Structures involved in binding, gating, and conduction in nicotinic acetylcholine receptors.
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Amino Acid Sequence↗
Biomedical subjects
M Xu
Publications and source records attributed to M Xu.
Hearing loss and trace elements Fe2+ and Zn2+ in the perilymph.
Fe2+ and Zn2+ levels in perilymph of guinea pigs injected with gentamicin (GM) were examined and compared with the corresponding concentrations in CSF, serum and hairs. We observed a preventive and therapeutic action of sea buckthorn oil and injectio gastrodini to hearing loss. The results showed that: (1) the Fe2+ content in GM-injected guinea pigs was increased in perilymph and hairs; it was decreased after prevention and treatment, but there was no obvious change in CSF and serum; (2) the Zn2+ content in perilymph and CSF was increased in GM-injected guinea pigs. It rose further after prevention, but in serum and hairs it decreased. The results indicate that the ototoxic reaction to GM is related to the rise of the Fe2+ content in perilymph. The elevation of Zn2+ is a compensatory reaction. The changes in the chemical composition of perilymph are more important than those in CSF, serum and hairs for pathological changes of the cochlea. Sea buckthorn oil can prevent GM ototoxicity.
Animals↗
Chronic thermotolerance with continued cell proliferation.
The human colon adenocarcinoma cell line, NSY42129, is capable of proliferation at 41.1 degrees C. This ability appears to be due to a type of chronic thermotolerance, as opposed to selection or adaptation, that allows these cells to traverse S phase at elevated temperatures. Four other human cell lines were studied for their ability to proliferate at 41.1 degrees C. Of those only one, also a colon adenocarcinoma, showed the ability to sustain proliferation at 41.1 degrees C. While all the cell lines examined showed increased levels of the major heat shock proteins at 41.1 degrees C, the cellular amounts of these proteins did not correlate with their ability to proliferate at 41.1 degrees C. However, the ability of the cells to proliferate at 41.1 degrees C did correlate with their ability to sustain elevated rates of synthesis of hsp70 and hsp90. These results could have implications in the clinical application of hyperthermia, particularly the use of long duration moderate hyperthermia.
Bromodeoxyuridine↗
Intracellular distribution of hsp70 during long duration moderate hyperthermia.
Hyperthermia causes cell killing and is also an effective radiosensitizer. In recent years, the protocol of long duration moderate hyperthermia (LDMH) has been used to treat cancer patients in the clinic. However, the results of many studies indicate that some tumour cells may reveal the capability to express chronic thermotolerance, a factor of potentially critical impact in the efficacy of clinical hyperthermia. Previously it has been reported that two out of five human cell lines studied were able to proliferate at 41.1 degrees C. In the present study, the intracellular distribution of hsp70 during LDMH was measured as a potential marker for chronic thermotolerance with continued cell proliferation. In all cell lines studied, hsp70 became localized in the nucleus immediately after the cells were shifted from 37 degrees C to 41.1 degrees C. However, in the two cell lines which recovered and continued to proliferate, NSY42129 and HT29, hsp70 was delocalized from the nucleus within 4 h. Conversely, in the cell lines for which 41.1 degrees C was lethal, hsp70 did not delocalize from the nucleus but rather became localized in the nucleolar regions. Neither the NSY42129 cells nor the HT29 cells showed any preferential nucleolar punctate staining. Thus, it appears that the pattern of hsp70 nuclear localization and delocalization is related to the cells' ability to survive moderate heat shocks.
Cell Division↗
Application of non-radioactive europium (Eu3+) release assay to a measurement of human natural killer activity of healthy and patient populations.
Europium (Eu3+) release assay is a non-radioactive method for a measurement of cytotoxicity of lymphocytes and has several advantages compared with a conventional 51Cr release assay. However, the Eu3+ release assay has not been applied to a natural killer (NK) activity measurement of a large number of the human population mainly due to a lack of comparability with the 51Cr release assay. With some modifications of the procedures and careful manipulation of cells, constant and reproducible results were obtained by the Eu3+ release assay. NK activity of several individuals was measured by the Eu3+ release assay and was compared with data obtained by 51Cr release assay performed simultaneously. The obtained values by the two methods were almost identical. We applied the Eu3+ method to measure NK activity of a large number of individuals, including 68 apparently healthy donors and 36 autoimmune and 21 cancer patients. Some of these diseases are known to show abnormal NK activity. The obtained cytotoxicities were mostly consistent with the previously reported data obtained by the 51Cr release assay. These results indicated that the Eu3+ release assay could be used as an alternative method for a measurement of human NK activity of mass population including patients.
Adult↗
Comparison of 0.5% articaine and 0.5% prilocaine in intravenous regional anesthesia of the arm: a cross-over study in volunteers.
BACKGROUND AND OBJECTIVES: Earlier studies of the use of articaine in intravenous regional anesthesia (IVRA) are conflicting. In fact, despite similar physicochemical properties and regional anesthetic action, significant differences between articaine and prilocaine in IVRA have been reported. Articaine, being a potent local anesthetic with low degree of toxicity and being rapidly metabolized by esterases, could be a useful local anesthetic particularly in IVRA and, perhaps, could challenge prilocaine, the present local anesthetic of choice for this technique. METHODS: A double-blind, cross-over study of IVRA of the upper extremity in 10 healthy volunteers was performed. There was at least a 1-week interval between the use of the two anesthetics in each volunteer. After exsanguination with an Esmarch bandage, IVRA was induced either with preservative-free 0.5% articaine (5% Ultracaine, Hoechst, Germany, diluted with 0.9% NaCl) or 0.5% prilocaine (Citanest, Astra, Södertälje, Sweden) (35-50 mL, according to weight), injected in 2 minutes. Sensation at defined skin spots that were innervated by the median, musculocutaneous, radial, and ulnar nerves was tested by pinprick; motor function was tested by the movements of the wrist. After 20 minutes, the tourniquet cuff was deflated in one step. Circulatory, toxic, and skin reactions were registered. At least 1 week after the second IVRA intracutaneous allergy testing with 0.5% articaine, 0.5% prilocaine, histamine, and saline was performed. RESULTS: There were no significant differences between the two local anesthetics in the onset of analgesia or anesthesia, degree of motor block, and recovery of IVRA. Onset of analgesia occurred 4.2-5.6 minutes, on average, after the injection. One volunteer had short-lasting tinnitus after tourniquet cuff deflation when prilocaine was used. Erythematous nonitching skin rashes developed in 8 of 10 volunteers when articaine was used, and two volunteers had rashes when prilocaine was used. These rashes disappeared within an hour, and negative intracutaneous test results confirmed their nonallergic origin. CONCLUSION: Both 0.5% articaine and 0.5% prilocaine, in a median dose of 40 mL in adults, injected in 2 minutes, are effective and equipotent local anesthetics in IVRA of the arm. An earlier reported four-time faster onset time of the block by articaine in comparison with prilocaine may be caused by a very rapid injection rate (40 mL/30 sec) by the investigators of that study. The erythematous skin rashes after IVRA, in particular when articaine was used, may be a sign of venous endothelial irritation.
Adult↗
Progressive supranuclear palsy with widespread cerebral lesions.
A 51-year-old woman with no history of any familial neurological diseases initially presented with numbness in her extremities, slowing of movements, comprehension deficit, memory disturbance, dyscalculia, muscle rigidity, hyperreflexia, Parkinsonian gait, increasing disorientation, left-right disturbance, finger agnosia, alexia, acalculia, apraxia, aspontaneity, euphoria, gait disturbance, aphasia, echolalia, and in the terminal stage, mutism, contracture of lower extremities and cachexia. She died of bronchopneumonia at the age of 55. The brain showed widespread cerebral lesions, consisting of nerve cell loss and neurofibrillary tangles in the frontal, parietal and occipital cortex, demyelination and gliosis in the frontal, parietal and occipital subcortical white matter in addition to the typical pathological findings of progressive supranuclear palsy (PSP): severe neuronal loss with gliosis and neurofibrillary tangles (NFTs) in the subthalamic nucleus, globus pallidus and substantia nigra. In conclusion, we present a case of PSP with unusual clinical features (extrapyramidal signs, frontal and parietal lobe syndromes without ophthalmoplegia) and neuropathologically widespread cerebral lesions in addition to the typical pathological findings of PSP. The differential diagnosis of PSP and Alzheimer's disease and other degenerative disorders is discussed.
Alzheimer Disease↗
MR spectroscopy in sinus mucocele: N-acetyl mimics of brain N-acetylaspartate.
We describe MR spectroscopy in 2 patients with frontal sinus mucoceles that showed a dominant metabolite peak at 2.0-ppm chemical shift, simulating N-acetylaspartate (NAA) of normal neuronal tissue. In vitro analysis of postsurgical mucocele samples confirmed that the signal at 2.0 ppm was arising from the methyl moiety of an N-acetyl compound. This is probably caused by N-acetylgalactosamine or N-acetylglucosamine, which are glycoproteins found in normal respiratory mucus produced by the paranasal sinus epithelium.
Acetylgalactosamine↗
IL-2 gene therapy of advanced lung cancer patients.
We report here Phase I clinical-trial studies of retroviral-mediated interleukin-2 (IL-2) gene transfer to tumor-infiltrating lymphocytes that are re-infused to advanced lung cancer patients with pleural effusions. Ten lung cancer patients with malignant pleural effusions for whom all conventional therapy had failed were included in this Phase I protocol. Tumor infiltrating lymphocytes (TIL) from the patients were exposed to the retroviral plasmid pL(IL-2)SN containing the human IL-2 gene. Approximately 1-6 x 10(10) TIL cells transfected with IL-2 were re-infused into the chest cavity of each patient. The toxicity of this treatment with TIL/IL-2 gene therapy in these patients was minimal with transient slight fever of approximately 37.5. Pleural effusions did not re-accumulate for at least 4 weeks in six of ten patients. One patient was observed to have not only the resolution of the pleural effusions, but in addition the size of the original tumor decreased as seen by CT. The clinical results indicate this method of cancer gene therapy is safe and possibly efficacious against pleural effusions due to advanced lung cancer.
Adenocarcinoma↗
Anticancer efficacy of methioninase in vivo.
Therapeutics that are selective for cancer would have a high potential for efficacy. We have previously shown that the metabolic defect of enhanced methionine dependence is a broad cancer-selective target. Methionine depletion can completely arrest the growth of methionine-dependent tumor cells in vivo with a reversible pre-mitosis cell-cycle block. Dietary methionine depletion can partially arrest the growth of methionine-dependent rodent tumors in vivo. This report demonstrates that methioninase isolated from Pseudomonas putida can arrest rodent and human tumors in nude mice with no apparent toxic side effects. Methioninase injected i.p. arrested the growth of the Yoshida sarcoma in nude mice and greatly slowed the growth of the H460 human non-small-cell-lung carcinoma in nude mice. The effectiveness of methioninase against H460 was in contrast to 5-fluorouracil and vincristine, which were inactive against this tumor. The activity of the administered methioninase did not cause weight loss for up to 10 days treatment at 40-120 units/day indicating the possibility of low toxicity. In contrast, vincristine was highly toxic despite its ineffectiveness. Methioninase also induced a tumor-specific late cell-cycle block. The tumor-selective late cell-cycle block induced by methioninase should be able to be exploited to enhance the tumor specificity of antimitotic drugs and other agents in future experiments. Thus methioninase is a highly effective antitumor agent with a new tumor-selective mode of action with minimal toxicity, demonstrating potential clinical effectiveness against solid tumors.
Animals↗
Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients.
The growth dependence of human tumors on elevated levels of methionine has been shown in preclinical in vitro and in vivo studies to be a frequently occurring, highly effective, tumor-selective therapeutic target. High purity endotoxin-free methioninase was produced from Pseudomonas putida in order to develop anti-methionine chemotherapy targeting of human tumors. A pilot Phase I clinical trial has been initiated in order to determine methioninase toxicity, the pharmacokinetics of methioninase and methionine-depletion and maximum tolerated dose. A two hour i.v. infusion of 5,000 units (0.4 g) and 10,000 units (0.8 g) and a ten hour i.v. infusion of 20,000 units (1.6 g) of methioninase was administered to patient-1, patient-2, and patient-3, respectively. All patients had advanced breast cancer. Blood and urine samples were obtained at frequent intervals between 0 and 24 hours. The toxicity evaluations were carried out according to FDA criteria. Pharmacokinetics data were obtained for both methioninase and methionine levels in the serum. No acute clinical toxicity was observed for all the toxicity criteria measured in patient-1, patient-2 and patient-3. The depletion of serum methionine started within 30 minutes of the infusion, and was maintained for 4 hours after the infusion was completed in patient-1 and patient-2. The lowest serum methionine levels were 35% and 19% of the pretreatment level, respectively, in patient-1 and patient-2. Patient-3 received a ten hour i.v. infusion of 20,000 units of methioninase without any signs of side effects. Patient-3 maintained serum levels of methioninase as high as 50% of the maximum level for a subsequent 6 hours after infusion. Methionine was depleted over 200-fold from 23.1 microM to 0.1 microM by the 10-hour infusion of patient-3. No clinical toxicity was observed whatsoever in all the toxicity criteria measured in patient-3. The results of the methioninase pilot Phase 1 clinical trial suggested that i.v. infusion of the methioninase is safe and effectively depletes serum methionine without any signs of side effects. Clinical studies are continuing to determine the maximum length of time complete serum methionine depletion can be tolerated.
Antimetabolites, Antineoplastic↗
Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients.
The tumor-specific increased minimal requirement for methionine has been shown to be a highly promising therapeutic target. To attack this target we have previously cloned the methioninase gene from Pseudomonas putida and produced recombinant methioninase (rMETase). A pilot Phase I clinical trial has been carried out to determine rMETase toxicity, rMETase pharmacokinetics, and serum MET-depletion in cancer patients. Patients with advanced breast cancer, lung cancer, renal cancer and lymphoma were given a single rMETase treatment at doses ranging from 5,000 to 20,000 units by i.v. infusion over 6-24 hours. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels reached 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum methionine levels in rMETase-treated patients were 0.1% of the pre-treatment levels corresponding to approximately 0.1 microM, which also correlates to therapeutic levels in vitro. The results of the rMETase pilot Phase I clinical trial therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum methionine suggesting potential efficacy in future clinical trials.
Antimetabolites, Antineoplastic↗