Intracellular activity of clinical concentrations of phenothiazines including thioridiazine against phagocytosed Staphylococcus aureus

The effect of thioridazine (TZ) was studied on the killing activity of human peripheral blood monocyte derived macrophages (HPBMDM) and of human macrophage cell line THP-1 at extracellular concentrations below those achievable clinically. These macrophages have nominal killing activity against bacteria and therefore, would not influence any activity that the compounds may have against intracellular localised Staphylococcus aureus. The results indicated that whereas TZ has an in vitro minimum inhibitory concentration (MIC) against the strains of S. aureus of 18, 0.1 mg/l of TZ in the medium completely inhibits the growth of S. aureus that has been phagocytosed by macrophages. The latter concentration was non-toxic to macrophages, did not cause cellular expression of activation marker CD69 nor induction of CD3+ T cell production of IFN-gamma, but blocked cellular proliferation and down-regulated the production of T cell-derived cytokines (IFN-gamma, IL-5). These results suggest that TZ induces intracellular bactericidal activities independent of the capacity to generate Type 1 responses against S. aureus.     

Hyponatraemia associated with psychotropic medications. A review of the literature and spontaneous reports

Psychotropic medication-induced hyponatraemia is an uncommon but important clinical problem with potential serious consequences if not recognised and treated early. Several risk factors have been associated with the development of hyponatraemia. This article reviews reported cases of hyponatraemia associated with the use of psychotropic medications and evaluates possible risk factors and causes. The data were sourced by a search of Medline for reports of hyponatraemia associated with the use of psychotropic medication between January 1966 and December 2000 and a search of US Food and Drug Administration (FDA) spontaneous reporting system database between January 1966 and December 1999. All the reports were included in this review. In the case reports the following data were assessed: age, gender, daily dosage, days to onset, days to recovery, medical condition, concurrent medications. Several risk factors were identified: advanced age, female gender, use of other medications, medical comorbidity. The risk of hyponatraemia was found to be higher during the first 2 weeks of treatment. Administration of the dosage of the drug was not found to be related to the development of hyponatraemia. Hyponatraemia can cause confusion, agitation and lethargy. Any change in the course of illness should alert the physician to the possibility of hyponatraemia.     

A prognostic model for survival in chronic lymphocytic leukaemia based on p53 expression

As the abnormal expression of p53 protein is prognostically significant in some human cancers, its significance in patients with B-cell chronic lymphocytic leukaemia (CLL) was assessed. Two investigators evaluated the percentage of bone marrow mononuclear cells that stained for p53, using biopsies stained with anti-p53 monoclonal antibody (DO-7), and graded the degree of staining (0, +, ++, +++). Samples from a cohort of 90 patients with CLL were studied (median age 60 years, range 30-89 years; 57 patients were (63%) previously untreated, 22 patients (24%) had received one or two prior regimens, 11 patients had received (12%) three to seven regimens. The overall percentage of cells positive for p53 staining was a median of 43 (range 1-88). No investigator effect was detected either in overall percentage cells rated p53 positive or on the degree of staining (Pearson's correlation coefficient 0.980, P-value < 0.001). A Cox proportional hazards model showed that the percentage of ++ and +++ p53-positive cells correlated with various prognostic factors in CLL (P < 0.0001). A multivariate model incorporating prior therapy, Rai stage, beta2 microglobulin (beta2M) and p53 expression showed that only the percentage of p53-positive cells and beta2M were predictive of survival, and enabled the development of a highly predictive model of survival based on these two parameters.     

Distal myasthenia gravis: case report

We report the case of a 30-year-old woman with a 7-year history of distal lower limbs weakness that evolved to upper limbs weakness. On neurological examination, she presented normal cranial nerves, bilateral quadriceps and feet interosseous atrophy, normal muscular tonus, muscular weakness more severe in dorsal feet interosseous and anterior tibial, and decreased deep tendon reflexes. Repetitive nerve stimulation of the ulnar and fibular nerves showed a decrement greater than 10% of the compound muscle action potential. Antibody against acetylcholine receptor titer was positive. Computed tomography scan of the thorax was normal. Thyroid function tests showed evidence of hyperthyroidism. Distal muscular weakness is a rare onset presentation of myasthenia gravis. However, myasthenia gravis must be considered in the differential diagnosis of distal limb weakness.     

Dopamine inhibits ATP-induced responses in the cat petrosal ganglion in vitro

The petrosal ganglion (PG) provides sensory innervation to the carotid sinus and carotid body through the carotid (sinus) nerve (CN). Application of either acetylcholine (ACh) or adenosine 5'-triphosphate (ATP) to the PG superfused in vitro activates CN fibers. Dopamine (DA) modulates the effects of ACh. We have previously shown that DA when applied to the PG modulates the effects of ACh on carotid sinus nerve fibers. We currently report the effects of DA on the ATP-induced responses in the isolated PG in vitro. While DA had no effect on the basal activity recorded from the CN, it reduced ATP-induced responses in a dose-dependent manner, when preceding ATP applications by 30 s. Our results suggest that DA-a transmitter present in a group of PG neurons and in carotid body cells-may act as an inhibitory modulator of ATP-evoked responses in PG neurons.     

Proteomic characterisation of neuronal sphingolipid-cholesterol microdomains: role in plasminogen activation

Sorting of certain membrane proteins requires a mechanism involving rafts, protein-lipid complexes enriched in glycosphingolipids and cholesterol. These microdomains remain at the plasma membrane of different cell types and play a role in signal transduction. Although recent reports have begun to describe molecules associated with rafts, their protein composition remains largely unknown, especially in neuronal cells. To address this question, we have purified detergent-insoluble raft fractions (DRMs) from primary cultures of hippocampal neurons. Bidimensional gel analysis and pharmacological raft lipid manipulation allowed the identification of neuronal raft proteins and their characterisation by MALDI-TOF analysis. Enolases were found among the proteins identified and functional studies demonstrate their participation in plasminogen binding. We also show the specific enrichment in rafts of several other plasminogen binding molecules and the exclusive activation of plasminogen to the protease plasmin in these microdomains. These observations suggest that neuronal rafts may play, in addition to intracellular signaling, a role in extracellular/membrane protein proteolysis.