Multiple sclerosis and serial computerized tomography. Delayed contrast enhancement of acute and early lesions.

By demonstrating periventricular contrast-enhanced lesions cranial computerized tomography (CT) supported the diagnosis of multiple sclerosis in a patient with recurrent transient hemiparesis. These abnormalities were present only on delayed films taken one hour after contrast injection and probably represented acute and early demyelinating plaques. Areas of contrast enhancement evolved to isodensity with and without corticosteroid treatment. Brain scan findings mirrored cranial CT abnormalities, and both could be correlated with the clinical status and the course of the disease.

Isolated bilateral oculomotor paresis due to lymphoma.

A patient with histiocytic lymphoma developed bilateral oculomotor nerve palsies, sparing the pupils. At postmortem examination, there was lymphomatous infiltration in the oculomotor nerves. To our knowledge, this is the first patient with lymphoma to manifest these isolated findings.

Physiologic analysis of the myoclonus of Alzheimer's disease.

Ten patients with clinically diagnosed Alzheimer's disease, including three cases of trisomy 21 (Down's syndrome), developed a chronic myoclonic disorder. The technique of jerk-locked averaging of EEG activity was used to analyze the myoclonus. Seven subjects demonstrated a focal, contralateral central, negative cerebral potential antecedent to the myoclonic jerks. This EEG event differs from that previously reported to be associated with the myoclonus of subacute spongiform encephalopathy (Creutzfeldt-Jakob disease).

Cisplatin and low dose rate irradiation in cisplatin resistant and sensitive human glioma cells.

PURPOSE: Human glioma cell lines resistant (U373MGCP) and sensitive (U373MG) to cisplatin were used to evaluate the effect of cisplatin as a sensitizer to low dose rate irradiation (LDRI). METHODS AND MATERIALS: A cisplatin resistant glioma cell line U373MGCP was developed by chronic exposure of parental U373MG cells to cisplatin. Plateau phase cells were treated with cisplatin, high dose rate (HDR) irradiation (1.12 Gy/min), LDRI (0.0088 Gy/min), or cisplatin concurrent with LDRI. Cell survival was determined by the colony forming assay. RESULTS: Both cell lines showed increased resistance to radiation at LDR compared with HDR, with Dose Modifying Factors (DMF at 10% survival level) of 1.7 for U373MG and 2.5 for U373MGCP. The increased LDR sparing effect in the cisplatin resistant U373MGCP cells indicates increased repair proficiency. The resistant cell line showed a fourfold increase in resistance to cisplatin cytotoxicity at the 10% survival level compared with the parental U373MG cells. Cisplatin enhanced the response of both cell lines to LDRI. The DMFs were 1.2, 1.2, and 1.7, respectively, for the sensitive U373MG cell line given 1 microgram/ml, and the resistant cell line given 3 or 6 micrograms/ml cisplatin treatments concurrent with LDRI. CONCLUSIONS: These data show that cisplatin can be an effective sensitizer to LDRI in both cisplatin resistant and sensitive glioma cell lines. However, in the resistant cell line, higher concentrations of cisplatin were necessary to achieve the same level of sensitization as in the sensitive cell line.

Adenosine receptor-mediated contraction and relaxation of guinea-pig isolated tracheal smooth muscle: effects of adenosine antagonists.

1. The effects of several adenosine analogues and antagonists on guinea-pig isolated trachea have been examined. 2. 5'-N-ethylcarboxamidoadenosine (NECA), 5'-N-methylcarboxamidoadenosine (MECA) and adenosine (in the presence and absence of dipyridamole) elicited concentration-dependent tracheal relaxation. 3. The R(-)- and S(+)-enantiomers of N6-(2-phenylisopropyl)adenosine (R-PIA and S-PIA respectively), N6-cyclohexyladenosine (CHA) and 2-chloroadenosine (CADO) caused contractions at low concentrations (0.05-2.0 microM), whereas at higher concentrations, relaxation resulted. 4. For tracheal relaxation, the adenosine analogues exhibited the following rank order of potency: NECA greater than CADO greater than R-PIA = MECA greater than S-PIA greater than adenosine. The rank order of potency for inducing contractions was R-PIA greater than CHA greater than CADO greater than S-PIA. These data suggest that relaxation is mediated by adenosine A2-receptors, whereas contraction is the result of activation of A1-receptors. 5. 8-Phenyltheophylline (8-PT), aminophylline, the triazoloquinazoline CGS 15943A and NPC205 (1,3-di-n-propyl-8-(4-hydroxyphenyl)xanthine) each inhibited the R-PIA-induced contractile response, whereas enprofylline was without effect. NPC205, aminophylline and 8-PT were competitive antagonists, but CGS15943A was non-competitive. 6. That the most potent antagonist was the A1-selective agent, NPC205 (pA2 = 7.80), further suggests that the contraction is mediated by A1-receptors. Moreover, NPC205 was 13 times more potent as an antagonist of R-PIA-induced contractions (A1) than of NECA-induced relaxations (A2). 7. The antagonists were also found to relax the trachea by an unknown mechanism. That enprofylline did not antagonize the R-PIA-induced contractions, but was 3-4 times more potent a tracheal relaxant than aminophylline, further suggests that a direct effect on airway smooth muscle, rather than antagonism of endogenous adenosine, is more relevant to the bronchodilator effect of alkylxanthines in the treatment of asthma.

Effects of bradykinin receptor antagonists on antigen-induced respiratory distress, airway hyperresponsiveness and eosinophilia in guinea-pigs.

1. We examined effects of bradykinin (BK) receptor antagonists on airway hyperresponsiveness and eosinophilia in sensitized guinea-pigs that had been administered single, as well as repeated (chronic) challenges with inhaled ovalbumin. In addition, the effects of BK antagonists on antigen-induced respiratory distress during the chronic study were noted. 2. At 24 h following single antigen challenge, guinea-pigs exhibited airway hyperresponsiveness to the bronchoconstrictor effect of i.v. histamine, characterized by a left shift in the dose-response curve. In addition, responses to the maximum dose of histamine that could be used were significantly increased in hyperresponsive guinea-pigs. The percentages of bronchoalveolar fluid, eosinophil and neutrophils also increased. 3. A BK B1 receptor antagonist, desArg9-[Leu8]-BK, significantly inhibited airway hyperresponsiveness induced by single antigen challenge. A B2 receptor antagonist, D-Arg-[Hyp3, Thi5,8,D-Phe7]-BK (NPC 349) had a small, but statistically significant inhibitory effect on responsiveness to the highest histamine dose in challenged animals. DesArg9-[Leu8]-BK significantly inhibited the neutrophilia, whereas NPC 349 inhibited infiltration by both cell types. 4. Chronic antigen challenge also caused airway hyperresponsiveness to i.v. acetylcholine (ACh), distinguished by an increase in the slope of the dose-response curve. Thus, the magnitude of the bronchoconstrictor responses to the maximum dose of ACh that could be used was significantly increased. No change in sensitivity to ACh was evident. Marked eosinophilia was also noted in the trachea, bronchi and lung parenchyma. 5. Airway hyperresponsiveness and eosinophilia, induced by chronic antigen challenge, were markedly inhibited by the B2 antagonists, D-Arg-[Hyp3,D-Phe7]-BK (NPC 567) or D-Arg-[Hyp3,Thi5d-Tic7,Tic8]-BK (NPC 16731).NPC 16731 also abolished antigen-induced cyanosis, and delayed the onset of dyspnoea,doubling the time taken for animals to exhibit respiratory distress.6. The ability of BK receptor antagonists to inhibit antigen-induced airway hyperresponsiveness, in addition to eosinophilia, indicates an important role for endogenous kinins. Moreover, the abrogation of eosinophil infiltration suggests that BK has a significant function in maintaining allergic inflammation of the airways.

Cell cycle perturbations in cisplatin-sensitive and resistant human ovarian carcinoma cells following treatment with cisplatin and low dose rate irradiation.

PURPOSE: To investigate cell cycle pertubations in plateau-phase human ovarian carcinoma cells following treatment with cisplatin, low dose-rate irradiation (LDRI), or combined cisplatin and LDRI, in order to understand cell cycle mechanisms by which these two treatment modalities interact. METHODS: Human ovarian carcinoma cells sensitive (A2780) and resistant (2780CP) to cisplatin were grown to plateau phase and given protracted cisplatin treatments (A2780 0.7 and 2 microg/ml; 2780CP 5 and 15 microg/ml) and/or LDRI (0.41 cGy/min). Cell cycle distribution following treatment was determined by two-parameter flow cytometry, based on bromodeoxyuridine (BrdU) uptake and DNA content using propidium iodide staining. RESULTS: The cisplatin-sensitive A2780 cells exposed to cisplatin alone for up to 28 h showed depletion of the G1 fraction and accumulation in S-phase, although the percentage of S-phase cells actively incorporating BrdU dropped to almost zero. The cisplatin-resistant 2780CP cells exposed to cisplatin alone showed a G1 arrest when exposed to 15 microg/ml, but not when exposed to 5 microg/ml. LDRI alone caused little cell cycle redistribution different from controls in either cell line. When LDRI was combined with cisplatin, no significant cell cycle redistribution was observed, apart from a decline in the actively incorporating S-phase fraction. CONCLUSIONS: Cisplatin caused A2780 cells to accumulate in nonincorporating S-phase, with no evidence of G1 arrest. Cisplatin-resistant 2780CP cells showed a G1 block when exposed to a high enough cisplatin concentration. This could indicate a mechanism of cisplatin resistance in these cells. LDRI alone or in combination with cisplatin did not result in significant cell cycle redistribution.

Cloning, sequencing and functional expression of a guinea pig lung bradykinin B2 receptor.

Kinin receptors are classified as B1 and B2 based upon agonist and antagonist potencies and cloning and expression studies. Using sequences from human and rat bradykinin B2 receptors, polymerase chain reaction (PCR) was utilized to isolate cDNA from guinea pig lung. The receptor obtained is predicted to have 372 amino acids and shares > 80% sequence homology with human, rat, rabbit and mouse B2 receptors. In competition binding experiments in Chinese hamster ovary (CHO-K1) cells in which the guinea pig cDNA was expressed, [3H]bradykinin was displaced by kinin receptor ligands with an order of potency consistent with a B2 subtype. In CHO cells expressing the guinea pig receptor, bradykinin caused a concentration 45Ca2+ efflux. A B1 receptor agonist, desArg9-bradykinin, also caused 45Ca2+ efflux but with a potency several orders of magnitude lower than bradykinin. Curiously, several B1 and B2 receptor antagonists induced 45Ca2+ efflux, indicating that this receptor may be coupled differently in CHO cells than in native tissues.

Inhibition of potentially lethal damage recovery by cisplatin in a brain tumor cell line.

Radiation resistant tumours such as gliomas show enhanced capacity for potentially lethal damage recovery (PLDR), which can be inhibited by cisplatin. The 9L rat brain tumour cell line, like human glioma cell lines, shows a large capacity for PLDR. Cisplatin administered at 6 micrograms/ml for 1 hour immediately following acute irradiation (18 Gy) is shown to cause significant inhibition of PLDR, while 3 micrograms/ml causes little inhibition. Cisplatin-radiation treatment sequence affects PLDR inhibition, with maximum effect seen when cisplatin is administered immediately after irradiation, during the period of rapid cellular recovery. These data suggest that optimum interaction between radiation and cisplatin treatments can be achieved by maximizing intratumoural cisplatin levels during the post-irradiation recovery period.

Myoclonus in Alzheimer's disease and minipolymyoclonus.

The typical electrophysiological correlates of myoclonus in Alzheimer's disease are similar to those of cortical reflex myoclonus, with a focal, contralateral negativity in the EEG preceding the myoclonic jerk. One difference from cortical reflex myoclonus is that the duration of the negativity is longer and its onset before the jerk earlier. The features differ from those described for subacute spongiform encephalopathy and should be helpful for differential diagnosis. The electrophysiological correlate of minopolymyoclonus that can be seen in Alzheimer's disease and in other pathological states is a bifrontal negativity in the EEG that precedes the myoclonic jerk. This new type of electrophysiological correlate of myoclonus may reflect activity of a subcortical generator.

Correlation between Gd-enhanced MR imaging and histopathology in treated and untreated 9L rat brain tumors.

Gadolinium-based MR imaging contrast agents cause signal enhancement of intracerebral tumors on T1-weighted MR images because they cross the compromised blood-brain barrier, increasing the T1 relaxation rate of extracellular water. Tumor extent measured by Gd-enhanced MR imaging often does not agree with T2-weighted MRI or biopsy measurements, due to possible peritumoral barrier defects or infiltration of tumor cells beyond the region of enhancement. In this study, the 9L rat brain tumor model was used to measure the correlation between tumor size measured by Gd-enhanced and unenhanced MRI and histological measurements. There was excellent agreement between Gd-enhanced MRI measurements and histology. Morphological features of untreated 9L intracranial tumors and those treated with radiation and/or cisplatin were compared with histological features. No significant change in intracranial tumor size was detected in the treated animals up to 7 days following treatment, despite substantial tumor necrosis evident on histological analysis.

Primary generalised epileptic myoclonus: a frequent manifestation of minipolymyoclonus of central origin.

A group of patients with myoclonus is described whose jerks are preceded by a bilaterally synchronous, frontocentrally predominant, negative cerebral potential in the EEG. This potential may be a slow wave with variable timing in relation to EMG bursts, and in this circumstance the muscle jerks are usually small amplitude and multifocal ("minipolymyoclonus"). The cerebral negativity can also be shorter in duration and time-locked to limb jerks, which are larger in amplitude and more widespread. We propose that the physiology of this distinct form of myoclonus is similar to that of primary generalised epilepsy.

Audiogenic startle reflex of man and its relationship to startle syndromes. A review.

The normal human audiogenic startle reflex is defined from a review of the literature, substantiated by a current investigation of normal subjects, and clarified pathophysiologically by a discussion of animal experimentation. The basic information is used to evaluate critically a variety of syndromes loosely termed 'startle' in the past. A new classification of startle syndromes is proposed.

Evidence for a pulmonary B3 bradykinin receptor.

We have examined pulmonary effects of bradykinin (Bk) in vivo and in vitro in guinea pigs and their potential inhibition by antagonists of Bk B1 and B2 receptors. Bk was a potent bronchoconstrictor in vivo and caused contractions of isolated, epithelium-denuded trachealis. D-Arg[Hyp3,D-Phe7]-Bk (NPC567) and D-arg[Hyp3,Thi5,8,D-Phe7]-Bk (NPC349), B2 receptor antagonists, were weak inhibitors of Bk-induced bronchoconstriction in vivo and were virtually inactive as antagonists of Bk-induced airway smooth muscle contraction. Several other B2 antagonists as well as B1 antagonist, des-Arg9-[Leu8]-Bk, did not inhibit Bk-induced tracheal contraction. The B1 receptor agonist des-Arg9-Bk was without effect on tracheal tone. Tracheal responses to Bk were unaffected by antagonists of muscarinic, histamine, serotonin, and catecholamine receptors. The inability of the antagonists to inhibit Bk is unlikely to be due to their degradation, because NPC567 was only weakly active in the presence of inhibitors of kininase I (EC 3.4.11.2), kininase II (EC 3.4.15.1), and neutral endopeptidase (EC 3.4.24.11). These studies were corroborated by ligand binding experiments in guinea pig and ovine airways. In [3H]Bk binding, the Bk antagonists had no effect in guinea pig trachea, slightly displaced [3H]Bk in ovine trachea, and inhibited approximately 60% of total specific binding in lung. des-Arg9-[Leu8]-Bk and several other agents, including atropine, neurokinin A, substance P, and vasoactive intestinal peptide, had no effect on lung Bk binding. Bk and its analogs were not degraded during the binding assay. These data suggest that pulmonary tissue, particularly in the large airways, contains a novel Bk binding site, a B3 receptor, which may be involved in Bk-induced bronchoconstriction.

Cisplatin, hyperthermia and radiation treatment in human cisplatin-sensitive and resistant glioma cell lines.

In this study, the effects of mild protracted hyperthermia, combined with prolonged exposure to cisplatin and low dose-rate irradiation (LDRI), were examined in two human cell lines. The cell lines are human glioma parental and cisplatin-resistant variant cells. The results show that mild hyperthermia at 40 degrees C was able to sensitize both the parental and the variant cisplatin-resistant cells to cisplatin treatments (1 microgram/ml for up to 20 h) when the two treatments were given concurrently. When mild hyperthermia and cisplatin were given with LDRI concurrently, additional enhanced cell killing was observed in both the parental and the cisplatin-resistant variant cells. Further analysis of the results showed that when the effects of the trimodality treatment were normalized to the effects of the combined treatment of mild hyperthermia with cisplatin, the residual cell killing was still greater than that observed for radiation alone, indicating a synergistic interaction. This synergistic interaction was greater for the parental line compared to the cisplatin-resistant line. Thus, these data show that the concurrent application of mild hyperthermia, low concentration, long duration, cisplatin and low-dose rate irradiation may be an effective form of treatment in both normally responding and cisplatin-resistant variant human tumour cell lines.