infusion of catecholamine until death that occurred two weeks after the onset of illness. In the second patient, her general circulation recovered on the next day resuscitation, and traces of brainstem reflexes reappeared thereafter, while her consciousness was severely disturbed throughout the three weeks' clinical course. Both of the patients failed to regain spontaneous respiration and required the ventilatory support. On general autopsy, the first patient had small cell carcinoma of the lung with metastasis to the pleura, hilar lymph nodes and liver. In the second patient, an old myocardial infarction and pneumothorax were found. The neuropathological findings in the two patients were similar, varying only in their severity, except for the presence of the degenerative changes compatible with those of progressive supranuclear palsy in the second patient. There were laminar necrosis in the cerebral cortex and severe ischemic changes in the basal ganglia, thalamus and cerebellum. The cerebral white matter, however, exhibited only myelin pallor without apparent destruction. There was no herniation in the brain. In the first patient, fresh hemorrhages were noted in the bilateral globus pallidus. In the brainstem, symmetrical necrosis was present exclusively in the gray matter: the superior and inferior colliculi, periaqueductal gray matter, substantia nigra and the several cranial nuclei including the spinal nucleus of the trigeminal nerve, solitary and vestibular nuclei. In the second patient the symmetrical necrotic foci were also found in the substantia gelatinosa of the lower lumbar and sacral cords which were available for examination. Around these sharply demarcated necrotic lesions of the brainstem and spinal cord were there rarefaction and pronounced astrogliosis. Unlike the cases of neonates or infants, symmetrical necrosis in the brainstem has been reported to be exceptional in adult patients of anoxic encephalopathy. Now that the medical technology of resuscitation is well advanced, the adult patients exhibiting the pathology presented here may be encountered more frequently than previously thought.

Aged↗

MR imaging of rhombencephalosynapsis: report of three cases and review of the literature.

We describe the clinical and MR findings in three cases of rhombencephalosynapsis, a rare congenital malformation of the posterior fossa consisting of vermian agenesis or severe hypogenesis, fusion of the cerebellar hemispheres, and apposition or fusion of the dentate nuclei. Associated anomalies include hydrocephalus, fusion of the inferior colliculi, deficiency or absence of the septum pellucidum, and hypoplasia of the anterior commissure. Fourteen previous cases of rhombencephalosynapsis have been reported including Obersteiner's first report in 1914. The clinical presentation is variable, ranging from early death to variable degrees of cerebellar dysfunction and developmental delay. Patients may reach young adulthood. We report three additional cases and provide radiographic (MR) images of this unusual anomaly detected during life. Diagnoses in three children with rhombencephalosynapsis were made on the basis of MR findings. To our knowledge, this is the first report of this disorder being diagnosed in living patients.

Abnormalities, Multiple↗