Tardive dyskinesia: an increased risk of neuroleptics in elderly women

Tardive dyskinesia is a side-effect of antipsychotic drugs. Elderly women with depression are at risk even on a low dosis. A case is presented in which a typical depression was treated with high dosis haloperidol resulting in orofacial dyskinesia and a less frequently seen grunting. Correct diagnosis, indication, dosis monitoring and regular evaluation of possible side-effects are the most important factors to prevent these serious invalidating conditions.     

Phase I study of cyclophosphamide (NSC 26271) by 72-hour continuous intravenous infusion

A phase I clinical study of cyclophosphamide administered by 72-hour continuous intravenous infusion was conducted in 13 patients with various types of advanced solid tumors to evaluate the drug's toxicity and efficacy. The initial dosage of 300 mg/m2/day X 3 days repeated at 3-week intervals was progressively increased by 150 mg/m2/day-increments to a maximum dosage of 750 mg/m2/day. The dose-limiting toxicities were hematologic and gastrointestinal. Neutropenia was more severe than was thrombocytopenia. The lowest granulocyte count less than 500/mm3 occurred during more than half of the treatment courses at doses of 600 mg/m2 and higher. Severe nausea and vomiting were observed in patients during three of four treatment courses at the 750 mg/m2 dose level. None of the patients had microscopic hematuria or symptoms suggestive of cystitis. Partial response occurred in a patient with parotid cancer metastatic to the lung. Disease stabilization occurred in four patients, while six patients had progression of disease. The recommended starting dosage of cyclophosphamide by continuous intravenous infusion for phase II trials is 600 mg/m2/day X 3 every 3 weeks for patients with good bone marrow reserve.     

Interactions between N-methyl-D-aspartate receptor antagonists and the discriminative stimulus effects of morphine in rats

NMDA receptor antagonists have previously been reported to alter some pharmacological and behavioral effects of acute and chronic opioid administration. The present study assessed the interactions of NMDA antagonists with the discriminative stimulus properties of morphine. Adult male Long Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water under a two-lever fixed-ratio 10 schedule of food reinforcement. During test sessions. I.p. injections of the noncompetitive NMDA receptor antagonist dizocilpine (0.03-0.2 mg/kg), the competitive antagonists NPC 17742 (1-16 mg/kg), and SDZ 220-581 (0.1-3 mg/kg), the polyamine site antagonist eliprodil (3-17.3 mg/kg), the glycine-site partial agonist (+)-HA-966 (3-56 mg/kg), and the nonselective glutamate antagonist kynurenic acid (30-150 mg/kg) were coadministered with s.c. morphine (1-3.2 mg/kg; interaction tests) or water (generalization tests). In generalization tests, none of the compounds completely substituted for morphine. Concurrent administration of morphine and NMDA antagonists did not greatly alter the discriminative stimulus properties of morphine. Various doses of NPC 17742, SDZ 220-581, or (+)-HA-966 somewhat increased levels of morphine-appropriate lever selection, whereas some attenuation of morphine-lever selection was obtained when morphine was coadministered with eliprodil. These results show that NMDA antagonists have minimal interactions with the discriminative stimulus effects of morphine.     

Host immune response to vesicular stomatitis virus infection of the central nervous system in C57BL/6 mice

In this report, the kinetics of cellular inflammatory changes in the brain of vesicular stomatitis virus (VSV)-infected C57BL/6 (B6) mice was determined. The behavior and survival rate of infected B6 were carefully monitored each day. Infectious viral titers and VSV antigen distribution were determined at several time points during the course of infection. Strong activation of both astrocytes and microglia was observed after VSV infection. Induction of type II nitric oxide synthase (iNOS) was detected in activated microglia in the olfactory bulb (OB) starting at day 4 postinfection. Induced expression of major histocompatibility complex (MHC) molecules and rapid infiltration of both T cells and natural killer (NK) cells were detected in the VSV-infected CNS. Collectively, these data indicate that the response to CNS infection in B6 mice, which is often primarily Th1 in characteristics, is comparable to BALB/c mice, a strain that often shows a Th2-dominated immune response.     

Study of human calcitonin fibrillation by proton nuclear magnetic resonance spectroscopy

The fibrillation of human calcitonin (hCT) has been investigated by NMR in aqueous solution. The time course of proton one- and two-dimensional NMR spectra of hCT (80 mg/mL at pH 2.9) was measured during the fibrillation. It showed a gradual broadening of the peptide peaks, followed by a rapid broadening and subsequent disappearance of the peaks. The gradual broadening can be attributed to equilibrium between monomer and associated hCT, whereas the rapid broadening can be attributed to formation of aggregates and to gelation of the peptide solution. All the peptide peaks did not broaden and disappear simultaneously. Peaks of residues in the N-terminal (Cys1-Cys7) and central (Met 8-Pro23) regions broadened and disappeared faster during the gradual broadening than those in the C-terminal region (Gln24-Pro32). Moreover, in the N-terminal and central residues, peaks of Cys1, Leu4,9, Met 8, Tyr12, Asp15, and Phe16,19,22 disappeared faster than those of Asn3,17, Ser5, Cys7, Gln14, Lys18, and His20. Hydrogen-deuterium exchange of amide protons indicated the formation of hydrogen bonds caused by association of hCT molecules. The amphiphilicity of the peptide appears to be important for the hCT association.     

Synaptic laminin prevents glial entry into the synaptic cleft

Presynaptic and postsynaptic membranes directly oppose each other at chemical synapses, minimizing the delay in transmitting information across the synaptic cleft. Extrasynaptic neuronal surfaces, in contrast, are almost entirely covered by processes from glial cells. The exclusion of glial cells from the synaptic cleft, and the long-term stability of synapses, presumably result in large part from the tight adhesion between presynaptic and postsynaptic elements. Here we show that there is another requirement for synaptic maintenance: glial cells of the skeletal neuromuscular synapse, Schwann cells, are actively inhibited from entering the synaptic cleft between the motor nerve terminal and the muscle fibre. One inhibitory component is laminin 11, a heterotrimeric glycoprotein that is concentrated in the synaptic cleft. Regulation of an inhibitory interaction between glial cells and synaptic cleft components may contribute to synaptic rearrangements, and loss of this inhibition may underlie the loss of synapses that results from injury to the postsynaptic cell.     

Altropane, a SPECT or PET imaging probe for dopamine neurons: II. Distribution to dopamine-rich regions of primate brain

Our understanding of the molecular pathology underlying the development and progression of ductal pancreatic cancer has been revolutionised during the last 5 years due to the spectacular development of novel molecular biological techniques. In the present article, we describe key molecular alterations of sporadic and inherited ductal pancreatic cancer. Overexpression of growth factors and growth factor receptors are present in a significant proportion of this tumour type. Mutation of the K-ras oncogene, and disruption of p53 or p16 tumour suppressor gene abrogates the control of the cyclin-dependent kinases (cdk) and retinoblastoma (Rb) gene pathway, causing continuous growth of the pancreatic tumour. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor beta signalling pathway. Lost or decreased expression of retinoid receptors and failure of telomerase activity may play a role in pancreatic carcinogenesis. Tumour-associated proteinases, matrix metalloproteinases and plasminogen activators are reported to be involved in pancreatic cancer invasion and metastasis. Furthermore, the cytogenetic changes in this cancer are summarised. This molecular pattern distinguishes pancreatic cancer from other epithelial tumours and represents a promising basis for the development of diagnostic and other clinical applications.