Patterns of mortality in patients with motor neurone disease

OBJECTIVE: Motor neurone disease (MND) is a rapidly fatal condition with survival of less than 4 years. Patients can deteriorate quickly in the preterminal stages resulting in inappropriate resuscitation or admission to intensive care units (ICU) or accident and emergency (A & E). MATERIAL AND METHODS: We looked at patterns of mortality with emphasis on the place of death. A retrospective study was performed of all patients attending an MND clinic, who had died within a 10-year period. RESULTS: Of 179 patients (63 female), 81 patients (45%) died at home, in a hospice or in a nursing home. Sixty-five patients (36%) died in hospital (11 in ICU or A & E). Nine of the latter were previously known to have MND and six admissions were probably avoidable. Most ward patients died of respiratory causes and were treated conservatively. CONCLUSION: The proportion of patients dying in A & E or ICU was small but could have been reduced further. A number of those who died on the wards could probably have been managed conservatively at home. Older patients and those with bulbar disease had a poorer prognosis.     

Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation

In this study, food-deprived (18 h) control rats and rats with alloxan-induced diabetes were orally administered saline or the amino acid leucine to assess whether it regulates protein synthesis independently of a change in serum insulin concentrations. Immediately after leucine administration, diabetic rats were infused with insulin (0.0, 4.0, or 20 pmol small middle dot min(-1) small middle dot kg(-1)) for 1 h to examine the role of the hormone in the protein synthetic response to leucine. In control rats, leucine stimulated protein synthesis by 58% and increased phosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E-binding protein (BP)-1, 4E-BP1, fivefold. Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). Diabetes attenuated protein synthesis compared with control rats. Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. Skeletal muscle protein synthesis was stimulated in diabetic rats infused with insulin, but rates of synthesis remained less than values in nondiabetic controls that were administered leucine. Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. The results suggest that leucine enhances protein synthesis in skeletal muscle through both insulin-dependent and -independent mechanisms. The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. In contrast, the insulin-independent effect on protein synthesis is mediated by an unknown mechanism.     

A sixteen-year epidemiological profile of a pediatric intensive care unit,Brazil

OBJECTIVE: To review epidemiological data from patients admitted to a Pediatric Intensive Care Unit (PICU), Brazil, and to compare them to medical aspects associated to disease severity and mortality. Also, to profile these patients, including demographic data, disease prevalence, mortality rates and associated factors. METHODS: Retrospective data were collected from all patients admitted in a PICU of a university hospital between 1978 and 1994. Data were presented as percentages and compared using Chi-square, and calculating the relative risk (RR) with a 95% confidence interval, p<0.05. RESULTS: Of 13, 101 patients selected, most of them were boys (58.4%), younger than 12 months of age (40.4%), well-nourished (69.5%), and with clinical disease (73.1%). The general mortality rate was 7.4%. Patients aged less than 12 months showed a RR of 1.86 (CI 1.65 - 2.10; p<0.0001), while the RR of malnutrition was 2.98 (CI 2.64 - 3.36; p<0.0001). CONCLUSIONS: The epidemiological survey showed that the mortality is higher in malnourished children younger than 12 months of age. Sepsis was the most main cause of death.     

The Brighton Collaboration: addressing the need for standardized case definitions of adverse events following immunization (AEFI)

To further scientific progress of immunization safety, comparability of data from clinical trials and surveillance systems is essential. Comparability requires the availability of standardized case definitions for adverse events following immunization (AEFI) and guidelines for case determination, recording and data presentation. METHOD: International collaborative working groups, consisting of professional volunteers from developed and developing countries, conduct systematic literature reviews to develop 50-100 AEFI definitions. Case definitions are finalized after a comment period by a reference group consisting of organizations concerned with immunization safety, and will be disseminated via the world-wide-web and other means for free world-wide use. RESULTS: Literature reviews yielded substantial diversity in data collection and presentation. We have developed standardized case definitions together with guidelines for use in clinical trials and surveillance systems. CONCLUSIONS: Diversity in safety methods leads to considerable loss of scientific information. We have built the necessary international network of currently about 300 participants from patient care, public health, scientific, pharmaceutical, regulatory and professional organizations to develop and assess standardized AEFI case definitions and guidelines. Evaluation studies, global implementation, ongoing definition development and a continuously growing network will be essential for the success of the collaboration.     

Regulation of in situ skeletal muscle arteriolar tone: interactions between two parameters

OBJECTIVE: The growing understanding of the complexity of mechanisms regulating arteriolar tone demands that a systematic determination of how these processes interact to alter diameter be undertaken. This study examined how five mediators of skeletal muscle distal arteriolar tone [adenosine concentration, oxygen content, alpha-adrenergic activation (norepinephrine), intravascular pressure and wall shear rate], taken two parameters at a time, interact to regulate vessel diameter. METHODS: The reactivity of distal arterioles of in situ rat cremaster muscle after alterations in each of the above mediators was assessed. In addition, arteriolar responses to all two-parameter combinations were evaluated to determine the effect of altered environment on vascular reactivity to stimuli. RESULTS: Arteriolar dilation to adenosine was unaltered by changes in other parameters. In contrast, wall shear rate-induced arteriolar dilation was impaired by 60-88% after increases in the other parameters. Myogenic reactivity was reduced by 28% with elevated O(2) and by 65% with norepinephrine (because of vessel closure) and was impaired by 89% with elevated adenosine. O(2)-induced arteriolar reactivity was impaired by 56% with increased adenosine and by 44% with increased norepinephrine concentration but was largely unaffected by elevated intravascular pressure. Adrenergic reactivity was attenuated with elevated intravascular pressure (by 69%) and O(2) (by 54%) because of vessel closure but was unaltered with elevated adenosine. CONCLUSIONS: These data suggest that (1) individual mediators contributing to the regulation of arteriolar tone exist within a hierarchy of importance and (2) mechanisms regulating arteriolar tone can be impacted by unidentified alterations in other processes. Ongoing investigation into interactions between multiple processes regulating arteriolar tone will allow for a more integrated understanding of how microvessels regulate their diameter.     

Caffeine modulates P50 auditory sensory gating in healthy subjects.

The P50 suppression paradigm is an index of sensory gating assumed to reflect an inhibitory process. Adenosine is a neuromodulator with mostly inhibitory activity that is released by physiological stimuli and can be blocked by non-selective adenosine receptor antagonists such as theophylline and caffeine. A previous study showed that a single dose of theophylline decreased P50 suppression in healthy volunteers. Here we investigated the effect of caffeine (0, 100, 200 and 400 mg p.o.) on P50 sensory gating in 24 healthy volunteers (15 habitual caffeine high-users and 9 low-users). The 200 and 400 mg doses reduced P50 gating, whereas 100 mg produced a non-significant effect. The effect of caffeine was independent of gender and habitual caffeine intake. High caffeine users also showed baseline differences, with lower S(2) amplitudes compared to low-users. These results reinforce the participation of adenosine in the modulation of P50 sensory gating and suggest that caffeine ingestion should be controlled for in the P50 sensory gating paradigm.