Agonist-induced calcium waves in oscillatory cells: a biological example of Burgers' equation

Oscillations in cytosolic Ca2+ concentrations in living cells are often a manifestation of propagating waves of Ca2+. Numerical simulations with a realistic model of inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ wave trains lead to wave speeds that increase linearly at long times when (a) IP3 levels are in the range for Ca2+ oscillations, (b) a gradient of phase is established by either an initial ramp or pulse of IP3, and (c) IP3 concentrations asymptotically become uniform. We explore this phenomenon with analytical and numerical methods using a simple two-variable reduction of the De Young-Keizer model of the IP3 receptor that includes the influence of Ca2+ buffers. For concentrations of IP3 in the oscillatory regime, numerical solution of the resulting reaction diffusion equations produces nonlinear wave trains that shows the same asymptotic growth of wave speed. Due to buffering, diffusion of Ca2+ is quite slow and, as previously noted, these waves occur without appreciable bulk movement of Ca2+. Thus, following Neu and Murray, we explore the behavior of these waves using an asymptotic expansion based on the small size of the buffered diffusion constant for Ca2+. We find that the gradient in phase of the wave obeys Burgers' equation asymptotically in time. This result is used to explain the linear increase of the wave speed observed in the simulations.     

GD3/proteosome vaccines induce consistent IgM antibodies against the ganglioside GD3

The gangliosides of melanoma and other tumours of neuroectodermal origin are suitable targets for immune intervention with tumour vaccines. The optimal vaccines in current use contain ganglioside plus bacillus Calmette-Guérin and induce considerable morbidity. We have screened a variety of new adjuvants in the mouse, and describe one antigen-delivery system, proteosomes, which is especially effective. Highly hydrophobic Neisserial outer membrane proteins (OMP) form multimolecular liposome-like vesicular structures termed proteosomes which can readily incorporate amphiphilic molecules such as GD3 ganglioside. The optimal GD3/proteosome vaccine formulation for induction of GD3 antibodies in the mouse is determined. Interestingly, the use of potent immunological adjuvants in addition to proteosomes augments the IgM and IgG antibody titres against OMP in these vaccines but GD3 antibody titres are unaffected. The application of proteosomes to enhance the immune response to GD3 extends the concept of the proteosome immunopotentiating system from lipopeptides to amphipathic carbohydrate epitopes such as cell-surface gangliosides. The demonstrated safety of meningococcal OMP in humans and the data in mice presented here suggest that proteosome vaccines have potential for augmenting the immunogenicity of amphipathic tumour antigens in humans.     

Percutaneous transluminal angioplasty of an innominate artery occlusion

A middle-aged woman presented with recent-onset left hemiparesis and right subclavian steal syndrome. She was found to have an obstructed innominate artery. We successfully performed balloon angioplasty of the occluded innominate artery and encountered no complications during follow-up of currently 8 months.     

Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes

Caspases are fundamental components of the mammalian apoptotic machinery, but the precise contribution of individual caspases is controversial. CPP32 (caspase 3) is a prototypical caspase that becomes activated during apoptosis. In this study, we took a comprehensive approach to examining the role of CPP32 in apoptosis using mice, embryonic stem (ES) cells, and mouse embryonic fibroblasts (MEFs) deficient for CPP32. CPP32(ex3-/-) mice have reduced viability and, consistent with an earlier report, display defective neuronal apoptosis and neurological defects. Inactivation of CPP32 dramatically reduces apoptosis in diverse settings, including activation-induced cell death (AICD) of peripheral T cells, as well as chemotherapy-induced apoptosis of oncogenically transformed CPP32(-/-) MEFs. As well, the requirement for CPP32 can be remarkably stimulus-dependent: In ES cells, CPP32 is necessary for efficient apoptosis following UV- but not gamma-irradiation. Conversely, the same stimulus can show a tissue-specific dependence on CPP32: Hence, TNFalpha treatment induces normal levels of apoptosis in CPP32 deficient thymocytes, but defective apoptosis in oncogenically transformed MEFs. Finally, in some settings, CPP32 is required for certain apoptotic events but not others: Select CPP32(ex3-/-) cell types undergoing cell death are incapable of chromatin condensation and DNA degradation, but display other hallmarks of apoptosis. Together, these results indicate that CPP32 is an essential component in apoptotic events that is remarkably system- and stimulus-dependent. Consequently, drugs that inhibit CPP32 may preferentially disrupt specific forms of cell death.     

Biochemical basis for increased susceptibility to Cidofovir of herpes simplex viruses with altered or deficient thymidine kinase activity

It has been observed that herpes simplex virus mutants with deficient or altered thymidine kinase activity are more susceptible to Cidofovir (CDV; 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate) in tissue culture than are the parental strains. During infection of cells, the elevation of the dCTP pool by thymidine kinase mutant viruses is less than that induced by the wild-type virus. The competition between CDV diphosphate and dCTP at the viral polymerase is therefore changed in favor of CDV diphosphate, enhancing its activity.     

Adverse environmental conditions in the respiratory and medical ICU settings

Sleep deprivation and fragmentation occurring in the hospital setting may have a negative impact on the respiratory system by decreasing respiratory muscle function and ventilatory response to CO2. Sleep deprivation in a patient with respiratory failure may, therefore, impair recovery and weaning from mechanical ventilation. We postulate that light, sound, and interruption levels in a weaning unit are major factors resulting in sleep disorders and possibly circadian rhythm disruption. As an initial test of this hypothesis, we sampled interruption levels and continuously monitored light and sound levels for a minimum of seven consecutive days in a medical ICU, a multiple bed respiratory care unit (RCU) room, a single-bed RCU room, and a private room. Light levels in all areas maintained a day-night rhythm, with peak levels dependent on window orientation and shading. Peak sound levels were extremely high in all areas representing values significantly higher than those recommended by the Environmental Protection Agency as acceptable for a hospital environment. The number of sound peaks greater than 80 decibels, which may result in sleep arousals, was especially high in the intensive and respiratory care areas, but did show a day-night rhythm in all settings. Patient interruptions tended to be erratic, leaving little time for condensed sleep. We conclude that the potential for environmentally induced sleep disruption is high in all areas, but especially high in the intensive and respiratory care areas where the negative consequences may be the most severe.     

Hearing and Sj?gren's syndrome

Immune sensorineural hearing loss is manifested in several systemic immune diseases. Although hearing loss has been previously documented in patients with Sj?gren's syndrome (SS), the effect of SS on hearing is unclear. This prospective study was designed to assess the presence of hearing loss in 14 patients with SS and, if sensorineural hearing loss was present, to determine if the hearing loss was immune-mediated. Patients were evaluated with basic audiologic tests as well as for cellular immune inner ear reactivity as measured by the lymphocyte transformation test (LTT). Three patients had evidence of sensorineural hearing loss. Two patients had a positive LTT without evidence of sensorineural hearing loss. This preliminary study suggests that SS may not directly cause sensorineural hearing loss, immuno-mediated or otherwise.     

Clinically significant hearing loss in renal allograft recipients treated with intravenous erythromycin

BACKGROUND: Hearing loss is generally regarded as a rare side effect of erythromycin therapy. However, our own clinical experiences in erythromycin-treated patients led us to suspect that this complication may be more common among renal allograft recipients. The purpose of this study was to evaluate the incidence, predisposing factors, clinical characteristics, and outcomes of erythromycin-induced hearing loss among renal allograft recipients. METHODS: We reviewed medical records of renal transplant patients treated for pneumonia with intravenous erythromycin lactobionate. Patients were evaluated for the occurrence of clinically significant hearing loss (including onset, duration, and reversibility), other signs and symptoms of ototoxicity (vertigo and tinnitus), daily erythromycin dose and duration of treatment, concurrent ototoxic drug therapy, renal and hepatic function, and history of previous otic disease. RESULTS: Eleven (32%) of 34 courses of intravenous erythromycin therapy resulted in hearing loss. The incidence of hearing loss was 53% (eight of 15 courses) in patients treated with 4 g of erythromycin daily compared with 16% (three of 19 courses) among those receiving 2 g/d (P = .05). In addition, courses of erythromycin were longer in those suffering auditory toxicity (9.6 +/- 4.7 days) than in nontoxic patients (5.7 +/- 3.6 days) (P < .05). Hepatic and renal function did not differ between toxic and nontoxic patients. All episodes of erythromycin-induced hearing loss were reversible. CONCLUSIONS: We conclude that clinically significant hearing loss occurs in more than 30% of renal allograft recipients treated for pneumonia with intravenous erythromycin lactobionate. Patients who require prolonged courses of erythromycin and those treated with 4 g/d are at particular risk for the development of auditory toxicity. With prompt recognition and modification of therapy, erythromycin-induced hearing loss appears to be completely reversible.