33 research outputs found
Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions
<p>Abstract</p> <p>Background</p> <p>It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism.</p> <p>Results</p> <p>Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes.</p> <p>Conclusion</p> <p>We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems.</p
On the notion of home and the goals of palliative care
The notion of home is well known from our everyday experience, and plays a crucial role in all kinds of narratives about human life, but is hardly ever systematically dealt with in the philosophy of medicine and health care. This paper is based upon the intuitively positive connotation of the term βhome.β By metaphorically describing the goal of palliative care as βthe patientβs coming home,β it wants to contribute to a medical humanities approach of medicine. It is argued that this metaphor can enrich our understanding of the goals of palliative care and its proper objectives. Four interpretations of βhomeβ and βcoming homeβ are explored: (1) oneβs own house or homelike environment, (2) oneβs own body, (3) the psychosocial environment, and (4) the spiritual dimension, in particular, the origin of human existence. Thinking in terms of coming home implies a normative point of view. It represents central human values and refers not only to the medical-technical and care aspects of health care, but also to the moral context
Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker substudy)
Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (nβ=β110) were randomized to receive 1βg paracetamol 4Γ daily or matched placebo for 2βweeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (β₯50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9βΒ±β9.7βng/ml, placebo arm: 11.1βΒ±β5.4βng/ml, ROC-AUCβ=β0.80, 95% CI 0.71β0.89; miR-122: 15.1βΒ±β12.9fM V 4.9βΒ±β4.7fM, ROC-AUCβ=β0.83, 0.75β0.91; and GLDH: 24.6βΒ±β31.1U/l V 12.0βΒ±β11.8U/l, ROC-AUCβ=β0.66, 0.49β0.83). All biomarkers were correlated with ALT (K18 rβ=β0.68, miR-122 rβ=β0.67, GLDH rβ=β0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3βdays earlier). K18 identified the subsequent ALT increase (K18 ROC-AUCβ=β0.70, 0.59β0.80; miR-122 ROC-AUCβ=β0.60, 0.49β0.72, ALT ROC-AUCβ=β0.59, 0.48β0.70; GLDH ROC-AUCβ=β0.70, 0.50β0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice
Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome
Purpose This study aimed to develop a utility index (the
ABC-UI) from the Aberrant Behavior Checklist-Community
(ABC-C), for use in quantifying the benefit of
emerging treatments for fragile X syndrome (FXS).
Methods The ABC-C is a proxy-completed assessment of
behaviour and is a widely used measure in FXS. A subset
of ABC-C items across seven dimensions was identified to
include in health state descriptions. This item reduction
process was based on item performance, factor analysis and
Rasch analysis performed on an observational study dataset,
and consultation with five clinical experts and a
methodological expert. Dimensions were combined into
health states using an orthogonal design and valued using
time trade-off (TTO), with lead-time TTO methods used
where TTO indicated a state valued as worse than dead.
Preference weights were estimated using mean, individual
level, ordinary least squares and random-effects maximum
likelihood estimation [RE (MLE)] regression models.
Results A representative sample of the UK general public
(n = 349; mean age 35.8 years, 58.2 % female) each valued
12 health states. Mean observed values ranged from
0.92 to 0.16 for best to worst health states. The RE (MLE)
model performed best based on number of significant
coefficients and mean absolute error of 0.018. Mean utilities
predicted by the model covered a similar range to that
observed.
Conclusions The ABC-UI estimates a wide range of
utilities from patient-level FXS ABC-C data, allowing
estimation of FXS health-related quality of life impact for
economic evaluation from an established FXS clinical trial
instrument
A Low T Regulatory Cell Response May Contribute to Both Viral Control and Generalized Immune Activation in HIV Controllers
HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127dim), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected βnon-controllersβ with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (Pβ=β0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (Pβ€0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion
Bioinspired Artificial Melanosomes As Colorimetric Indicators of Oxygen Exposure
Many industries require irreversibly
responsive materials for use as sensors or detectors of environmental
exposure. We describe the synthesis and fabrication of a nontoxic
surface coating that reports oxygen exposure of the substrate material
through irreversible formation of colored spots. The coating consists
of a selectively permeable rubber film that contains the colorless
organic precursors to darkly pigmented synthetic melanin. Melanin
synthesis within the film is triggered by exposure to molecular oxygen.
The selectively permeable rubber film regulates the rate of oxygen
diffusion, enabling independent control of the sensitivity and response
time of the artificial melanosome, while preventing leaching of melanin
or its precursors