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Demonstration of neuron-specific enolase in nonneuronal tumors using a specific monoclonal antibody.

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References
1. Barbeau A, Cloutier T, Roy M, e t al: Eco-genetics of Parkin-
son's disease: I-The 4-hydroxylarion of debrisoquine. Lancet
2:12 13-1216, 1985
2. Barbeau A, Roy M: Etiology of Parkinson's disease: a research
strategy. Can J Neurol Sci 11:24-28, 1984
3. Baumann RJ, Jameson HD, McKean HE, et a]: Cigarette smoking and Parkinson's disease: I. A comparison of cases with
matched neighbors. Neurology ( N Y ) 30338-843, 1980
4. Branch RA, Wilkinson GR, McAllisrer CB, et al: Association of
polymorphic oxidative drug metabolism, cigarette smoking and
alcohol consumption with bladder cancer. Clin Res 33:527A,
1985
5. Burch PRJ: Cigarette smoking and Parkinson's disease. Neurology (NY) 31:>00-501, 1981
6. Hetzel MR, Law M, Keal EE, e t al: Is there agenetic component
in bronchial carcinoma in smokers? Thorax 35:709, 1980
7 . Idle JR, Mahgoub A, Sloan TP, et al: Some observations on the
oxidation phenotype status of Nigerian patients presenting wirh
cancer. Cancer Lett 11:331-338, 1981
8. Jansson B, Jankovic J: Low cancer rates among patients with
Parkinson's disease. Ann Neurol 17:505-509, 1985
9. Lennard MS, Silas J H , Smith AJ, et al: Determination of debrisoquine and its 4-hydroxy-metabolite in biological fluids by
gas chromatography wirh flame-ionization and nitrogen-selecrive detection. J Chromarogr 133:161-166, 1977
10. Price-Evans DA, Mahgoub A, Sloan TP, et al: A family and
population srudy of rhe genetic polymorphism of debrisoquine
oxidation in white British population. J Med Genet 17:102105, 1980
Demonstration of
Neuron-Specific Enolase
in Nonneuronal Tumors
Using a Specific
Monoclonal Antibody
Patrick Cras, MD," Salvador Soler Federsppiel, MSc,t
Jan Gheuens, MD,? Jean-Jacques Martin, MD,"
and Armand Lowenthal. M D I
The y-isoenzyme of enolase (neuron-specific enolase, NSE)
is generally considered to be specific to neurons, aminoprecursor uptaking and decarboxylating (APUD) cells f 11,
and the diffuse neuroendocrine system [ S ] . NSE has been
localized in neuroblasromas, insulinomas, Merkel cell
tumors, pheochromocytomas, melanomas, and other tumors
of neuronal or APUD origin 131. An early study of the
enolase isoenzyme distribution in brain tumors failed to
show y-enolase in astrocytomas or meningiomas [2). Recently the report of Vinores and associates [4] has cast some
doubt on the neuronal specificity of NSE. Although this
study was performed using well-characterized, monospecific
polyclonal antisera, the possibility remains that these results
were influenced by cross-reacting or contaminating antibodies directed to the a-or P-isoenzymes of enolase.
We developed a monoclonal antibody (mAb) [BBSiNCi
VILH14 (Hlct)} directed to an epitope specific to human
106 Annals of Neurology
Vol 20
N o 1 July 1986
Numerous neuron-specifEcenolase ( H 14)-positive gemirto,ytir artrocytes (arrows) in a glioblajtoma. (Paraffin jection. avirtinbiotin complex method, hematoxylin counterstain;bar = 100
Fm.1
y-enolase. Details of its deveiopment and characteristics
will be published elsewhere (S. Soler Federsppiei et al,
submitted for publication). The H14 mAh was an IgG,, K.
Its specificity for the y-isoenzyme of enolase was determined using an immunoblotting technique following
two-dimensional-isofocusing-sodium dodecylsulfate electrophoresis and solid-phase radioimmunoassay of highly
purified enolase isoenzymes. Using the H14 mAb, y-enolase
could be demonstrated immunohistologically in neurons,
APUD cells, ganglion cells in the gastrointestinal tract, and
myelinated and unmyelinated nerve fibers. Astrocytomas of
different malignancy grades frequently contained numerous
y-enolase-positive abnormal glial cells (Figure). Furthcrmore, reactive astrocytes surrounding the mass lesion
showed the same phenomenon. In mixed tumors (e.g., gangliogliomas), the ganglionic cells were always more intensively labeled than was the astroglial component. In meningiomas, y-enolase-positive cells were usually localized in the
whorls, tending to form psammoma bodies. Cells were also
frequently labeled in endotheliomatous areas. In metastases,
y-enolase positivity was highest in the vicinity of necrotic
regions. The specificity of the reaction was demonstrated
by absorption controls and replacement by another monoclonal antibody of the same class and type in the same
concentration.
Immunolocalization of y-enolase using specific mAb in a
wide range of nonneuronal tumors limits its use as a marker.
Great care should be exercised in interpreting immunocytochemical studies to demonstrate y-enolase in tissue
sections.
Several authors have already speculated on the functional
importance of y-enolase expression in nonneuronal tissues.
The most striking differences between y-enolase and a-and
p-enolases are that the former is more stable in the presence
of high concentrations of chloride ions and that its activity
suffers less from the inhibitory effect of excess substrate. We
submit that some cells (not strictly neuronal in origin) can
express y-enolase under appropriate conditions, enabling
them to keep up with extra energy demands.
Laboratories of *Neuropathohgy and TNeurochemisty
The Born-Bunge Foundation
University of Antwerp
Universiteitsplein 1
8261 0 Wiiriyk, Belgium
This study was supported by grants of the “Programma voor
Wetenschapsbeleid” (Grant No. 84/89-68) and the “Fonds voor
Geneeskundig Wetenschappelijk Onderzoek” (Grant No.
3.0004.81).
References
1. Marangos PJ, Zomzely-Neurath C, Luk DCM, York C: Isolation
and characterization of the nervous system-specific protein 14-32 from rat brain. J Biol Chem 250:1884-1891, 1975
2. Royds JA, Parsons MA, Taylor CB, Timperley WR: Enolase
isoenzyme distribution in the human brain and its rumors. J
Pathol 137:37-49, 1982
3. Royds ,JA, Taylor CB, Timperley WR: Enolase isoenzymes as
diagnostic markers. Neuropathol Appl Neurobiol 1l:l-16, 1985
4. Vinores SA, Bonnin JM, Rubinstein LJ, Marangos PJ: Immunohistochemical demonstration of neuron-specific enolase in
neoplasms of the CNS and other tissues. Arch Pathol Lab Med
108:536-540, 1984
5. Wharton J, Polak JM, Cole GA, et al: Neuron-specific enolase as
an immunocytochemical marker for the diffuse neuroendocrine
system in human fetal lung. J Histochem Cytochem 29:13591364, 1981
Internuclear
Ophthhoplegia with
Narcotic Overdosage
There was a history of chronic alcoholism and recent alcohol,
acetaminophen, and codeine consumption, but no other history was available. Initially he was awake, alert, and belligerent, but soon became lethargic. Blood pressure was 110/70
mm Hg, pulse was regular at 56 per minute, and he had
apneic periods lasting 5 seconds with total respirations of 16
per minute. His only response to deep pain was withdrawal
of the affected limb. Examination of eyes revealed pinpoint
pupils and roving, dysconjugate eye movements. The right
eye would not adduct past the midline spontaneously or
with oculocephalic maneuver. There was no nystagmus in
the left eye. His serum alcohol level was 350 mddl and
acetaminophen and opiate screening was positive. Naloxone
(0.8 mg) was administered intravenously, and within 3 minutes his respirations were regular, he became alert, was able
to follow commands, and had fully intact ocular movements.
A half hour later the patient again became unresponsive,
with prolonged periods of apnea, pinpoint pupils, and dysconjugate gaze with inability to adduct the right eye past the
midline. Following injection of another 0.8 mg of naloxone
the patient’s examination became normal. He was admitted
and treated with naloxone as needed and discharged the next
day with no neurological deficits.
Internuclear ophthalmoplegia is anatomically correlated with
structural lesions of the medial longitudinal fasciculus El}.
Metabolic and toxic ophthalmoplegia have also been described [4}. Rizzo and Corbett [2] have described the only
previous case of internuclear ophthalmoplegia reversed by
naloxone. Their patient was also a chronic alcohol and drug
abuser who was seen following ingestion of multiple drugs.
Naloxone administration rapidly improved both the mental
status and ocular findings in their patient and ours.
Although rapid reversal of ophthalmoplegia with naloxone
suggests a narcotic effect, the lack of reports of internuclear
ophthalmoplegia in pure narcotic intoxication seems to implicate indirect pathways in dysfunctioning of the medial longitudinal fasciculus. Internuclear ophthalmoplegia has been
reported in Wernicke’s syndrome resulting from chronic alcoholism 131 but not in acute alcoholic intoxication {5]. Both
our patient and the previously reported one [2] had a history
of long-term alcohol abuse. This raises the question of an
interaction between thiamine deficiency and narcotics in
large dosage, but our current knowledge is insufficient to
establish the mechanism of this ophthalmoplegia.
Department of Neurology
University of Connecticut School of Medicine
263 Farmington Ave
Farmington, C T 06032
Rif S. El-Mallakh, M D
The presenting signs of acute, severe narcotic poisoning are
well known. The triad of decreased consciousness, pinpoint
pupils, and respiratory depression is considered enough evidence for the administration of opiate antagonists [ll. Focal
neurological deficits are typically absent. This report describes a case of acute narcotic intoxication accompanied by
internuclear ophthalmoplegia.
A 41-year-old man was brought to the emergency department after being found at the bottom of a flight of stairs.
Referencej
1. Henry J, Volans G: ABC of poisoning. Analgesics:opioids. Br
Med J 289:990-993, 1984
2. Rizzo M, Corbett J: Bilateral internuclear ophthalmoplegia reversed by naloxone. Arch Neurol40:242-243, 1983
3. Smith JL, Cogan DG: Internuclear ophthalmoplegia. A review of
fifty-eight cases. Arch Ophchalmol 61:687-694, 1959
4. Spector RH, Schnapper R Amitriptyline-induced ophthalmoplegia. Neurology (NY) 31:1188-1190, 1981
5. Wilkinson IMS, Kime R, Purnell M: Alcohol and human eye
movement. Brain 97:785-792, 1974
Annals of Neurology
Vol 20 No 1 July 1986 107
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using, nonneuronal, enolase, specific, monoclonal, demonstration, neurons, antibody, tumors
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