1,069 research outputs found
Interstitial fluid glucose is not just a shifted-in-time but a distorted mirror of blood glucose: Insight from an in Silico study
Glucose sensors measure glucose concentration in the interstitial fluid (ISF), remote from blood. ISF glucose is well known to be "delayed" with respect to blood glucose (BG). However, ISF glucose is not simply a shifted-in-time version of BG but exhibits a more complex pattern.
METHODS:
To gain insight into this problem, one can use linear systems theory. However, this may lose a more clinical readership, thus we use simulation and two case studies to convey our thinking in an easier way. In particular, we consider BG concentration measured after meal and exercise in 12 healthy volunteers, whereas ISF glucose is simulated using a well-accepted model of blood-ISF glucose kinetics, which permits calculation of the equilibration time, a parameter characterizing the system. Two metrics are defined: blood and ISF glucose difference at each time point and time to reach the same glucose value in blood and ISF.
RESULTS:
The simulation performed and the two metrics show that the relationship between blood-ISF glucose profiles is more complex than a pure shift in time and that the pattern depends on both equilibration time and BG.
CONCLUSIONS:
In this in silico study, we have illustrated, with simple case studies, the meaning of the of ISF glucose with respect to BG. Understanding that ISF glucose is not just a shifted-in-time version but a distorted mirror of BG is important for a correct use of continuous glucose monitoring for diabetes management
Stretch- and carbachol-induced ATP release from bladder wall preparations of young and aged mice
Aims
Bladder wall stretch increases tissue tension and releases adenosine 5'âtriphosphate (ATP) as part of a transduction process to sense bladder filling. Aging is associated with bladder fibrosis to produce a stiffer bladder wall: this may augment ATP release and contribute to ageâdependent urgency. Muscarinic agonists also release ATP and present a potential target for antimuscarinic agents, but its ageâdependency is unknown. This study aimed, in young and old mice, to: (a) quantify the relationship between bladder wall stiffness and stretchâdependent ATP release and; (b) characterize muscarinic agonistâdependent release.
Methods
ATP release from young (9â12 weeks) and aged (24 months) mouse bladder wall was measured in vitro, with a luciferinâluciferase assay, after stretch or carbachol exposure. Bladder wall stiffness, measured simultaneously during stretch, was compared to histological proportions of connective tissue and detrusor muscle.
Results
With young mice, stretchâactivated ATP release required an intact mucosa and was positively associated with wall stiffness. ATP release by carbachol was about fourâfold greater compared to stretch. With aged mice: ATP release varied a hundredâfold and no association with stiffness; carbachol release diminished; connective tissue and mucosa thickness increased.
Conclusions
With young mice, stretch, or muscarinic agonists potently induce bladder wall ATP release. Stretchâdependent release is proportional to bladder wall stiffness, independent of the extent of stretch. With aged mice dependence of stretchâactivated ATP release with stiffness was lost. The huge variability of release suggests that aged mice do not form a homogenous cohort and may underlie the heterogeneity in bladder filling sensations.</p
Nurses' Work Environment and Spirituality: A Descriptive Study
Quality of care is a major health concern in the hospital setting. A work environment thatsupports professional nursing as well as the spirituality of nurses, or the meaning/purpose nurses find intheir work may contribute to quality of patient care. Yet, little is known about the nursing workenvironment and even less about the spirituality of nurses. Thus, the aims of this study were to measuremedical-surgical nursesâ perceived professional work environment score and perceived spiritual well-beingscore and determine if the two instruments are related. This cross-sectional survey consisted of aconvenience sample of 68 nurses who completed the Professional Practice Environment Scale (PPE) andSpiritual Well-Being Scale (SWB) on the hospital website during working hours. Several PPE subscalescores differed significantly among the various clinical units. As the nurseâs age, and years of clinicalexperience increased, specific PPE subscale scores also increased. The nursesâ mean SWB scores were allwithin the moderate range and did not differ significantly among the clinical units. The overall PPE andSWB scores were not significantly correlated. Nursing administrators can use the PPE scores from thisstudy to address the specific needs of individual clinical units. Older and more experienced nurses mayserve as resources for younger, less experienced nurses. Both instruments can be administered repeatedlyover time to monitor trends. Based on the SWB data, nurses in this study reported average levels ofspiritual well-being. However, there is a need to learn more about the specific spiritual needs of nurses.Spirituality of nurses as well as the nurseâs work environment are separate concepts that each merit furtherinvestigation and may add to the knowledge base for increased quality patient care
Insulin doseresponse curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes.
To determine whether the insulin dose-response curves for suppression of endogenous glucose production (EGP) and stimulation of splanchnic glucose uptake (SGU) differ in nondiabetic humans and are abnormal in type 2 diabetes, 14 nondiabetic and 12 diabetic subjects were studied. Glucose was clamped at Ďł9.5 mmol/l and endogenous hormone secretion inhibited by somatostatin, while glucagon and growth hormone were replaced by an exogenous infusion. Insulin was progressively increased from Ďł150 to Ďł350 and Ďł700 pmol/l by means of an exogenous insulin infusion, while EGP, SGU, and leg glucose uptake (LGU) were measured using the splanchnic and leg catheterization methods, combined with a [3-3 H]glucose infusion. In nondiabetic subjects, an increase in insulin from Ďł150 to Ďł350 pmol/l resulted in maximal suppression of EGP, whereas SGU continued to increase (P < 0.001) when insulin was increased to Ďł700 pmol/l. In contrast, EGP progressively decreased (P < 0.001) and SGU progressively increased (P < 0.001) in the diabetic subjects as insulin increased from Ďł150 to Ďł700 pmol/l. Although EGP was higher (P < 0.01) in the diabetic than nondiabetic subjects only at the lowest insulin concentration, SGU was lower (P < 0.01) in the diabetic subjects at all insulin concentrations tested. On the other hand, in contrast to LGU and overall glucose disposal, the increment in SGU in response to both increments in insulin did not differ in the diabetic and nondiabetic subjects, implying a right shifted but parallel dose-response curve. These data indicate that the dose-response curves for suppression of glucose production and stimulation of glucose uptake differ in nondiabetic subjects and are abnormal in people with type 2 diabetes. Taken together, these data also suggest that agents that enhance SGU in diabetic patients (e.g. glucokinase activators) are likely to improve glucose tolerance. Diabete
Characterisation of nerveâmediated ATP release from bladder detrusor muscle and its pathological implications
Background and Purpose.
To characterise the molecular mechanisms that determine variability of atropineâresistance of nerveâmediated contractions in human and guineaâpig detrusor smooth muscle
Experimental Approach.
Atropineâresistance of nerveâmediated contractions, and the role of P2X1 receptors, was measured in isolated preparations from guineaâpigs and also humans with or without overactive bladder syndrome, from which the mucosa was removed. Nerveâmediated ATP release was measured directly with amperometric ATPâsensitive electrodes. EctoâATPase activity of guineaâpig and human detrusor samples was measured in vitro by measuring the concentrationâdependent rate of ATP breakdown. The transcription of ectoâATPase subtypes in human samples was measured by qPCR.
Key Results
Atropine resistance was greatest in guineaâpig detrusor, absent in human tissue from normallyâfunctioning bladders and intermediate in human overactive bladder. Greater atropine resistance correlated with reduction of contractions by the ATPâdiphosphoâhydrolase apyrase, directly implicating ATP in their generation. EâNTPDaseâ1 was the most abundantly transcribed ectoâATPase of those tested and transcription was reduced in tissue from human overactive, compared to normal, bladders. EâNTPDaseâ1 enzymatic activity was inversely related to the magnitude of atropine resistance. Nerveâmediated ATP release was continually measured and varied with stimulation frequency over the range 1â16 Hz.
Conclusion and Implications
Atropineâresistance in nerveâmediated detrusor contractions is due to ATP release and its magnitude is inversely related to EâNTPDaseâ1 activity. ATP is released under different stimulation conditions compared to acetylcholine that implies different routes for their release</p
New targets for overactive bladder-ICI-RS 2109
Aim: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. Methods: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. Results: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotideâdependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1, TRPV4, TRPA1, and TRPM4) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+-activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathwayâthe canonical fibrosis pathway. Conclusions: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor
Large-scale automated analysis of news media: A novel computational method for obesity policy research: Novel Media Analysis of Obesity Framing
Analyzing news media allows obesity policy researchers to understand popular conceptions about obesity, which is important for targeting health education and policies. A persistent dilemma is that investigators have to read and manually classify thousands of individual news articles to identify how obesity and obesity-related policy proposals may be described to the public in the media. We demonstrate a novel method called âautomated content analysisâ that permits researchers to train computers to âreadâ and classify massive volumes of documents
Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia
Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children
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