Interaction of Mg2+ and phencyclidine in use-dependent block of NMDA channels.

The interaction between Mg2+ and phencyclidine (PCP) in blocking open N-methyl-D-aspartate (NMDA) channels was investigated in Xenopus oocytes injected with rat brain mRNA. These receptors exhibit the pharmacological and physiological properties of the neuronal receptors, and the oocyte is readily amenable to electrical recording and application of well-controlled chemical stimuli. We found that Mg2+ at physiological concentrations greatly impeded the ability of PCP to block the NMDA channel. The interaction between Mg2+ and PCP was competitive; 0.5 mM Mg2+ caused a four-fold decrease in the potency of PCP in blocking open NMDA channels. Moreover, Mg2+ speeded the recovery from PCP block in the presence of agonist, suggesting that Mg2+ reduced reblock of NMDA channels by PCP that had escaped from open channels. Our observations suggest that the presence of Mg2+ in the channel tends to prevent PCP entry and block. Since depolarization is likely to reduce channel occupancy by Mg2+ more than that by PCP, neural activity may have an important influence on the actions of PCP and related drugs.     

Early tracheostomy in closed head injuries: experience at a tertiary center in a developing country – a prospective study

Background

An important factor contributing to the high mortality in patients with severe head trauma is cerebral hypoxia. The mechanical ventilation helps both by reduction in the intracranial pressure and hypoxia. Ventilatory support is also required in these patients because of patient's inability to protect the airway, persistence of excessive secretions, and inadequacy of spontaneous ventilation. Prolonged endotracheal intubation is however associated with trauma to the larynx, trachea, and patient discomfort in addition to requirement of sedatives. Tracheostomy has been found to play an integral role in the airway management of such patients, but its timing remains subject to considerable practice variation. In a developing country like India where the intensive care facilities are scarce and rarely available, these critical patients have to be managed in high dependency cubicles in the ward, often with inadequately trained nursing staff and equipment to monitor them. An early tracheostomy in the selected group of patients based on Glasgow Coma Score(GCS) may prove to be life saving.Against this background a prospective study was contemplated to assess the role of early tracheostomy in patients with isolated closed head injury.

Methods

The series consisted of a cohort of 50 patients admitted to the surgical emergency with isolated closed head injury, that were not considered for surgery by the neuro-surgeon or shifted to ICU, but had GCS score of less than 8 and SAPS II score of more than 50. First 50 case records from January 2001 that fulfilled the criteria constituted the control group. The patients were managed as per ATLS protocol and intubated if required at any time before decision to perform tracheostomy was taken. These patients were serially assessed for GCS (worst score of the day as calculated by senior surgical resident) and SAPS scores till day 15 to chart any changes in their status of head injuries and predictive mortality. Those patients who continued to have a GCS score of <8 and SAPS score of >50 for more than 24 hours (to rule out concussion or recovery) underwent tracheostomy. All these patients were finally assessed for mortality rate and hospital stay, the statistical analysis was carried out using SPSS10 version. The final outcome (in terms of mortality) was analyzed utilizing chi-square test and p value <0.05 was considered significant.

Results

At admission both tracheostomy and non-tracheostomy groups were matched with respect to GCS score and SAPS score. The average day of tracheostomy was 2.18 ± 1.0038 days. The GCS scores on days 1, 2, 3, 4, 5, 10 between tracheostomy and non-tracheostomized group were comparable. However the difference in the GCS scores was statistically significant on day 15 being higher in the tracheostomy group.Thus early tracheostomy was observed to improve the mortality rate significantly in patients with isolated closed head injury

Conclusion

It may be concluded that early tracheostomy is beneficial in patients with isolated closed head injury which is severe enough to affect systemic physiological parameters, in terms of decreased mortality and intubation associated complications in centers where ICU care is not readily available. Also, in a selected group of patients, early tracheostomy may do away with the need for prolonged mechanical ventilation.     

Progressive platelet activation with storage: evidence for shortened survival of activated platelets after transfusion

Platelets are known to become activated during storage, but it is unclear whether such activation affects recovery or survival after platelet concentrate (PC) transfusion. With the use of flow cytometry to determine the percentage of platelets expressing the alpha-granule membrane protein 140 (GMP-140), a known adhesive ligand appearing on the platelet surface after activation, several studies were conducted. These investigations evaluated 1) the occurrence of significant platelet activation over time in PCs (n = 46) stored under standard blood bank conditions; 2) the correlation between platelet activation and platelet recovery in normal subjects after PC storage (n = 12), as assessed by the recovery of Indium-labeled platelets; and 3) the recovery of activated and unactivated platelets in thrombocytopenic cancer patients transfused with standard PCs (n = 11). It was determined 1) that an increasing duration of storage of PC was associated with increasing platelet activation as measured by the percentage of platelets expressing GMP-140, progressing from a mean of 4 +/- 2 percent (SD) on the day of collection to a mean of 25 +/- 8 percent by 5 days of storage: 2) that, in normal subjects, posttransfusion recovery of autologous platelets stored for 2 to 4 days and then labeled with In111 was inversely correlated with the percentage of activated platelets in the transfused PC (r = -0.55, p = 0.05); and 3) that, when thrombocytopenic patients were transfused with standard PCs, the recovery of the activated platelets in the transfused PCs averaged only 38 +/- 15 percent of the number predicted by the absolute platelet increment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spermine potentiation of recombinant N-methyl-D-aspartate receptors is affected by subunit composition.

The present study shows that both the NR1 and NR2 subunits critically affect spermine potentiation of heteromeric recombinant N-methyl-D-aspartate receptors. NR1(011), the most prominent NR1 splice variant in rat forebrain, and NR1(100), prominent in midbrain, were expressed in Xenopus oocytes singly and in combination with NR2A, NR2B, and NR2C subunits. As for NR1(011) homomers, NR1(011)/NR2B receptors exhibited spermine potentiation by two mechanisms: by increasing glycine affinity and by increasing current through receptors with bound N-methyl-D-aspartate and glycine. NR1(011)/NR2A receptors exhibited only the increase in glycine affinity, and NR1(011)/NR2C receptors exhibited neither. As for NR1(100) homomers, NR1(100)/NR2B and NR1(100)/NR2A receptors exhibited spermine potentiation only by increasing the glycine affinity. Spermine produced no potentiation of NR1(100)/NR2C receptors. Thus, the NR2B subunit "permits" both forms of spermine potentiation, the NR2A subunit permits spermine potentiation only by increasing the glycine affinity, and th NR2C subunit permits neither form of potentiation. Spermine actions on NR1/NR2 showed little voltage dependence. These observations are of interest because the NR1 and NR2 subunits are differentially distributed and developmentally regulated. At early postnatal ages, NR2B subunit mRNA was more highly expressed than NR2A and NR2C mRNAs in hippocampus, neocortex, and caudate-putamen. These findings account for many of the observed differences among neurons in polyamine actions and suggest that these actions will vary in a cell-specific and age-related manner.     

Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death

Kainic acid (KA)-induced status epilepticus in adult rats leads to delayed, selective death of pyramidal neurons in the hippocampal CA1 and CA3. Death is preceded by down-regulation of glutamate receptor 2 (GluR2) mRNA and protein [the subunit that limits Ca(2+) permeability of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] in CA1 and CA3, as indicated by in situ hybridization, immunolabeling, and quantitative Western blotting. GluR1 mRNA and protein are unchanged or slightly increased before cell death. These changes could lead to formation of GluR2-lacking, Ca(2+)-permeable AMPA receptors and increased toxicity of endogenous glutamate. GluR2 immunolabeling is unchanged in granule cells of the dentate gyrus, which are resistant to seizure-induced death. Thus, formation of Ca(2+)-permeable AMPA receptors may be a critical mediator of delayed neurodegeneration after status epilepticus.     

Epstein–Barr virus in the pathogenesis of oral cancers

Epstein–Barr virus (EBV) is a ubiquitous gamma‐herpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral life cycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV‐positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.