Helicobacter pylori vaccine development and use: a cost-effectiveness analysis using the Institute of Medicine Methodology

Background. Prophylactic vaccination has been suggested as a better strategy than antibiotics to control Helicobacter pylori infection. We evaluated the cost-effectiveness (CE) of H. pylori vaccine development and use in the United States and developing countries, using a method developed by the Institute of Medicine (IOM).
Methods. The IOM model includes costs of vaccine development, vaccination program, and averted medical treatments; morbidity and mortality prevented; expected efficacy and use; and proportion of disease that is vaccine-preventable. The model employs infant mortality equivalence (IME) to estimate disease burden; with IME, the societal cost of infection-related morbidity is expressed as equivalent to a specific rate of infant deaths. We tested model assumptions by univariate sensitivity analyses.
Results. In the United States, H. pylori vaccine would save 1,176 IME and would cost $58.71 million (1997 dollars) annually, yielding a CE ratio of $49,932 per IME; the health benefits would exceed all IOM-studied vaccines, even when efficacy dropped to 55%. H. pylori vaccine could be cost-saving if priced at less than $60 per course. In developing countries, H. pylori vaccine would rank unfavorably both in terms of health benefits (33,518 IME) and costs ($5,254 million). None of the changes in assumptions improved significantly the H. pylori vaccine's ranking relative to other IOM-studied vaccines.
Conclusions. Compared to other vaccines evaluated in the IOM study, H. pylori vaccine warrants public resource allocation for accelerated development and use in the United States but not for use in developing countries.     

Pollination of Picea orientalis (Pinaceae): saccus morphology governs pollen

Sacci of conifer pollen do not function primarily to increase the efficiency of wind pollination as is widely thought. Rather, they are bladders and cause pollen to float upwards in a liquid drop into the ovules. This observation is seemingly unsupported in the case of oriental spruce (Picea orientalis (L.) Link), which has saccate pollen. Ovulate cones are pendant at the time of pollination, which requires that pollen sink into the ovules. Pollen of oriental spruce floats at first but within 1-2 min sinks into the ovule. As sinking does not occur in saccate pollen of other Pinaceae, a variety of techniques was used to determine anatomical differences leading to this uncharacteristic tendency. Light, scanning electron, and confocal microscopy of the pollen surface yielded no significant appearing difference between pollen of oriental spruce and white spruce. However, transmission electron microscopy of freeze-fixed/freeze-substituted hydrated pollen revealed that the ektexine of oriental spruce pollen sacci is porous compared to that of white spruce. Confocal microscopy allowed examination of pollen hydration dynamics. Water enters pollen at the distal pole between sacci, and resulting rapid expansion of the tube cell forces air out of the saccate space. White spruce pollen remains buoyant because of enclosed air pockets in the saccus ektexine. Evolutionary change in pollen wall anatomy with resultant loss of saccus function is correlated with a change in ovulate strobilus orientation at pollination in oriental spruce. A suite of characters interact in the conifer pollination mechanism, and concerted change in these characters may lead to speciation.     

Size and stability of vertebrate leks

Lek size varies greatly among lekking species. At present there is no explicit theoretical explanation for this diversity. We extend an existing model of optimal lek size that incorporates female mating preferences and male-male contest competition. The model shows that variation in lek size is predicted by the interaction between lek size, overall copulation rate and the proportion of copulations accruing to males of different rank. In species where females prefer to mate on the largest leks and high-ranking males are able to monopolize females irrespective of the size of the lek, the maximum lek size will be large. Conversely, in species where females show weak preference for mating on large leks or increasing lek size quickly results in scramble competition, the maximum lek size will be smaller. Thus, differences between species in lek size may be due largely to differences in the extent to which high-ranking males can monopolize mating opportunities. Leks become unstable and break down when high-ranking males can no longer get their 'expected' copulation success. Therefore, the mechanism that generates male clustering, that is, sexual parasitism of high-ranking males by subordinates, also sets a limit to the largest stable lek size. Copyright 1999 The Association for the Study of Animal Behaviour.     

Postnatal ontogeny of glucose homeostasis and insulin action in sheep

Glucose tolerance declines with maturation and aging in several species, but the time of onset and extent of changes in insulin sensitivity and insulin secretion and their contribution to changes in glucose tolerance are unclear. We therefore determined the effect of maturation on glucose tolerance, insulin secretion, and insulin sensitivity in a longitudinal study of male and female sheep from preweaning to adulthood, and whether these measures were related across age. Glucose tolerance was assessed by intravenous glucose tolerance test (IVGTT, 0.25 g glucose/kg), insulin secretion as the integrated insulin concentration during IVGTT, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (2 mU insulin.kg(-1).min(-1)). Glucose tolerance, relative insulin secretion, and insulin sensitivity each decreased with age (P < 0.001). The disposition index, the product of insulin sensitivity, and various measures of insulin secretion during fasting or IVGTT also decreased with age (P < 0.001). Glucose tolerance in young adult sheep was independently predicted by insulin sensitivity (P = 0.012) and by insulin secretion relative to integrated glucose during IVGTT (P = 0.005). Relative insulin secretion before weaning was correlated positively with that in the adult (P = 0.023), whereas glucose tolerance, insulin sensitivity, and disposition indexes in the adult did not correlate with those at earlier ages. We conclude that glucose tolerance declines between the first month of life and early adulthood in the sheep, reflecting decreasing insulin sensitivity and absence of compensatory insulin secretion. Nevertheless, the capacity for insulin secretion in the adult reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment.     

Tricyclic pyridones as functionally selective human GABAA alpha 2/3 receptor-ion channel ligands

A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the alpha(3) over the alpha(1) containing subtype of the human GABA(A) receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam.     

Predictors of mortality of patients with acute respiratory failure secondary to chronic obstructive pulmonary disease admitted to an intensive care unit: A one year study

Background

Patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) commonly require hospitalization and admission to intensive care unit (ICU). It is useful to identify patients at the time of admission who are likely to have poor outcome. This study was carried out to define the predictors of mortality in patients with acute exacerbation of COPD and to device a scoring system using the baseline physiological variables for prognosticating these patients.

Methods

Eighty-two patients with acute respiratory failure secondary to COPD admitted to medical ICU over a one-year period were included. Clinical and demographic profile at the time of admission to ICU including APACHE II score and Glasgow coma scale were recorded at the time of admission to ICU. In addition, acid base disorders, renal functions, liver functions and serum albumin, were recorded at the time of presentation. Primary outcome measure was hospital mortality.

Results

Invasive ventilation was required in 69 patients (84.1%). Fifty-two patients survived to hospital discharge (63.4%). APACHE II score at the time of admission to ICU {odds ratio (95 % CI): 1.32 (1.138–1.532); p < 0.001} and serum albumin (done within 24 hours of admission) {odds ratio (95 % CI): 0.114 (0.03-0.432); p = 0.001}. An equation, constructed using the adjusted odds ratio for the two parameters, had an area under the ROC curve of 91.3%. For the choice of cut-off, sensitivity, specificity, positive and negative predictive value for predicting outcome was 90%, 86.5%, 79.4% and 93.7%.

Conclusion

APACHE II score at admission and SA levels with in 24 hrs after admission are independent predictors of mortality for patients with COPD admitted to ICU. The equation derived from these two parameters is useful for predicting outcome of these patients.     

Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig

Maternal nutrient restriction and impaired fetal growth are associated with postnatal insulin resistance, hyperinsulinemia, and glucose intolerance in humans but not consistently in other species, such as the rat or sheep. We therefore determined the effect of mild (85% ad libitum intake/kg body wt) or moderate (70% ad libitum intake/kg body wt) maternal feed restriction throughout pregnancy on glucose and insulin responses to an intravenous glucose tolerance test (IVGTT) in the young adult guinea pig. Maternal feed restriction reduced birth weight (mild and moderate: both P < 0.02) in male offspring. Moderate restriction increased plasma glucose area under the curve (P < 0.04) and decreased the glucose tolerance index (K(G)) (P < 0.02) during the IVGTT in male offspring compared with those of mildly restricted but not of ad libitum-fed mothers. Moderate restriction increased fasting plasma insulin (P < 0.04, adjusted for litter size) and the insulin response to IVGTT (P < 0.001), and both moderate and mild restriction increased the insulin-to-glucose ratio during the IVGTT (P < 0.003 and P < 0.02) in male offspring. When offspring were classed into tertiles according to birth weight, glucose tolerance was not altered, but fasting insulin concentrations were increased in low compared with medium birth weight males (P < 0.03). The insulin-to-glucose ratio throughout the IVGTT was increased in low compared with medium (P < 0.01) or high (P < 0.05) birth weight males. Thus maternal feed restriction in the guinea pig restricts fetal growth and causes hyperinsulinemia in young adult male offspring, suggestive of insulin resistance. These findings suggest that mild to moderate prenatal perturbation programs postnatal glucose homeostasis adversely in the guinea pig, as in the human.     

Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice

Clearance rates for serotonin (5-HT) in heterozygote (+/-) and homozygote (-/-) serotonin transporter (5-HTT) knockout (KO) mice have not been determined in vivo. Moreover, the effect of selective serotonin reuptake inhibitors (SSRIs) on 5-HT clearance in these mice has not been examined. In this study, the rate of clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus of anesthetized mice using high-speed chronoamperometry. Compared with wild-type mice, the maximal rate of 5-HT clearance from extracellular fluid (ECF) was decreased in heterozygotes and more markedly so in KO mice. Heterozygote mice were more sensitive to the 5-HT uptake inhibitor, fluvoxamine, resulting in longer clearance times for 5-HT than in wild-type mice; as expected, the KO mice were completely unresponsive to fluvoxamine. There were no associated changes in norepinephrine transporter density, nor was there an effect of the norepinephrine uptake inhibitor, desipramine, on 5-HT clearance in any genotype. Thus, adaptive changes in the norepinephrine transport system do not occur in the CA3 region of hippocampus as a consequence of 5-HTT KO. These data highlight the potential of the heterozygote 5-HTT mutant mice to model the dynamic in vivo consequences of the human 5-HTT polymorphism.