Sesquiterpenes from clove (Eugenia caryophyllata) as potential anticarcinogenic agents.

Bioassay-directed fractionation of clove terpenes from the plant Eugenia caryophyllata has led to the isolation of the following five active known compounds: beta-caryophyllene [1], beta-caryophyllene oxide [2], alpha-humulene [3], alpha-humulene epoxide I [4], and eugenol [5]. Their structures were determined on the basis of spectral analysis (hreims, 1H and 13C nmr). These compounds showed significant activity as inducers of the detoxifying enzyme glutathione S-transferase in the mouse liver and small intestine. The ability of natural anticarcinogens to induce detoxifying enzymes has been found to correlate with their activity in the inhibition of chemical carcinogenesis. Thus, these sesquiterpenes show promise as potential anticarcinogenic agents.


Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy?

A total of 276 patients with a high risk of developing postoperative seizures were randomised to treatment with carbamazepine or phenytoin for six or 24 months, or to no treatment. No significant differences were found (though the confidence limits were fairly wide) between the regimes in respect of the incidence of seizures or death. In a substantial proportion of the patients postoperative epilepsy remained a continuing disability. A high incidence of drug-related side effects was found in the treatment groups. Prophylactic anticonvulsants cannot therefore be recommended routinely following supratentorial craniotomy.


A longitudinal assessment of seizure outcome and overall benefit from 100 cortectomies for epilepsy.

Results of 100 cortical resections for 76 temporal, 23 frontal and one parietal lobe epilepsies were studied in terms of seizure relief and overall benefit. A non-homogenous Markov chain model was used to take into account both the intravariability of post-surgical outcome and the differences in duration of follow-up in a group of patients consecutively operated. The seizure free (SF) state was defined as no seizure in the previous five months at first follow up visit and none in the preceding 12 months at subsequent annual visits. For the whole of the population the SF probability was 82%, 66%, 61%, and 62% at six months, one year, two and five years respectively. A better outcome was found for temporal lobe epilepsy (SF probability: 68% at the fifth postoperative year) than for frontal lobe epilepsy (SF probability: 42% at the fifth postoperative year) with a statistically significant difference. Pre- and postoperative interictal signs and symptoms were classified according to their clinical significance: (a) mild handicap--symptoms recognisable but no interference with usual life, and (b) moderate or severe handicap--interference with some or all daily activities. The interictal state was considered more impaired after surgery than before in two situations: (a) either symptoms, absent before surgery, appeared in the postoperative period involving a moderate or severe handicap, or (b) symptoms present before surgery and answerable for a mild or moderate handicap that increased to involve a moderate or severe handicap respectively in the postoperative period. Surgery was considered a major benefit when two conditions were fulfilled-namely, a SF state and no deterioration of the interictal stage when compared with the preoperative period. The probability of obtaining such a benefit was 58%, 51%, 48% and 56% at six months, one year, two and five years respectively. The results suggest that surgery is an effective treatment for more than 50% of long lasting medically intractable epilepsies.


Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment.

Depression with cognitive impairment, so called depressive pseudodementia, is commonly mistaken for a neurodegenerative dementia. Using positron emission tomography (PET) derived measures of regional cerebral blood flow (rCBF) a cohort of 33 patients with major depression was studied. Ten patients displayed significant and reversible cognitive impairment. The patterns of rCBF of these patients were compared with a cohort of equally depressed non-cognitively impaired depressed patients. In the depressed cognitively impaired patients a profile of rCBF abnormalities was identified consisting of decreases in the left anterior medial prefrontal cortex and increases in the cerebellar vermis. These changes were additional to those seen in depression alone and are distinct from those described in neurodegenerative dementia. The cognitive impairment seen in a proportion of depressed patients would seem to be associated with dysfunction of neural systems distinct from those implicated in depression alone or the neurodegenerative dementias.


The effect of immunosuppression on the development of cerebral oedema in an experimental model of intracerebral haemorrhage: whole body and regional irradiation.

The oedema which forms around an intracerebral haemorrhage has a complex aetiology. The immune response may have a role in its formation. There is clinical and experimental evidence that circulating leucocytes and platelets may mediate oedema formation. Global depletion of circulating leucocytes and platelets by whole body irradiation in a rodent model of intracerebral haemorrhage was found to confer protection against both ischaemia and oedema formation. This was not a direct effect of irradiation of the brain. The possible mechanisms for this protection are discussed.


Intracranial blood flow velocity after head injury: relationship to severity of injury, time, neurological status and outcome.

Middle cerebral artery (MCA) blood flow velocity was measured daily by transcranial Doppler ultrasonography in 121 patients with severe (50), moderate (16) and minor (55) head injury during their hospital stay, and the results compared with findings in control subjects. Admission MCA velocity was significantly lower after severe 35.8 (31.9-39.7) cm/s, mean (95% confidence limits), moderate 45.5 (40.0-51.0) cm/s and minor 51.7 (47.9-55.5) cm/s head injury when compared with normal controls 60.1 (56.9-63.3) cm/s. Initial mean velocity in severe head injury was significantly lower than in moderate and minor injury. At discharge, MCA velocity in severe injury remained below normal 46.2 (43.2-49.0) cm/s, whereas, in moderate and minor injury flow velocity had returned to normal. Correlation (r = 0.46, p less than 0.01) was found between MCA velocity and Glasgow Coma Score (GCS) on admission but not on discharge. Persistently low flow velocity was found in all 10 patients who died within 72 hours (early deaths). An admission MCA velocity of less than 28 cm/s correctly predicted 80% of the early deaths. Patients who made a good recovery or had only moderate disability at six months showed a significant increase in velocity from admission 36.2 (31.5-41.2) cm/s to discharge 47.8 (43.7-51.9) cm/s in contrast to those who were severely disabled, in whom velocity generally remained low.


Spatiomotor cueing in unilateral left neglect: three case studies of its therapeutic effects.

Limb activation contralateral to a cerebral lesion seems to reduce visual neglect, though whether this is due to perceptual cueing or hemispheric activation is controversial. Three case studies are presented which attempt to use this experimental finding therapeutically in the rehabilitation of unilateral left neglect. The first study used a combination of perceptual anchoring training with left arm activation procedures and produced improvements. The second used the same method, but stimulated left arm activation using an avoidance conditioning procedure, again with positive results. The third case treatment focused on cueing for left arm activation without explicit instructions for perceptual anchoring, with positive results.


The combined monitoring of brain stem auditory evoked potentials and intracranial pressure in coma. A study of 57 patients.

Continuous monitoring of brainstem auditory evoked potentials (BAEPs) was carried out in 57 comatose patients for periods ranging from 5 hours to 13 days. In 53 cases intracranial pressure (ICP) was also simultaneously monitored. The study of relative changes of evoked potentials over time proved more relevant to prognosis than the mere consideration of "statistical normality" of waveforms; thus progressive degradation of the BAEPs was associated with a bad outcome even if the responses remained within normal limits. Contrary to previous reports, a normal BAEP obtained during the second week of coma did not necessarily indicate a good vital outcome; it could, however, do so in cases with a low probability of secondary insults. The simultaneous study of BAEPs and ICP showed that apparently significant (greater than 40 mm Hg) acute rises in ICP were not always followed by BAEP changes. The stability of BAEP's despite "significant" ICP rises was associated in our patients with a high probability of survival, while prolongation of central latency of BAEPs in response to ICP modifications was almost invariably followed by brain death. Continuous monitoring of brainstem responses provided a useful physiological counterpart to physical parameters such as ICP. Serial recording of cortical EPs should be added to BAEP monitoring to permit the early detection of rostrocaudal deterioration.


The alien hand and related signs.

Alien limb sign includes failure to recognise ownership of one's limb when visual cues are removed, a feeling that one body part is foreign, personification of the affected body part, and autonomous activity which is perceived as outside voluntary control. Although the hand is most frequently affected, any limb or combination of limbs may fulfil the alien limb criteria. Alien hand sign should be reserved for cases in which the hand feels foreign together with observable involuntary motor activity. To characterise this phenomenon, seven patients with alien hand sign and other motor or behavioural manifestations are described. Aetiologies included multiple infarcts and cortobasal ganglionic degeneration (CBD). In this study, all patients had apraxia in response to verbal commands and problems with bimanual coordination. Most displayed non-goal directed involuntary motor activities, and two had self destructive motor behaviours. Grasp reflex occurred with alien hand due to either aetiology. Cortical reflex myoclonus was frequently seen in CBD patients. The phenomenological spectrum is reviewed, a diagnostic protocol proposed, and possible anatomical bases of alien hand discussed.


Psychophysical correlates of phantom limb experience.

Phantom limb phenomena were correlated with psychophysiological measures of peripheral sympathetic nervous system activity measured at the amputation stump and contralateral limb. Amputees were assigned to one of three groups depending on whether they reported phantom limb pain, non-painful phantom limb sensations, or no phantom limb at all. Skin conductance and skin temperature were recorded continuously during two 30 minute sessions while subjects continuously monitored and rated the intensity of any phantom limb sensation or pain they experienced. The results from both sessions showed that mean skin temperature was significantly lower at the stump than the contralateral limb in the groups with phantom limb pain and non-painful phantom limb sensations, but not among subjects with no phantom limb at all. In addition, stump skin conductance responses correlated significantly with the intensity of non-painful phantom limb paresthesiae but not other qualities of sensation or pain. Between-limb measures of pressure sensitivity were not significantly different in any group. The results suggest that the presence of a phantom limb, whether painful or painless, is related to the sympathetic-efferent outflow of cutaneous vasoconstrictor fibres in the stump and stump neuromas. The hypothesis of a sympathetic-efferent somatic-afferent mechanism involving both sudomotor and vasoconstrictor fibres is proposed to explain the relationship between stump skin conductance responses and non-painful phantom limb paresthesiae. It is suggested that increases in the intensity of phantom limb paresthesiae follow bursts of sympathetic activity due to neurotransmitter release onto apposing sprouts of large diameter primary afferents located in stump neuromas, and decreases correspond to periods of relative sympathetic inactivity. The results of the study agree with recent suggestions that phantom limb pain is not a unitary syndrome, but a symptom class with each class subserved by different aetiological mechanisms.


A timed test of swallowing capacity for neurological patients.

A timed test of swallowing capacity has been designed for use in patients with neurogenic dysphagia. Swallowing speed (ml/s) has been demonstrated to have high intra- and inter- rater and test- retest reliability, and to be essentially independent of flavour or temperature. "Guideline" normal values were established in individuals without a swallowing disorder: swallowing speed was less in females than males and declined in both groups with age. The validity of a swallowing speed less than 10 ml/s as an index of abnormal swallowing was tested by comparison with the complaint of abnormal swallowing in a group of 81 neurological patients. Swallowing speed had a sensitivity of 96% and specificity of 69%: some apparent false positive responses were found in patients with disordered swallowing, mainly due to multiple sclerosis. Using a standard questionnaire and examination a similar pattern of symptoms and signs were statistically associated with both the clinical complaint of abnormal swallowing and swallowing speed. It is concluded that swallowing speed is a reliable and valid index for assessing disordered swallowing in neurological patients and may be of value in monitoring response to therapy.


Haemorrhagic thiamine deficient encephalopathy following prolonged parenteral nutrition.

Neuropathological examination of three patients who were maintained on parenteral nutrition without substitution of thiamine demonstrated an acute haemorrhagic encephalopathy. The lesions differed substantially from the classic features of thiamine deficient encephalopathy regarding the histopathological alterations and the topographical distribution. The extreme rapidity of thiamine deprivation may have been responsible for the abrupt clinical onset of the disease and the intensity of the morphological alterations.


Lupus-related myelopathy: report of three cases and review of the literature.

Transverse myelopathy is an uncommon complication of systemic lupus erythematosus (SLE). Three patients with SLE are reported who developed transverse myelopathy, including the neuropathological findings in one patient on whom necropsy was performed. Paraparesis was present in all three cases, but definite sensory changes were present in only one patient. In two patients, the CSF findings were remarkable for elevated protein and depressed glucose concentrations. Microscopic examination of the brain demonstrated small, scattered foci of recent necrosis consistent with microinfarctions. Striking abnormalities were found in the spinal cord at all levels, including multiple foci of vacuolar spongy degeneration in the peripheral white matter, as well as ballooning of myelin sheaths, swollen axons, myelin pallor, and loss of glial nuclei. The pathological findings in previously reported cases of SLE-related transverse myelopathy are reviewed, and the possible pathogenesis of the findings in our case are discussed.


Paraplegia due to a ruptured aneurysm of the distal posterior inferior cerebellar artery.

A case of paraplegia was due to a ruptured aneurysm of the distal posterior inferior cerebellar artery. The paraplegia was caused by a unilateral lesion located between the cervicomedullary junction and the C2 level, where it involved both crossed and uncrossed pyramidal fibres projecting to the lower extremities. Since a vascular lesion near the cervicomedullary junction is likely to be missed, special attention should be paid to this region when investigating subarachnoid haemorrhage with paraplegia.


MRI of anterior spinal artery syndrome.

In this serial MRI study a 24 year old man presenting anterior spinal artery syndrome was examined. In the acute stage, spin echo sequences showed an enlarged cervical cord on a T1 weighted image and high signal intensity in the enlarged portion of the cord on a T2 weighted image. The findings were interpreted as oedema in the grey and white matter subsequent to ischaemia. In the chronic stage, inversion recovery techniques revealed a distinct focus in the anterior two thirds of the cord at the low cervical level.


Unilateral upper cervical posterior spinal artery syndrome following sneezing.

A 35 year old man experienced severe transitory neck pain following a violent sneeze. This was followed by neurological symptoms and signs indicating a left sided upper cervical cord lesion. MRI showed an infarct at this site in the territory of the left posterior spinal artery. This discrete infarct was probably due to partial left vertebral artery dissection secondary to sneezing.


Plus-minus lid syndrome.

A patient presented with ipsilateral ptosis and contralateral superior eyelid retraction due to a nuclear third nerve syndrome. The CT brain scan revealed a paramedian mesencephalic lesion contiguous with the oculomotor nucleus, sparing the midbrain tectum and the posterior commissure.


Creutzfeldt-Jakob disease with congophilic kuru plaques: CT and pathological findings of the cerebral white matter.

In a patient whose Creutzfeldt-Jakob disease with congophilic kuru plaques that was proved at necropsy, the early brain CT showed low-density areas in the cerebral white matter before cortical atrophy and ventricular enlargement became apparent. Subsequently, there occurred diffuse white matter lucency and severe brain atrophy. At necropsy, there was severe white matter destruction which was more prominent than cortical neuronal loss. Serial CT scans were of great value for demonstrating the early and predominant changes in the cerebral white matter.


Narcolepsy associated with primary temporal lobe B-cells lymphoma in a HLA DR2 negative subject.

Narcolepsy and cataplexy began one year before treatment of a left mid-temporal primary B-cells lymphoma in a HLA DR2 negative man. Treatment with radio therapy and immunosuppression induced regression of the lymphoma and disappearance of narcolepsy and cataplexy.


Lacunar thalamic stroke with pure cerebellar and proprioceptive deficits.

Case reports of two patients with cerebellar ataxia and proprioceptive sensory loss are presented. MRI of the brain revealed lesions of the ventroposterior part of the thalamus. These patients illustrate clinically the anatomical independence of cerebellar and sensory pathways in the thalamus. We suggest that the ataxic deficit is caused by interruption of cerebellar outflow pathways in the thalamus and not secondary to sensory deafferentation.


Clinical and laboratory findings with giant cell arteritis.

Out of 66 patients who were diagnosed as suffering from polymyalgia rheumatica (PMR; n = 40), temporal arteritis (AT; n = 14) or both (n = 12) in a 6.5 year period (incidence 3.4/100,000 per year), 9 died and 49 were followed up for an average period of 28 months. Exacerbations of the illness (n = 24) and complications in the course (n = 32) were more frequent with an initial ESR greater than 90 mm/h. Postural vertigo (n = 11), amaurosis fugax (n = 11) and polyneuropathy (n = 8) were the most frequent neurological complications. Persisting unilateral blindness and aromatic anosmia developed in 2 patients each. Complications were significantly more frequent in patients with initial symptoms of AT (chi 2 P less than 0.001). CRP-levels correlated better with persisting symptoms in the course than did the ESR. Recurrences after treatment were significantly more frequent when the length of corticosteroid-therapy was less than 20 months (chi 2 P less than 0.009). On follow up there were normal values for neopterin, tumour necrosis factor and antibodies against Borrelia burgdorferi.


Presence of typical neuronal markers in serially cultured cells from adult human brain.

Typical markers for neurons but not for astroglia have been identified in cells cultured from a sample of normal adult human temporal lobe, which was removed to gain access to a glioma. Cells were grown in medium containing growth factors, including fibroblast growth factor and nerve growth factor. The cells grew slowly (doubling time, 18 days) and have been carried as far as passage 8 over 10 months. Both immunoblotting and immunocytochemistry with redundant antibodies demonstrated the presence of neurofilaments (NF-H, NF-M, NF-L), but not glial fibrillary acidic protein (GFAP). Neuron-specific enolase (NSE) was also found. Morphologically, the cultures consisted of a pleimorphic population of cells with frequent long processes. Cells demonstrating neuronal rather than astroglial markers can be cultured from normal adult human brain.


Effect of high-dose methylprednisolone on anti-oxidant enzymes after experimental SAH.

Lipid peroxidation has been considered one of the most important factors involved in the pathogenesis of neuronal damage following subarachnoid hemorrhage. In the brain, the protective systems most involved against peroxidative and free radicals generated reactions are superoxide-dismutase (SOD) and glutathione-peroxidase (GSH-Px). Since these activities are subjected to a significant reduction following experimental SAH induction in rats, we investigated in the present study if the beneficial effect of high-dose methylprednisolone (MP) in inhibiting lipid peroxidative processes in SAH is possibly linked to an influence on anti-oxidant enzymatic activities. In brain cortex, after MP treatment, Cu-Zn SOD activity in the early phase and more dramatically in the late phase after SAH was restored (4.06 +/- 0.06 and 4.07 +/- 0.14 enzymatic units/mg of protein, respectively) if compared to hemorrhagic non-treated controls (3.69 +/- 0.16 and 2.96 +/- 0.06 enzymatic U/mg of protein) while Mn-SOD and GSH-Px activities were improved in treated animals only in the early and late phases after SAH, respectively. In the hippocampus, in treated rats Cu-Zn activity was partially restored only at 6 h, while Mn-SOD activity recovered at 48 h after SAH; no significant changes in GSH-Px activity were found in treated animals at any time. In the brain stem, in treated animals, Cu-Zn SOD activity was restored in the early phase (3.86 +/- 0.12 enzymatic U/mg of protein) up to control values of non-hemorrhagic rats (3.44 +/- 0.30 enzymatic U/mg of protein), while GSH-Px activity recovered in the late phase.(ABSTRACT TRUNCATED AT 250 WORDS)


Superficial siderosis of the central nervous system: report of three cases and review of the literature.

We present 3 cases and a review of the literature to demonstrate the current state of clinical diagnosis and therapy of superficial siderosis of the central nervous system. Typical symptoms were progressive cerebellar ataxia, spasticity and hearing loss. Repeated subarachnoid hemorrhage was indicated by persistent xanthochromia of the cerebrospinal fluid and confirmed by the presence of erythrophages, siderophages and iron-containing pigments. Deposition of free iron and hemosiderin in pial and subpial structures leads to intoxication of the central nervous system and represents the pathophysiological mechanism of superficial siderosis. Hypointensity of the marginal zones of the central nervous system on T2 weighted MR images indicates an iron-induced susceptibility effect and seems pathognomonic for superficial siderosis. In 39 of the 43 previously described cases superficial siderosis was verified by biopsy or autopsy. Today magnetic resonance imaging enables diagnosis at an early stage of the disease. Therapeutic management requires the elimination of any potential source of bleeding. In patients with unknown etiology no proofed therapy is yet available.


Beta A4 deposition in the temporal cortex of adults with Down's syndrome.

The deposition of beta A4 has been quantified in the temporal cortex of 9 adults (4 male, 5 female) with Down's syndrome (DS), mean age (+/- SD) 54.7 +/- 8.8 years (range 41-67 years) at the time of death. Immunostaining with antibodies, raised to different portions of the beta A4 protein, showed a greater number of deposits than were seen with traditional silver impregnation or amyloid stains. Antibody to beta A4(1-10) identified fewer plaques than the antibody to beta A4(12-28), the mean ratio of beta A4(1-10)/beta A4(12-28) plaques being 0.30 +/- 0.10 (mean +/- SD). Morphologically, 'diffuse' and 'neuritic' deposits could be distinguished but there was no significant difference in the beta A4(1-10)/beta A4(12-28) ratio according to plaque morphology, nor did the ratio change with age. Quantitatively, the beta A4(12-28) load in the temporal cortex of DS patients was high, occupying some 14% of the field area, and it was not related to the age of the subject over the range studied. Similarly, the total beta A4(12-28) plaque count was high and not age-related. The proportion of morphological plaque types visualised by the Glees and Marsland silver impregnation and by beta A4(12-28) immunostaining were compared. In both techniques 'diffuse' plaques (D) were predominant in the younger subjects and the proportion of 'neuritic' plaques (N) increased with age. The relative proportions of cored plaques (Cp) and plaque cores (C) did not change significantly with age.(ABSTRACT TRUNCATED AT 250 WORDS)


Cerebral cortical amyloid protein precursor mRNA expression is similar in Alzheimer's disease and other neurodegenerative diseases.

The expression of 3 beta-amyloid protein precursor (APP) mRNAs (695, 751, and 770) in the cerebral cortex in Alzheimer's disease and other neurodegenerative diseases was analyzed by the S1 nuclease protection assay. We found no significant Alzheimer's disease-specific alteration of APP mRNA expression when compared to the other neurological diseases as controls. Since the expression of this mRNA was not correlated with amyloid deposition, it is possible that gliosis/neuronal loss may secondarily alter APP mRNA expression. However, the current study revealed no significant correlation between them.


Postural inflexibility in parkinsonian subjects.

In order to identify the types of postural deficits seen in parkinsonian patients with postural instability, we compared the performance of parkinsonian subjects with young and old control subjects in 3 aspects of postural control: (1) the use of sensory information for postural orientation, (2) the coordination of postural movement patterns in response to surface displacements, and (3) the flexible modification of postural response patterns to changes in support conditions. Parkinsonian subjects had very small sway, even under altered sensory conditions. Postural response latencies to displacements were also normal. Postural instability was associated with abnormal patterns of postural responses including excessive antagonist activity and inflexibility in adapting to changing support conditions. Some parkinsonian subjects appeared to have difficulty sequencing motor programs for postural correction. The parkinsonian subjects appeared stiffer since the rate-of-change of sway in response to displacements was reduced. Levodopa improved postural coordination but not the flexible adaptation to changing support conditions.


Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction.

From August 1987 through December 1989 all consecutive conscious patients younger than 70 years with a recent (less than 48 h) brain infarction of the carotid territory were prospectively included in the study. Blood samples for fasting blood glucose and glycosylated haemoglobin (HbA1c) were taken after a median delay of 23 h of the onset of symptoms. The severity of hemiparesis was assessed on admission, at 1 week, 3 weeks, and 3 months. The functional outcome was assessed at 3 months. Computed cerebral tomography was performed on admission, and later on at 3 weeks or 3 months. The brain infarct volume was measured from the CTs. The patients were diagnosed to have prestroke normoglycemia (n = 76) and prestroke hyperglycemia (n = 23) on basis of the HbA1c level. The case fatality rate, severity of hemiparesis, functional outcome, and infarct size did not differ between these 2 groups. On the other hand, fasting blood glucose level of the non-diabetics correlated strongly with the severity of hemiparesis and predicted stroke outcome. A statistically significant correlation was observed between blood glucose values and the volumes of cortical infarcts in non-diabetics. Because prestroke blood glucose level, in contrast to post-stroke blood glucose level, did not have any predictive value concerning stroke outcome it is concluded that high fasting blood glucose values after stroke reflect a stress response to a more severe ischemic brain lesion.


Significance of CSF total neopterin and biopterin in inflammatory neurological diseases.

Total neopterin (T-N), a by-product in the biopterin biosynthesis and an indicator of activation of the cellular immune system, and total biopterin (T-B) levels in cerebrospinal fluid (CSF), were measured in patients with various inflammatory neurological diseases and Parkinson's disease, and the following results were obtained. (1) In patients with neuro-sarcoidosis, neuro-Behçet's disease and meningitis, CSF T-N levels were markedly elevated in the exacerbation or acute stages of their neurological symptoms and remarkably decreased in the remission or chronic stages. In the neuro-sarcoidosis and neuro-Behçet's disease patients, however, CSF T-B levels showed no substantial change. (2) There was a significant positive correlation between CSF T-N levels and CSF/serum albumin ratios only in the meningitis patients. However, increases of CSF T-N levels were not associated with those of plasma T-N levels. (3) In the Parkinson's disease patients, CSF T-N levels remained normal, although CSF T-B levels significantly decreased. (4) A gradient for the CSF T-N value (lumbar greater than ventricular CSF), being reverse to the CSF T-B value, was observed. These results indicate that the significance of CSF T-N is quite different from CSF T-B, and that CSF T-N appears to be a valuable biochemical marker for evaluating the activity of inflammation within the central nervous system. Its measurement seems useful for therapeutic monitoring, especially of patients showing the chronic exacerbating-remitting course.


Serum levels of vitamin A in Parkinson's disease.

To elucidate a possible role of vitamin A in the pathogenesis of Parkinson's disease (PD) we compared serum levels of retinol (vitamin A), measured by HPLC, and the vitamin A/retinol binding protein (RBP) ratio of 42 PD patients (22 males and 20 females, mean age 67.3 +/- 1.34 years) and their respective spouses as control group (20 males and 22 females, mean age 66.2 +/- 1.42). The serum levels of vitamin A did not differ significantly between the 2 groups (0.59 +/- 0.03 microgram/dl for PD patients and 0.57 +/- 0.03 microgram/dl for controls), nor did the vitamin A/RBP ratio (0.87 +/- 0.04 and 0.82 +/- 0.03, respectively). There was no influence of antiparkinsonian therapy on vitamin A or vitamin A/RBP ratio. Serum levels of vitamin A, and vitamin A/RBP ratio did not correlate with age, age at onset, scores of the Unified Parkinson's Disease Rating Scale or the Hoehn and Yahr staging in the PD group. These results suggest that serum concentrations of vitamin A, do not play a role in the pathogenesis of PD.


Cortical activity-associated negative myoclonus.

A patient with myoclonus epilepsy had 2 types of negative myoclonus as well as positive myoclonus at rest. One type followed a large EMG discharge at the end of continuous contraction and the other did not. Both types of negative myoclonus and positive myoclonus were preceded by EEG activity, predominantly distributed in the contralateral central region. It is suggested that an abnormal activity around the motor cortex suppresses a voluntary contraction as well as induces myoclonus. Clonazepam was markedly effective on both positive and negative myoclonus.


Characterisation of dystrophin in fetuses at risk for Duchenne muscular dystrophy.

Dystrophin, the product of the Duchenne muscular dystrophy (DMD) gene, was studied in muscle from 16 human fetuses at risk for the disease. Eleven high risk (greater than 95% probability) and 5 low-risk (less than 25% probability) fetuses were studied with antibodies raised to different regions of the protein. All low-risk fetuses showed a similar pattern to that of normal fetuses of a comparable age: using Western blot analysis, a protein was detected of similar size and abundance to that of normal fetuses (i.e. smaller molecular weight than that of adult muscle); immunocytochemistry showed uniform sarcolemmal staining in fetuses older than 18 weeks gestation and differential staining of myotubes at different stages of development (distinguished by size) in younger fetuses (less than 15 weeks gestation). In contrast, Western blot analysis of high-risk fetuses detected low levels of dystrophin in 4 cases; 7 fetuses had no detectable protein. Immunocytochemistry with some dystrophin antibodies showed weak staining of the sarcolemma and around central nuclei in younger fetuses; in older fetuses there was little sarcolemmal staining with any antibody other than occasional positive fibres. These results indicate that careful study of dystrophin in fetuses at risk for DMD can be used to establish the clinical phenotype and provide additional information for future family counselling.


Proliferation of human and mouse astrocytes in vitro: signalling through the protein kinase C pathway.

While several mitogens for astrocytes have been described, the signal transduction pathway(s) that mediates their proliferative effect remains unclear; in this report, a major role for the protein kinase C (PKC) system is suggested by several lines of evidence. Firstly, biologically active phorbol esters, 4 beta-phorbol-12,13-dibutyrate and phorbol-12-myristate-13-acetate, increase the proliferation of astrocytes as determined by [3H]thymidine incorporation or bromodeoxyuridine immunofluorescence; this effect is not reproduced by a phorbol ester that binds to PKC but does not activate it (4 alpha-phorbol-12,13-didecanoate). Secondly, 2 relatively selective inhibitors of PKC, H7 and staurosporine, attenuate the basal rate of proliferation of astrocytes in concentrations that were not cytotoxic to cells. Thirdly, mitogen-enhanced proliferation of astrocytes can be blocked by PKC inhibitors; this is observed for all astrocyte mitogens tested. Fourthly, measurements of PKC enzyme activity in astrocytes in response to serum-mitogenic factors, or to staurosporine, revealed a statistically significant correlation with proliferation rate. The mediation by PKC is not dependent on species- or age factors, since neonatal mouse or adult human astrocytes gave comparable results. The results have relevance to normal development and reactive gliosis post-injury, 2 conditions where astrocytes undergo proliferation, and to glioma growth.


Myelination of regenerated axons in goldfish optic nerve by Schwann cells.

This study uses immunohistochemistry and EM to examine the site of injury in goldfish optic nerve during axonal regeneration. Within seven days of nerve crush axons begin to regrow and a network of GFAP+ reactive astrocytes appears in the nerve on either side of the injury. However, the damaged area remains GFAP-. By 42 days after nerve crush, the sheaths of new axons acquire myelin marker 6D2, and the crush area becomes populated by a mass of longitudinally-orientated S-100+ cells. Ultrastructurally, the predominant cells in the crush area bear a strong resemblance to peripheral nerve Schwann cells; they display a one-to-one association with myelinated axons, have a basal lamina and are surrounded by collagen fibres. It is proposed that these cells are Schwann cells which enter the optic nerve as a result of crush, where they become confined to the astrocyte-free crush area.


Regrowth of PNS axons through grafts of the optic nerve of the Browman-Wyse (BW) mutant rat.

We have examined the behaviour in vivo of regenerating PNS axons in the presence of grafts of optic nerve taken from the Browman-Wyse mutant rat. Browman-Wyse optic nerves are unusual because a 2-4 mm length of the proximal (retinal) end of the nerve lacks oligodendrocytes and CNS myelin and therefore retinal ganglion cell axons lying within the proximal segment are unmyelinated and ensheathed by processes of astrocyte cytoplasm. Schwann cells may also be present within some proximal segments. Distally, Browman-Wyse optic nerves are morphologically and immunohistochemically indistinguishable from control optic nerves. When we grafted intact Browman-Wyse optic nerves or 'triplets' consisting of proximal, junctional and distal segments of Browman-Wyse optic nerve between the stumps of freshly transected sciatic nerves, we found that regenerating axons avoided all the grafts which did not contain Schwann cells, i.e., proximal segments which contained only astrocytes; regions of Schwann cell-bearing proximal segments which did not contain Schwann cells; junctional and distal segments (which contained astrocytes, oligodendrocytes and CNS myelin debris). However, axons did enter and grow through proximal segments which contained Schwann cells in addition to astrocytes. Schwann cells were seen within grafts even after mitomycin C pretreatment of sciatic proximal nerve stumps had delayed outgrowth of Schwann cells from the host nerves; we therefore conclude that the Schwann cells which became associated with regenerating axons within the grafts of Browman-Wyse optic nerve were derived from an endogenous population. Our findings indicate that astrocytes may be capable of supporting axonal regeneration in the presence of Schwann cells.


GAP-43 distribution is correlated with development of growth cones and presynaptic terminals.

GAP-43 (F1, B-50, pp46) has been associated with neuronal development and regeneration, but precise localization within neurons is not known. Pre-embedding electron microscopic immunocytochemistry using silver-enhanced 1 nm gold particles was used to localize GAP-43 label in cell cultures of cerebellar neurons. In the plasma membranes of early cultures, high levels of GAP-43 were seen in all parts of the neuron. In older cultures, consistent with previous reports, the first loss of GAP-43 label was seen in the soma and then the axon. Growth cones had high levels of GAP-43 label on the plasma membrane, with increased distribution over unattached relative to attached filopodia. The amount of GAP-43 seen over the plasma membrane of forming presynaptic terminals is lower than over growth cones, indicating a possible correlation between the presence of GAP-43 and the stage of presynaptic terminal development. Intracellular GAP-43 in axons and growth cones was highest in membranes of smooth cisternae. The levels of GAP-43 in smooth cisternae in axons fell by seven days in culture while the levels of GAP-43 in smooth cisternae of growth cones fell at 14 days. When mini-explant cerebellar cultures were examined with light microscopic immunocytochemistry, GAP-43 label of plasma membrane was highest at the periphery of the radial axonal outgrowth, suggesting that addition of GAP-43 to the plasma membrane can occur in the distal axon or at the growth cone.


Regeneration of axons in the optic nerve of the adult Browman-Wyse (BW) mutant rat.

We have studied the regeneration of axons in the optic nerves of the BW rat in which both oligodendrocytes and CNS myelin are absent from a variable length of the proximal (retinal) end of the nerve. In the optic nerves of some of these animals, Schwann cells are present. Axons failed to regenerate in the exclusively astrocytic environment of the unmyelinated segment of BW optic nerves but readily regrew in the presence of Schwann cells even across the junctional zone and into the myelin debris filled distal segment. In the latter animals, the essential condition for regeneration was that the lesion was sited in a region of the nerve in which Schwann cells were resident. Regenerating fibres appeared to be sequestered within Schwann cell tubes although fibres traversed the neuropil intervening between the ends of discontinuous bundles of Schwann cell tubes, in both the proximal unmyelinated and myelin debris laden distal segments of the BW optic nerve. Regenerating axons never grew beyond the distal point of termination of the tubes. These observations demonstrate that central myelin is not an absolute requirement for regenerative failure, and that important contributing factors might include inhibition of astrocytes and/or absence of trophic factors. Regeneration presumably occurs in the BW optic nerve because trophic molecules are provided by resident Schwann cells, even in the presence of central myelin, oligodendrocytes and astrocytes. All the above experimental BW animals also have Schwann cells in their retinae which myelinate retinal ganglion cell axons in the fibre layer. Control animals comprised normal Long Evans Hooded rats, BW rats in which both retina and optic nerve were normal, and BW rats with Schwann cells in the retina but with normal, i.e. CNS myelinated, optic nerves. Regeneration was not observed in any of the control groups, demonstrating that, although the presence of Schwann cells in the retina may enhance the survival of retinal ganglion cells after crush, concomitant regrowth of axons cut in the optic nerve does not take place.


MHC-positive, ramified macrophages in the normal and injured rat peripheral nervous system.

Resident endoneurial macrophages form a prominent, but little recognized component of the PNS. We have studied immunocytochemically the distribution, morphology and immunophenotype of endoneurial macrophages in several normal peripheral nerves of the rat. In addition, we investigated the macrophage response following crush injury of the sciatic nerve. Resident endoneurial macrophages had a ramified morphology with processes oriented parallel to the long axis of nerve fibres. They were positive for several monocyte/macrophage markers such as ED1, ED2 and the recently-described MUC 101 and MUC 102 antibodies. They furthermore expressed the complement type three receptor, the CD4 antigen and MHC class I and II molecules. These results were consistent in all the peripheral nerves studied. In addition, 1000 rad of gamma-irradiation led to a strong reduction in the number of MHC class II-positive ramified cells in the peripheral nerves similar to that observed in other peripheral organs such as the heart. A considerable percentage of resident macrophages in the PNS and/or their precursor cells are therefore radiosensitive and could be related to the lineage of dendritic cells. Following crush injury, ED1-3-, OX-42-, MUC 101- and MUC 102-positive round macrophages were observed from 24 h postlesion onward at the site of trauma. In the distal part, they were observed to form strings of round, foamy macrophages probably involved in myelin phagocytosis. In contrast, the number of MHC class II-positive resident macrophages was only slightly increased at the site of trauma and in the distal part. These cells transformed from a ramified to a round morphology, but did not appear as typical strings of foamy macrophages. These results demonstrate that the PNS is provided with a resident macrophage population analogous in many respects to microglial cells in the CNS. These constitutively MHC class II-positive PNS microglial-like cells could act as the major antigen-presenting cells in the peripheral nerve. They may thus constitute a local immune defense system of the PNS with a function similar to that of microglial cells in the CNS.


Division and migration of satellite glia in the embryonic rat superior cervical ganglion.

While distinct precursors committed to a neuronal or glial cell fate are generated from neural crest cells early in peripheral gangliogenesis, little is known about the subsequent generation and maturation of young satellite glia from restricted glial precursor cells. To examine the division and migration of glial precursor cells and their satellite cell progeny, morphological, immunocytochemical and culture techniques were applied to the developing rat superior cervical ganglion. At embryonic day (E)18.5, numerous clusters of nonneuronal cells appeared transiently in the ganglion. Individual cells with a similar morphology were present in E16.5 ganglia, and are likely to represent the precursor cells which generate these clusters. The clustered cells were distinguishable from neighbouring neurons as well as from endothelial cells and fibroblasts. Morphologically similar cells were present in nerve bundles at E18.5 and surrounding principal neurons and nerve bundles in the adult ganglion. Double-label studies of the E18.5 ganglion with tyrosine hydroxylase to identify noradrenergic neurons and propidium iodide counterstaining to visualize all cell nuclei revealed that the cells in clusters stained with propidium iodide but lacked tyrosine hydroxylase immunoreactivity. To determine if cell clusters arose from division, bromodeoxy-uridine, a thymidine analogue, was administered to pregnant mothers between E16.5-E18.5, and ganglionic cells examined at E18.5 both in vivo and in vitro. Numerous non-neuronal cells divided during this period in situ and composed portions of clusters. When dissociated, superior cervical ganglion satellite glia reacted with an NGF-receptor antibody (MAb 217c) and possessed a flattened shape, in contrast to bipolar Schwann cells. Over half of the 217c-immunoreactive glia at E18.5 had incorporated bromodeoxyuridine during E16.5-18.5 in vivo. At birth, non-neuronal cells were no longer grouped in clusters, but were associated with neuronal cell bodies and processes. These findings suggest that, between E16.5-E18.5, glial precursors divide rapidly to form clusters, and that, after the peak of neurogenesis, daughter cells migrate within the ganglion to associate with nerve cell bodies and processes where proliferation continues at a slower rate. Distinct cellular and molecular interactions are likely to trigger the initial rapid division of glial precursors, initiate their migration and association with neuron cell bodies, and control their subsequent slower division.


Hypertrophy and reversal of hypertrophy in rat pelvic ganglion neurons.

An experimental procedure which chronically reduces the lumen of the urethra in adult female rats produced distension of the bladder and conspicuous thickening of its wall, resulting within 6-8 weeks in a ten-fold increase in muscle weight (muscle hypertrophy). During this process, the neurons in the pelvic ganglion that innervate the bladder undergo a large increase in size (neuronal hypertrophy). The average neuronal volume increased by 83%; small neurons became less numerous and large neurons became more numerous than in controls, but there was no increase in the maximum neuronal size. Six weeks after re-operation and removal of the urethral obstruction, the weight of the bladder was reduced (although not quite to the control levels), while the average neuronal size reversed to values very close to controls. In separate experiments, the pelvic ganglion of one side was removed. The nerve fibres in the hemidenervated bladder sprouted, grew and spread to innervate the whole bladder. The neurons in the surviving pelvic ganglion hypertrophied, the average cell volume increasing by 50% in seven weeks. The experiments showed that: (i) the pelvic neurons of adult rats are capable of very extensive growth when the tissue they innervate (bladder muscle) undergoes hypertrophy; (ii) the neuronal hypertrophy is reversible. This was taken to imply that there are factors within the bladder, including trophic substances, that regulate nerve cell volume not only by inducing growth but also by inducing the opposite effect, a cell size reduction; (iii) unilateral ganglionectomy, which did not induce muscle hypertrophy but doubled the amount of muscle innervated by the contralateral ganglion, was followed by marked neuronal hypertrophy.


Evidence for supporting cell mitosis in response to acoustic trauma in the avian inner ear.

Acoustic overstimulation can lead to sensory cell (hair cell) loss in the auditory epithelium. Damaged hair cells in the organ of Corti (the mammalian auditory end-organ) degenerate and are replaced by non-sensory cells (supporting cells) which construct an irreversible scar. In birds, however, auditory hair cells which are damaged by acoustic trauma or ototoxic drugs may be replaced by new hair cells. As first step in determining the mechanism of hair cell regeneration, we developed an assay for cell divisions in the auditory epithelium after acoustic trauma. The results of these experiments demonstrate that supporting cells in damaged regions of the auditory epithelium incorporate the DNA-specific marker bromodeoxyuridine as early as one day after noise exposure. We provide direct evidence that following acoustic insult to the avian inner ear, supporting cells which reside within the sensory epithelium divide near the luminal surface and repopulate the epithelium. These results suggest that supporting cells participate in scar formation during hair cell degeneration, and produce new cells for regeneration.


Localization of vasopressin-like immunoreactivity in the CNS of Aplysia californica.

Chromatographic and immunological evidence indicates that a vasopressin-like peptide might be present in the CNS of Aplysia californica, and that this peptide may be involved in modulating the behaviour of the gill. Immunocytochemical techniques using antisera raised against various vasopressin-like peptides were used to localize the sites containing these peptides in the CNS of Aplysia. Vasopressin-like immunoreactivity was found to be restricted to one single neuron in the abdominal ganglion and two small neurons located bilaterally in each pedal ganglion. Immunoreactive fibres were present in the neuropile of the abdominal, pedal, pleural and cerebral ganglia, but not in the buccal ganglion. The identification of these neurons provides a morphological localization for vasopressin-like substances detected previously in CNS extracts of Aplysia californica. In addition, the possibility of electrophysiological studies involving the immunoreactive neurons identified in the present paper will allow a more direct approach to study the physiological role of vasopressin-like peptides in Aplysia.


Different kinds of axon terminals forming symmetric synapses with the cell bodies and initial axon segments of layer II/III pyramidal cells. III. Origins and frequency of occurrence of the terminals.

The cell bodies of the layer II/III pyramidal cells in rat visual cortex receive three morphologically distinct types of axon terminals. These axon terminals all form symmetric synapses and have been termed large, medium-sized, and dense axon terminals. The present study shows that each of these different kinds of axon terminals contains gamma-aminobutyric acid (GABA) which suggests that they are inhibitory. From an analysis of the profiles of 50 cell bodies it is calculated that the average layer II/III pyramidal cell has 65 axosomatic synapses, of which 43 are formed by medium-sized terminals, 10 by large terminals, and 12 by dense terminals. Comparison of these different kinds of axon terminals with labelled axon terminals of known origin suggests that the medium-sized terminals are derived from smooth multipolar cells with unmyelinated axons, and that at least some of the dense terminals originate from bipolar cells that contain vasoactive intestinal polypeptides. The source of the large axon terminals is not known, but it is suggested that they originate from multipolar non-pyramidal cells with myelinated axons. Since the initial axon segments of these same neurons receive GABAergic axon terminals from chandelier cells, at least four different types of neurons provide inhibition to the cell bodies and axons of layer II/III pyramidal cells. This serves as an illustration of the complexity of the neuronal circuits in which pyramidal cells are involved.


The Guillain-Barré syndrome: no longer a simple concept.

Acute inflammatory demyelinating polyneuropathy or the Guillain-Barré syndrome (GBS) has come to be accepted as a clinical entity, although the boundary between it and chronic inflammatory demyelinating polyneuropathy has given rise to discussion. Recent observations have suggested that the GBS may represent the consequence of more than one pathogenetic mechanism. In most cases the salient pathological change is demyelination. In some this may be mediated predominantly by lymphocytes; in others, where the demyelination is produced primarily by macrophages, the process may be antibody-mediated. Both electrophysiological and pathological evidence indicates that occasional patients with the GBS show extensive axonal degeneration. Although this could represent a "bystander effect" secondary to inflammatory infiltration, at times it may reflect a direct attack on axons. Elucidation of the nature of the pathogenetic mechanisms is essential before rational therapy can be devised.


rCBF abnormalities detected, and sequentially followed, by SPECT in neuro-Behçet's syndrome with normal CT and MRI imaging.

Conventional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) may show abnormalities in central nervous system Behcet's syndrome but is normal in some cases. Recently in two cases positron emission tomography has shown abnormalities in blood flow and glucose metabolism far more extensive than the abnormalities seen on CT and MRI scans in the same patients. We report a patient with neuro-Behcet's syndrome presenting with headache and personality change in whom CT and MRI brain imaging was normal, but regional cerebral blood flow imaging using single photon emission tomography with the tracer HMPAO showed extensive perfusion deficits which partially reversed after 3 months of prednisolone therapy. This technique may aid the diagnosis of cerebral involvement in Behcet's syndrome, although the cause and incidence of the perfusion deficits need further evaluation.


Asymptomatic nerve hypertrophy in lepromatous leprosy: a clinical, electrophysiological and morphological study.

In order to learn more about early nerve lesions observed in leprosy, we performed a clinical, electrophysiological and morphological study in seven patients with untreated lepromatous leprosy, palpably enlarged radial cutaneous nerve and preserved sensation in the corresponding territory. The conduction velocity of the cutaneous radial nerve, which was decreased in all patients, did not significantly differ from that of a group of patients with lepromatous leprosy, hypertrophy of the radial cutaneous nerve and sensory loss. In contrast, the sensory action potential was significantly lower in patients with sensory loss, which demonstrates that axon loss is more important than demyelination in producing sensory loss. In all patients nerve enlargement was due to thickening of the epineurium and of the perineurium subsequent to inflammatory infiltrates and proliferation of fibroblasts and perineurial cells. In several fascicles, the inflammatory infiltrates and the infected cells infiltrated endoneurial connective tissue septa and blood vessels. Mycobacteria leprae were abundant in perineurial cells, fibroblasts, macrophages, Schwann cells and endothelial cells, and lymphocytic vasculitis present in all cases. The average density of myelinated fibres was 2600 SD 880 fibres/mm2 (control: 7700 fibres/mm2), with marked differences between individual fascicles, versus 420 fibres/mm2 in patients with nerve hypertrophy and sensory loss (range 0-2080 fibres/mm2). Single fibre preparations showed that segmental demyelination predominated in two patients, axonal degeneration in one, while inflammatory infiltrates and proliferation of connective tissue adhering to individual fibres were prominent in the others.(ABSTRACT TRUNCATED AT 250 WORDS)


Local botulinum toxin in the treatment of spastic drop foot.

Ten patients with spastic drop foot were treated by local injections of botulinum toxin A (botulinum toxin A haemagglutinin complex). The purpose was to improve stance and gait and/or to facilitate physiotherapy and patient care. Various calf muscles were injected using EMG guidance. The average dose used was 23 ng. Prior to and 4 weeks after treatment, positions of the upper and lower ankle joint at rest and the corresponding end positions of passive and active movement were determined. In addition, changes of spasticity and pain, the transmission phenomenon and stance and gait were evaluated. Most patients showed improvement of some aspects of the spastic drop foot. Positions of the upper and lower ankle joint were improved in most of the patients, as were the other parameters examined. Except for weakness of the injected muscles no side-effects were observed. The results appear promising and may be optimized in further trials by using higher doses of the toxin.


Subacute diencephalic angioencephalopathy: an entity similar to angiodysgenetic necrotizing encephalopathy and Foix-Alajouanine disease.

A previously healthy 58-year-old man developed neurological illness with progressive dementia, hallucinations, central motor and vegetative impairment which led to death in 14 weeks. Autopsy revealed lesions in a symmetrical centrencephalic distribution. Inner cerebral veins and arteries were surrounded by extravasation of plasma and perivascular haemorrhage and were thickened by fibrous scarring and muscle fibre proliferation. Necrotized blood vessels were also found. The parenchyma was damaged by incomplete to complete necrosis. The age and sex of the patient, the progressive clinical course, the increase of cerebrospinal fluid protein, and the histopathology of the lesion show some similarities to angiodysgenetic necrotizing encephalopathy and spinal Foix-Alajouanine disease.


Does hyperglycaemia play a role on the outcome of acute ischaemic stroke patients?

A consecutive series of 327 patients (188 males, 139 females; mean age 68.4, SEM 1.33) were hospitalized within 12 h of the onset of their first-ever hemispheric infarct. Three groups of patients were identified: diabetics (n = 70), non-diabetic hyperglycaemics (n = 93) and normoglycaemics (n = 164). Case-fatality ratios at 30 days after stroke were 38.6%, 22.6% and 9.2% (P less than 0.001) respectively, whereas the causes of death and functional outcome of survivors were not significantly different between the groups. Mean admission serum glucose levels (SGLs) of decreased, impaired/unchanged and improved patients within each one of the three groups, were also not significantly different as opposed to their mean Canadian Neurological Scale (CNS) scores at entry (P less than 0.01). Among patients with less severe initial neurological deficit (i.e., CNS score greater than or equal to 7.0), 82.6% of non-diabetic hyperglycaemic subjects fared well, in comparison with 56.5% of diabetic and 70.1% of normoglycaemic individuals. The size of the infarcted areas at the second CT correlated with mean CNS scores (P less than 0.01) but not with mean SGLs on admission. The site of the ischaemic areas did not correlate with mean SGLs at entry. Therefore the influence of initial SGLs on the clinical course of the present series of patients is questionable or, alternatively, varied probably according to the pattern of residual cerebral blood flow after arterial occlusion.


Cerebrospinal fluid cytokines in AIDS dementia complex.

We evaluated cerebrospinal fluid (CSF) and serum concentrations of interleukin-1-alpha (IL-1-alpha), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in 30 patients with AIDS dementia complex (ADC), and in 20 HIV-seronegative subjects with other neurological diseases (OND). CSF TNF-alpha, IL-1-alpha and IL-6 were more frequently detectable in ADC patients than in OND subjects. These cytokines were also detectable in CSF of ADC patients with minimal symptoms. In contrast, the majority of both ADC and OND patients did not contain detectable serum levels of cytokines. Our data support the notion of intrathecal synthesis of cytokines in ADC patients and raise the possibility that activated macrophages may play a significant role in the pathogenesis of ADC.


The clinical use of apomorphine in Parkinson's disease.

Our 2-year experience in the therapeutic use of subcutaneous apomorphine has involved 25 patients with Parkinson's disease, 10 of whom continue to use it chronically. On the basis of this experience, we have formulated certain indications for its use, together with suggested approaches to modify patients' oral drug regimes so that apomorphine can best be deployed to improve their quality of life.


Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy.

Two cases of severe myeloneuropathy and macrocytic anemia associated with a low serum level of vitamin B12 after prolonged exposure to nitrous oxide are reported. In both cases, the neurological manifestations worsened initially despite B12 supplementation, although in one case the use of methionine seemed to arrest the progression of the disease and accelerate recovery. This offers further support for the biochemical hypothesis of methionine synthetase inhibition by nitrous oxide and reproduces in man previously reported animal studies with methionine. Methionine may be an important first-line therapy in the initial treatment of neuropathy and myeloneuropathy induced by nitrous oxide, and has a hypothetical role in the treatment of subacute combined degeneration of the cord.


Magnetic resonance imaging follow-up in Creutzfeldt-Jakob disease.

The history of a 67-year-old woman with histologically proven Creutzfeldt-Jakob disease (CJD) is presented. Before typical clinical and neurophysiological signs of CJD developed, magnetic resonance imaging (MRI) showed slightly enhanced signal intensity of the caudate nuclei and putamina in T2-weighted and proton density images, corresponding to spongiform degeneration in neuropathological examination. Five weeks later characteristical progressive cortical atrophy was demonstrated by follow-up MRI.


Was it infarction or haemorrhage? A clinical diagnosis by means of the Allen score.

Since the clinical distinction between haemorrhagic and ischaemic stroke cannot be achieved with a simple clinical evaluation, and it is virtually impossible to submit all stroke patients to CT, a weighted clinical score may offer some advantages to physicians who are involved in stroke management. The Allen score (also referred to as the Guy's Hospital score), a validated clinical score, has been tested in two different clinical settings, comprising 289 patients. When only the values under 4 and those over 24 are taken into account (i.e. greater than 90% probability of ischaemia and haemorrhage), the global accuracy of the score is 97%, and the diagnostic gain (given a pretest probability for haemorrhage of 11% and a likelihood ratio of 194) is 85%. Therefore, we conclude that this simple clinical method can be used for epidemiological studies of stroke incidence and outcome, as well as for a first bedside screening to decide which patients should have priority for CT.


Quantum chemical study on the interaction of some bisphosphonates and Ca2+: the role of molecular electrostatic potentials in the prediction of binding geometry.

Molecular electrostatic potentials have been used to model the calcium binding properties of some bisphosphonate drugs, which are used to treat various bone diseases. The mechanism of action involves the binding of bisphosphonates to the bone surface, where calcium plays an important role. Electrostatic potential maps derived from ab initio partial charges have been compared with both the crystal structure and the fully optimized ab initio structure of (dichloro)methylene-bisphosphonate-calcium ion complex. Molecular electrostatic potentials can correctly predict the calcium binding geometry of bisphosphonate-type compounds and this type of information can be used in the practical drug design work.


On the suitability of semiempirical calculations as sources of force field parameters.

The suitability of Dewar's Hamiltonians as a source of bonded force field parameters is explored from the comparison analysis between up to 270 semiempirically derived force field parameters and experimentally derived values reported in some of the most popular force fields. From the statistical analysis of the results, some general conclusions about the semiempirical parametrization are formulated.


Applications of rule-induction in the derivation of quantitative structure-activity relationships.

Recently, methods have been developed in the field of Artificial Intelligence (AI), specifically in the expert systems area using rule-induction, designed to extract rules from data. We have applied these methods to the analysis of molecular series with the objective of generating rules which are predictive and reliable. The input to rule-induction consists of a number of examples with known outcomes (a training set) and the output is a tree-structured series of rules. Unlike most other analysis methods, the results of the analysis are in the form of simple statements which can be easily interpreted. These are readily applied to new data giving both a classification and a probability of correctness. Rule-induction has been applied to in-house generated and published QSAR datasets and the methodology, application and results of these analyses are discussed. The results imply that in some cases it would be advantageous to use rule-induction as a complementary technique in addition to conventional statistical and pattern-recognition methods.


Automated site-directed drug design: the generation of a basic set of fragments to be used for automated structure assembly.

If a method is to be developed to assemble putative ligand structures in site-directed drug design, from molecular graphs generated in the site, then basic building blocks are needed. Structure assembly is a combinatoric process that needs to be optimised if it is to be tractable. What has to be determined is whether small molecular fragments can have transferable properties from one molecule to another. In this paper we determine all possible combinations of 3-, 4- and 5-atom aliphatic fragments from a small set of atoms H, C, N, O, F or Cl. The frequency of occurrence of these candidate fragments is searched for in the Cambridge Structural Database. A similar analysis is performed on charged fragments. A more restricted search is carried out for P and S and aromatic structures. A basic set of fragments can be derived that have a significant frequency in known crystal structures. The transferability of fragment properties is discussed in subsequent papers.


Automated site-directed drug design: searches of the Cambridge Structural Database for bond lengths in molecular fragments to be used for automated structure assembly.

In this paper a database of small frequently occurring molecular fragments is used for the determination of fragment bond lengths from the Cambridge Structural Database. A large number of bond types are described that have not been reported previously.


Automated site-directed drug design: an assessment of the transferability of atomic residual charges (CNDO) for molecular fragments.

In this paper a database of atomic residual charges has been constructed for all the molecular fragments defined previously in a combinatorial search of the Cambridge Structural Database. The charges generated for the atoms in each fragment are compared with charges calculated for whole molecules containing those fragments. The fragment atomic charges lie within 1 S.D. of the mean for 68%, and within 2 S.D. for 91%, of the atoms whose charges were computed for whole molecules. The actual charges on any atom are strongly influenced by the adjacent connected atoms. There is a large spread of atomic residual charge within the fragments database.


Detection of tumor cells in bone marrow of patients with primary breast cancer: a prognostic factor for distant metastasis.

At the time of primary surgery, approximately 90% of all patients with breast cancer are free of metastases, but in the next 5 years almost 50% of them will relapse. We evaluated the significance of the presence of tumor cells in bone marrow of patients with primary breast cancer to investigate their predictive value for relapse. Two hundred sixty patients with primary breast cancer were examined for tumor cells in bone marrow aspirates taken from six sites of the skeleton. After density centrifugation, cells in interphase were smeared and stained. For the immunocytologic reaction, we used a new monoclonal antibody (2E11) that was reactive with the core protein of the tumor-associated glycoprotein TAG12. TAG12 is secreted by nearly all human breast carcinomas. A significant correlation was found between tumor-cell detection and tumor stage (P < .0001), nodal status (P < .0001), and tumor grading (P = .002). A good relation to progesterone receptor (PR; P = .008) was found, but there was no correlation to estrogen receptor (ER) and menopausal status. Follow-up examinations showed distant metastases in 26 of 211 patients (15%). Twenty-two relapses occurred among the 81 patients with 2E11-positive cells in bone marrow, but only four occurred among the 130 patients without tumor-cell detection. This study suggests that tumor-cell detection in bone marrow of patients with primary breast carcinoma is a good predictor for all distant relapses (P < .0005, Cox multiple regression analysis) and provides additional information in regard to other prognostic factors. The highest predicting value for distant metastasis results from the combination of nodal status, negative PR, and tumor-cell presence in bone marrow.


Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer.

A prospective study in breast cancer patients was undertaken to determine whether escalating doses of doxorubicin and cyclophosphamide would result in a higher fraction of patients free of disease, and to evaluate the role of leukocyte alpha-interferon. Between 1982 and 1986, 319 consecutive patients with stage II or III breast cancer with one or more positive nodes were assigned randomly to receive adjuvant chemotherapy that consisted of escalating doses of doxorubicin and cyclophosphamide in combination with vincristine and prednisone or the same chemotherapy regimen followed by 1 year of leukocyte alpha-interferon. Doxorubicin was administered by 72-hour continuous infusion through a central venous catheter (maximum total cumulative dose, 430 mg/m2). All patients with positive or unknown estrogen receptor status were also given tamoxifen for 1 year. The median follow-up was 71 months (range, 35 to 99 months). Correlation of disease-free survival (DFS) with dose-intensity of cyclophosphamide and doxorubicin showed no improvement in DFS for patients who were able to receive escalated drug doses compared with those who were not. Doxorubicin administered by continuous infusion was associated with a negligible risk of cardiotoxicity in this study despite the administration of higher accumulative doses than in our previous adjuvant therapy studies. The DFS rates of patients who did and those who did not receive leukocyte alpha-interferon were similar. In this study, there was no real evidence that higher drug dose intensity was associated with longer DFS. Leukocyte alpha-interferon as it was used in this study had no therapeutic value. Doxorubicin administered by infusion was associated with a reduced risk of cardiotoxicity.


Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years.

The study purpose was to evaluate aminoglutethimide (AG) as adjuvant therapy in patients with primary node-positive breast cancer in a randomized double-blind placebo-controlled trial. In a multicenter trial, 354 postmenopausal women with early breast cancer and histologically confirmed positive axillary lymph nodes were randomized after surgery to received aminoplac. Patients were prescribed either AG 250 mg four times per day and hydrocortisone 20 mg twice per day or placebos of identical appearance for 2 years. After a median follow-up of 8.1 years, there has been no overall benefit for AG in terms of either event-free survival or overall survival (OS). However, the results are consistent with interim analyses with a significantly improved event-free survival for patients who received AG for up to 4 years, although this benefit subsequently disappears. Similarly, there is an improved OS for patients who received AG for up to 4 years, but this also subsequently disappears. There was a marginal advantage for estrogen receptor (ER)-positive patients who received AG (n = 74; P = .054). There was no difference in the sites of relapse. There was a significant increase in toxicity for patients who received AG. The lack of survival benefit with long-term follow-up for AG may indicate that aromatase inhibitors have less of an impact on early breast cancer than tamoxifen and may imply different biologic mechanisms of action.


Ten-year outcome of patients with advanced epithelial ovarian carcinoma treated with cisplatin-based multimodality therapy.

At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatin-based combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cisplatin at 50 mg/m2 every 3 weeks until a total dose of doxorubicin of 450 mg/m2 had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altretamine) was administered to patients who did not have a documented histologic complete remission. The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease.


High-dose busulfan in patients with myeloma.

To evaluate the use of high-dose busulfan (HDB) with autologous bone marrow transplantation (ABMT) in patients with myeloma. Fifteen patients received HDB (16 mg/kg), eight of whom received high-dose melphalan (HDM) but had experienced a short remission or progression-free interval. Two patients had received HDM on two previous occasions, one had no response to low-dose melphalan, and four had impaired renal function (edathamil clearance < 40 mL/min). All patients received induction chemotherapy before HDB. Two patients were in complete remission (CR) after induction chemotherapy before HDB. Of the remaining 13 patients, four (31%) achieved CR and two (15%) achieved a partial remission for an overall response rate of 46%. There were three treatment-related deaths, but the toxicity was otherwise predictable and manageable. In heavily pretreated patients, HDB results in a relatively high response rate. It can also be used safely in patients with renal impairment who are not suitable for HDM.


Phase II trial of cisplatin and alpha-interferon in advanced malignant melanoma.

To evaluate the antitumor activity of combination cisplatin (CDDP) and alpha-interferon (alpha-IFN) in advanced, measurable metastatic melanoma. Adult patients with metastatic melanoma were required to have bidimensionally measurable lesions and a Karnofsky performance status > or = 60%. Serum creatinine < or = to 1.5 mg/dL, creatinine clearance > or = 60 mL/min, adequate organ and bone marrow function, and radiologic proof of the absence of brain metastases were required. CDDP 40 mg/m2 intravenously (IV) on day 1 and day 8, and alpha-IFN 3 million units/m2 subcutaneously on days 1 to 5 and 8 to 12 were administered every 3 to 4 weeks. Forty-two patients were entered onto this phase II trial and were assessable for response and toxicity. Three patients achieved complete responses (CRs) that lasted 31+, 5, and 8+ months. Seven patients had partial responses (PRs) and a median response duration of 4.4 months. The overall objective response rate was 24% (95% confidence interval, 12% to 39%). Toxicities were mild. Only 11% of the courses required dose reduction of alpha-IFN, and three of 128 courses required CDDP dose reduction for reversible nephrotoxicity. The combination of moderate-dose CDDP and alpha-IFN as administered in this schedule is well tolerated and possesses encouraging activity in metastatic melanoma.


A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup.

A randomized pilot study was undertaken to assess the acute and chronic toxicities of two short intensive chemotherapy regimens, and to evaluate the feasibility of conservative surgery in this setting. Additional aims were to determine the clinical and radiologic response and the degree of histologic necrosis after chemotherapy. With extension of the study, eventual accrual was sufficient to compare disease-free survival (DFS) and overall survival (OS). Between July 1983 and December 1986, the European Osteosarcoma Intergroup (EOI) entered 198 eligible patients with classic high-grade extremity osteosarcoma onto a randomized trial that compared doxorubicin (DOX) 25 mg/m2/d times three, intravenous (IV) bolus plus cisplatin (CDDP) 100 mg/m2, 24 hour infusion, every 3 weeks times six; the same combination was preceded 10 days earlier by high-dose methotrexate (HDMTX) 8 g/m2, 6-hour infusion, every 4.5 weeks times four. In the majority of patients (179), chemotherapy was commenced after biopsy; definitive surgery was scheduled at 9 weeks in both groups. Toxicities for both regimens did not differ substantially from those that occurred in other trials of adjuvant chemotherapy in osteosarcoma. Local recurrence (9%) and surgical complications (18%) after conservative surgery were acceptable. With a median follow-up of 53 months, DFS at 5 years is superior (P = .02) for DOX/CDDP, 57% versus 41%, although OS, 64% versus 50%, is not different significantly (P = .10). In a subset of 66 patients for whom pathologic data on the resected specimen were available, DFS (P = .003) and OS (P = .008) were better for those who demonstrated > or = 90% necrosis. A brief intensive chemotherapy regimen of DOX/CDDP has produced excellent long-term results, which are similar to those that have been achieved in cooperative group studies of longer, more complex multiagent chemotherapy, and provide the basis for a direct comparison in the next EOI study.


Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study.

A phase II study of etoposide (VP 16) and carboplatin (CBDCA) was performed in patients with metastatic neuroblastoma (NB). The aim of the study was to find an alternative treatment for induction with different toxicities than the VP 16/cisplatin (CDDP) combination. Forty-seven patients who were from 6 months to 16 years of age, with either relapsed (29) or primary resistant (18) NB, were included in a cooperative multicenter phase II study of the French Society of Pediatric Oncology (SFOP). The schedule consisted of 5 consecutive days of VP 16 100 mg/m2/d and CBDCA 160 mg/m2/d. The response rate for the 39 assessable patients was 43%; there were four complete remissions and 13 partial remissions. Neither the status of the patients nor the total dose of CDDP that was received previously influenced response. Hematologic toxicity was marked and caused considerable delay between courses (median interval, 39 days). In these heavily pretreated patients, 16% had a more than 50% decrease in creatinine clearance and a 22% World Health Organization (WHO) grade 2 ototoxicity. This VP 16/CBDCA combination deserves further evaluation for efficacy and toxicity in newly diagnosed patients, and the combination of both drugs should be considered for high-dose therapy with bone marrow transplantation.


Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance.

To determine the maximum-tolerated dose (MTD) of cyclosporine (CsA) infusion administered with etoposide for 3 days in patients with cancer. Of the 72 registered patients, 26 were treated initially with CsA and etoposide. Forty-six received etoposide alone until disease progression, and 31 of these proceeded to CsA and etoposide. CsA was administered as a 2-hour loading dose (LD) and as a 3-day continuous infusion (CI); doses were escalated from 2 to 8 mg/kg LD and 5 to 24 mg/kg/d CI. Fifty-seven patients were treated with 113 cycles of CsA with etoposide. Steady-state serum CsA levels (nonspecific immunoassay) more than 2,000 ng/mL were achieved in 91% of the cycles at CsA doses > or = 5 mg/kg LD and > or = 15 mg/kg/d CI. The major dose-related toxicity of CsA was reversible hyperbilirubinemia, which occurred in 78% of the courses with CsA levels > 2,000 ng/mL. Myelosuppression and nausea were more severe with CsA and etoposide. Other CsA toxicities included hypomagnesemia, 60%; hypertension, 29%; and headache, 21%. Nephrotoxicity was mild in 12% and severe in 2% of the cycles. Tumor regressions occurred in four patients after the addition of CsA (one non-Hodgkin's lymphoma, one Hodgkin's disease, and two ovarian carcinomas). Biopsy procedures for tumors from three of the four patients who responded were performed, and the results were positive for mdr1 expression. Serum CsA levels of up to 4 mumol/L (4,800 ng/mL) are achievable during a short-term administration with acceptable toxicities when administered in combination with etoposide. The CsA dose that is recommended in adults is a LD of 5 to 6 mg/kg, followed by a CI of 15 to 18 mg/kg/d for 60 hours. CsA blood levels should be monitored and the doses should be adjusted to achieve CsA levels of 2.5 to 4 mumol/L (3,000 to 4,800 ng/mL). Reversible hyperbilirubinemia may be a useful marker of inhibition by CsA of P-glycoprotein function. When used with high-dose CsA, etoposide doses should be reduced by approximately 50% to compensate for the pharmacokinetic effects of CsA on etoposide (Lum et al, J Clin Oncol, 10:1635-1642, 1992).


Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.

To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer. Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half-life (T1/2), and volume of distribution at steady state (Vss). CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P less than .001), a 38% decrease in total CL (P < .01), a > twofold increase in T1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels > 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles. High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.


Intravenous administration of recombinant human macrophage colony-stimulating factor to patients with metastatic cancer: a phase I study.

Recombinant human macrophage colony-stimulating factor (M-CSF) has been shown to stimulate specifically macrophage lineage differentiation in vitro and to induce cells capable of antitumor activity alone or in combination with an antibody. The administration of M-CSF to mice has demonstrated antitumor therapeutic effects in vivo. Therefore, a phase I trial of M-CSF administration to patients with metastatic cancer was undertaken. M-CSF was given by intermittent intravenous bolus infusion every 8 hours for 7 days; the treatment cycle was repeated once after a week of rest. Cohorts of three patients underwent dose escalation from 10 to 100,000 micrograms/m2/d; 23 patients received 27 courses of M-CSF administration. All patients had metastatic solid tumors refractory to conventional therapy, including renal cell carcinoma (RCC) (nine), melanoma (seven), and colorectal carcinoma (seven). Treatment-related toxicity was minimal; five patients developed transient signs of ocular or periorbital inflammation, with iridocyclitis as the most severe manifestation. At the highest doses, platelet counts decreased with therapy (but remained > 100,000/mm3) and the absolute monocyte count increased during the course of therapy. Only at 30,000 and 100,000 micrograms/m2/d was treatment limited because of toxicity (iritis and malaise). Pharmacokinetic studies demonstrated up to a 1,000-fold increase in circulating serum M-CSF after bolus infusion; half-life varied from 1 to 6 hours. Complete regression of mediastinal adenopathy and multiple pulmonary metastases were observed in one patient with RCC. Recombinant M-CSF can be administered safely to patients with metastatic cancer at doses that demonstrate biologic activity.


Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy. A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed. The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing. The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.


Breast cancer in patients irradiated for Hodgkin's disease: a clinical and pathologic analysis of 45 events in 37 patients.

To characterize the clinical and pathologic features of patients who developed breast cancer (BC) after treatment for Hodgkin's disease (HD). Recent epidemiologic studies have shown that women who are cured of HD have an increased risk of developing BC. The clinical data, mammograms, and pathologic specimens of 37 women who developed 45 BCs (eight bilateral events), and had a prior history of treatment for HD were analyzed. The median age at diagnosis of HD was 27 years (range, 11 to 60). All patients received radiotherapy (RT) to the upper part of their body, and 10 also had chemotherapy for HD. The median interval from the treatment of HD to the diagnosis of BC was 15 years (range, 8 to 34). The median age at diagnosis of BC was 43 years (range, 27 to 75), 41% of patients were 39 years old or younger. Most mammograms (81%) showed abnormal findings of mass and/or microcalcifications. Of the eight patients (22%) with bilateral tumors, four were synchronous and four were metachronous. Involvement of the medial half of the breast occurred more frequently than in patients with primary BC (39% and 21%, respectively; P < .002). But, the histologic types, grades, presence of lymphocytic reaction, and lymphatic invasion were similar to those observed in 935 primary BC patients who were previously analyzed at our center. The 6-year actuarial relapse-free survival (RFS) for node-negative BC after HD was 85%. Node-positive patients had a significantly lower RFS of 33% (P = .002). In comparison to patients with primary BC, patients who develop BC after HD are more likely to be younger, have bilateral disease, and have their tumors more frequently involve the medial half of the breast. Pathologic characteristics, nodal involvement, and prognosis are similar to those of primary BC. BC in women who were treated for HD is becoming an increasing problem, as more patients cured of HD reach a follow-up time of 10 to 15 years. Breast examination and mammography at an early age should be part of the follow-up program for women who are cured of HD.


High-dose carmustine, etoposide, and cisplatin and autologous bone marrow transplantation for relapsed and refractory lymphoma.

We determined the toxicity and efficacy of a new preparative autologous bone marrow transplantation (ABMT) regimen in patients with relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's disease. Forty-four non-Hodgkin's lymphoma and 35 Hodgkin's disease patients 16 to 63 years of age were given intravenous carmustine (BCNU) 600 to 1,050 mg/m2, etoposide 2,400 to 3,000 mg/m2, and cisplatin 200 mg/m2 (BEP) and ABMT. Fifty-nine patients also received 15 to 20 Gy local radiation (involved-field radiotherapy [RI]) to active or previously bulky (> 5 cm) disease sites. Nonhematologic toxicities included nausea, vomiting, high-tone hearing loss, stomatitis, esophagitis, diarrhea, and hepatic and pulmonary toxicity. Two patients died within 40 days of marrow infusion as a result of sepsis and one patient died 7 months after transplant as a result of pulmonary fibrosis. Complete remissions (CRs) were noted in 72% (n = 57) of patients (n = 33 non-Hodgkin's lymphoma; n = 24 Hodgkin's disease). Forty patients (51%) remained alive and disease-free (n = 24 non-Hodgkin's lymphoma; n = 16 Hodgkin's disease) at a median of 17 (range, 8 to 57) months after marrow reinfusion. This regimen seems to be effective for relapsed lymphoma patients whose disease continues to exhibit chemotherapy sensitivity (16 of 24 [67%] disease-free). Furthermore, this regimen seems to be effective in patients who have never attained a CR (seven of 19 [37%] disease-free).


Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data.

A case-controlled study of patients who reported to the European Bone Marrow Transplant Group (EBMTG) was performed to investigate the relative roles and efficacy of allogeneic (alloBMT) and autologous bone marrow transplantation (ABMT) in non-Hodgkin's lymphoma. Of 1,060 patients who reported to the lymphoma registry, 938 patients underwent ABMT and 122 patients underwent alloBMT. A case-controlled study was performed by matching 101 alloBMT patients with 101 ABMT patients. The case matching was performed after the selection of the main prognostic factors for progression-free survival by a multivariate analysis. The progression-free survival was similar in both types of transplants (49% alloBMT v 46% ABMT). The overall relapse and progression rate for the alloBMT patients was 23% compared with 38% in the ABMT patients. This difference was not significant statistically. In the lymphoblastic lymphoma subgroup, alloBMT was associated with a lower relapse rate than ABMT (24% alloBMT v 48% ABMT; P = .035). The progression-free survival, however, was not significantly different because patients with lymphoblastic lymphoma who underwent alloBMT had a higher procedure-related mortality (24% alloBMT v 10% ABMT; P = .06). A significantly lower relapse/progression rate was also observed in patients with chronic graft-versus-host disease (cGVHD) compared with those patients without (0% cGVHD v 35% no cGVHD; P = .02). Fourteen of 18 patients who had cGVHD also had lymphoblastic lymphoma. This study suggests that ABMT and alloBMT for non-Hodgkin's lymphoma are comparable, with the exception of lymphoblastic lymphoma in which a graft-versus-lymphoma effect may account for the lower relapse rate for patients who underwent alloBMT.


Imaging, dosimetry, and radioimmunotherapy with iodine 131-labeled anti-CD37 antibody in B-cell lymphoma.

This study was undertaken to evaluate the tumor targeting, toxicity, and therapeutic potential of the anti-B-cell-reactive monoclonal antibody MB-1 (anti-CD37) labeled with iodine 131 given in a nonmarrow ablative dose range in B-cell lymphoma patients who relapsed after chemotherapy. Twelve patients with MB-1-reactive tumors were infused first with 40 mg of trace-labeled (3 to 7 mCi) MB-1. Ten patients who had no serious toxicity postinfusion and who had successful tumor imaging on serial gamma scans then received at least one 40-mg radioimmunotherapy (RIT) dose (25 to 161 mCi). Tracer estimates of delivered whole-body dose (WBD) were used in prescribing a millicurie RIT dose for seven patients. Eleven patients had positive tumor imaging after a tracer dose, including patients with bulky tumors and/or large tumor burdens (> or = 1 kg) +/- splenomegaly. However, overall sensitivity for the detection of known tumor sites was only 39%. In six of eight patients with dose-assessable tumors, the radiation dose to at least one tumor was 1.1 to 3.1 times higher than to any normal organ, excluding the spleen for a 40-mg tracer dose. Tracer-dose toxicities included reversible glossal edema in one patient, grade 3 hepatic transaminasemia in another, and early drops in both circulating B and T cells (with decreases in B cells more pronounced) in nearly all patients. RIT toxicity was primarily myelosuppression (especially thrombocytopenia), which had a delayed onset and protracted recovery (without significant recovery until at least 2 months post-RIT). Grade 3 myelosuppression in two of two patients who were treated at a tracer-projected 50-cGy WBD level (133 and 149 mCi) precluded further planned RIT dose escalation. Less myelosuppression was generally observed in patients who were treated at < or = 40-cGy WBD levels. Antimouse antibodies developed in two patients. Six patients had tumor responses post-RIT. Four had responses that lasted more than 1 month (2 to 6 months), which included one complete response, one partial response, one minor response, and one mixed response. Responses seemed to occur more frequently in imaged tumors than in nonimaged tumors. The most durable response occurred in a patient who had the best antibody targeting to tumor. Although 131I-MB-1 has limited diagnostic value, it can produce tumor responses at nonmarrow ablative RIT doses. Further studies that focus on improving tumor targeting with this or other B-cell-reactive radiolabeled antibodies and on ameliorating the myelosuppression associated with the RIT-dosing approach used in this trial are warranted.