Caring for the dying at home: companions on the journey. Keri Thomas. (316 pages, {pound}27.95.) Radcliffe Medical Press Ltd, 2003. ISBN 1-85775-946-X

Those who are asked where they would prefer to die are muchmore likely to elect to die at home. Yet it is not an easy questionto ask and, because of this, it is very easy to find an excusefor postponing the asking. A central aim of this intensely usefulbook is to     

Perinatal group B streptococcal disease

Group B streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis. Despite optimal treatment of GBS-infected neonates it is associated with significant morbidity and mortality, and prevention strategies are required. As disease occurs rapidly, and is often evident at birth or within 12 hours of birth, antibiotics must be given prior to delivery, and when administered early enough, and at the correct doses, they will prevent the majority of early-onset GBS cases. Prevention is therefore in the hands of obstetricians and midwives. Women at higher risk of delivering infected infants can be identified through one of two strategies: the presence of one or more clinical risk factors, or the presence of GBS on lower vaginal/rectal swabs obtained late in pregnancy. Decisions on which strategy to use will depend on a number of factors. A swab-based approach appears to have higher efficacy but is likely to lead to more antibiotic exposure.     

An approach for evaluating the effects of dietary fiber polysaccharides on the human gut microbiome and plasma proteome

Increases in snack consumption associated with Westernized lifestyles provide an opportunity to introduce nutritious foods into poor diets. We describe two 10-wk-long open label, single group assignment human studies that measured the effects of two snack prototypes containing fiber preparations from two sustainable and scalable sources; the byproducts remaining after isolation of protein from the endosperm of peas and the vesicular pulp remaining after processing oranges for the manufacture of juices. The normal diets of study participants were supplemented with either a pea- or orange fiber-containing snack. We focused our analysis on quantifying the abundances of genes encoding carbohydrate-active enzymes (CAZymes) (glycoside hydrolases and polysaccharide lyases) in the fecal microbiome, mass spectrometric measurements of glycan structures (glycosidic linkages) in feces, plus aptamer-based assessment of levels of 1,300 plasma proteins reflecting a broad range of physiological functions. Computational methods for feature selection identified treatment-discriminatory changes in CAZyme genes that correlated with alterations in levels of fiber-associated glycosidic linkages; these changes in turn correlated with levels of plasma proteins representing diverse biological functions, including transforming growth factor type β/bone morphogenetic protein-mediated fibrosis, vascular endothelial growth factor-related angiogenesis, P38/MAPK-associated immune cell signaling, and obesity-associated hormonal regulators. The approach used represents a way to connect changes in consumer microbiomes produced by specific fiber types with host responses in the context of varying background diets.

Advances in our understanding of the role of the gut microbiome in regulating many aspects of human physiology hold the promise of evolving our view of human nutrition by establishing mechanistic connections between the foods we consume and how they affect health status. One manifestation of this effort is a series of studies, performed on well-phenotyped cohorts, that seek to relate features of gut microbial community composition (organisms, genes), dietary practices, and pre- and postprandial cardiometabolic responses to test meals (1–4). A key question raised by these initiatives relates to the nature of the “bioactive” components of foods. Specifically, what are the nutrients utilized by various gut community members or microbiome-encoded metabolic pathways? What products are produced by biotransformation of these nutrients? How are these products linked to specific host physiologic (or pathophysiologic) processes?Plant-derived dietary fibers represent a “poster child” for these efforts and illustrate the formidable challenges faced. The health benefits of dietary fibers are widely known, as is their inadequate representation in Western diets. However, natural fibers are structurally complex and highly diverse. They contain numerous, typically undefined polysaccharide structures and largely unspecified protein, lipid, and small molecule constituents. Their composition varies as a function of their origin (food staple and cultivar), the different methods employed to recover them from these sources, as well as the different techniques used to incorporate them into processed foods with acceptable organoleptic properties (5). Moreover, analyzing the host effects of metabolism of different fibers is confounded by the fact that there is substantial intra- and interpersonal variation in microbiome configuration (6, 7).Snacking is becoming an ever more dominant feature of daily life worldwide and thus provides an opportunity to introduce nutritious ingredients, such as fibers, into diets. However, obtaining structure-activity relationships for specific fiber types and their corresponding targets in the gut community is foundational for designing snack foods that evoke and/or reinforce microbiome responses that are beneficial to the host.Degradation of dietary polysaccharides is a function primarily performed by bacterial carbohydrate-active enzymes (CAZymes). The gut microbiome harbors tens of thousands of CAZyme genes belonging to at least 136 glycoside hydrolase (GH) and 29 polysaccharide lyase (PL) families [extrapolated and updated from El Kaoutari et al. (8)]. In contrast, the human genome only contains 98 GH and no PL genes (9), of which <20% contribute to the processing of dietary glycans.In the current study, we test the effects of dietary supplementation with two snack food prototypes, one containing pea fiber and the other orange fiber, in two pilot studies of overweight and obese individuals consuming their normal, unrestricted diets. Our strategy was to focus on fiber-associated changes in the abundances of microbial GH and PL genes to determine whether responses to the pea or orange fiber prototypes in the gut microbiome and host are decipherable against a background of varying dietary practices and starting microbiome configurations. Higher order singular value decomposition (10) was utilized as a feature selection tool to identify treatment-discriminating changes in GH and PL gene representation. Mass spectrometric assays of the levels of fecal glycan structures (glycosidic linkages) were subsequently performed and the results were correlated with changes in the abundances of treatment-discriminating GH and PL genes with known or predicted substrate specificities. Our analysis concluded by measuring changes in levels of 1,305 plasma proteins in each study participant as a function of fiber treatment and applying computational tools to identify links between these microbiome and plasma proteome changes in response to fiber consumption. Our results provide an approach, using pilot human studies, for selecting specific fiber preparations, plus informative microbiome and host biomarkers, that can be advanced to proof-of-concept clinical trials which assess their capacity for precise manipulation of microbiome and host features.     

Review: Astrocytes in Alzheimer's disease and other age‐associated dementias: a supporting player with a central role

Astrocytes have essential roles in the central nervous system and are also implicated in the pathogenesis of neurodegenerative disease. Forming non‐overlapping domains, astrocytes are highly complex cells. Immunohistochemistry to a variety of proteins can be used to study astrocytes in tissue, labelling different cellular components and sub‐populations, including glial fibrillary acidic protein, ALDH1L1, CD44, NDRG2 and amino acid transporters, but none of these labels the entire astrocyte population. Increasing heterogeneity is recognized in the astrocyte population, a complexity that is relevant both to their normal function and pathogenic roles. They are involved in neuronal support, as active components of the tripartite synapse and in cell interactions within the neurovascular unit (NVU), where they are essential for blood–brain barrier maintenance and neurovascular coupling. Astrocytes change with age, and their responses may modulate the cellular effects of neurodegenerative pathologies, which alone do not explain all of the variance in statistical models of neurodegenerative dementias. Astrocytes respond to both the neurofibrillary tangles and plaques of Alzheimer's disease, to hyperphosphorylated tau and Aβ, eliciting an effect which may be neuroprotective or deleterious. Not only astrocyte hypertrophy, in the form of gliosis, occurs, but also astrocyte injury and atrophy. Loss of normal astrocyte functions may contribute to reduced support for neurones and dysfunction of the NVU. Understanding how astrocytes contribute to dementia requires an understanding of the underlying heterogeneity of astrocyte populations, and the complexity of their responses to pathology. Enhancing the supportive and neuroprotective components of the astrocyte response has potential translational applications in therapeutic approaches to dementia.     

Comparison of the effects of pentagastrin and meal-stimulated gastrin on plasma calcitonin in normal man

We compared the effects of exogenous pentagastrin and meal-stimulated gastrin on plasma immunoreactive calcitonin (iCT) in various studies of 13 normal adult men. Bolus intravenous injection of pentagastrin (0.5 μg/kg) produced increases of iCT in 8 of 9 men. There was a linearly increasing response of iCT concentrations to increasing doses of pentagastrin (0.0625, 0.125, 0.25, and 0.5 μg/kg) and to achieved serum immunoreactive pentagastrin concentrations (r=0.72, P<0.01). To determine the effects of endogenous gastrin upon peripheral iCT concentrations, we measured serum immunoreactive gastrin (iG) and plasma iCT in four men at frequent intervals for 240 min after ingestion of low-(100 mg) and high- (400 mg) calcium meals. Serum iG increased in all subjects, with a peak at ～30 min. However, plasma iCT levels were unchanged from basal throughout the study. The increase of pentagastrin (0.3 pmol/ml) which caused a barely detectable increase of iCT was five-to tenfold greater than the mean maximal increases of gastrin after low- and high-calcium meals (0.04 and 0.06 pmol/ml, respectively). These results suggest that increases of plasma iCT concentrations after administration of pentagastrin in man reflect pharmacologic phenomena and that postprandial gastrin secretion may be insufficient to affect peripheral iCT concentrations.     

Genetic and environmental influences on the rate of progression to alcohol dependence in young women

Background: The development of alcohol dependence (AD) involves transitions through multiple stages of drinking behaviors and is shaped by both heritable and environmental influences. We attempted to capture this dynamic process by characterizing genetic and environmental contributions to the rate at which women progressed through 3 significant transitions along the pathway to AD: nonuse to initiation, initiation to onset of first alcohol‐related problem, and first problem to onset of AD. Methods: The sample consisted of 3,546 female twins from the Missouri Adolescent Female Twin Study. Participants ranged in age from 18 to 29 years. Retrospective reports of alcohol use histories were collected by telephone diagnostic interview and transition times between drinking milestones were coded ordinally. Standard genetic analyses were conducted in Mx to derive a trivariate model that provided estimates of genetic and environmental influences that were common as well as specific to the 3 transition times. Results: Heritable influences were found for rate of progression across all 3 transitions, accounting for 30 to 47% of the variance in transition times. Shared environmental contributions were evident only in rate of progression from nonuse to initiation (i.e., age at first drink). Heritable contributions to the rate of movement through successive drinking milestones were attributable to a common factor, whereas environmental influences were transition‐specific. Conclusions: The current study is unique in its use of a genetically informative design to document the rate of movement between drinking milestones in a female sample and to examine genetic contributions to multiple transition times over the course of AD development. Results indicate that an earlier report of heritability for males in rate of progression from regular drinking to AD generalizes to women and to other alcohol stage transitions. Findings also suggest the need to consider stage‐specific environmental contributions to alcohol outcomes in developing interventions.