Decision and Discovery in Defining “Disease”

This version (May 17, 2005) was published in its final form as: Schwartz PH. Decision and discovery in defining 'disease'. In: Kincaid H, McKitrick J, editors. Establishing medical reality: essays in the metaphysics and epistemology of biomedical science. Dordrecht: Springer; 2007. p. 47-63. http://dx.doi.org/10.1007/1-4020-5216-2_5The debate over how to analyze the concept of disease has often centered on the question of whether to include a reference to values, in particular the ‘disvalue’of diseases, or whether to avoid such notions. ‘Normativists,’such as King ([1954], 1981) and Culver and Gert (1982) emphasize the undesirability of diseases, while ‘Naturalists,’ most prominently Christopher Boorse (1977, 1987, 1997), instead require just the presence of biological dysfunction. The debate between normativism and naturalism often deteriorates into stalemate, with each side able to point out significant problems with the other. It starts to look as if neither approach can work. In this paper, I argue that the standoff stems from deeply questionable assumptions that have been used to formulate the opposing positions and guide the debate. In the end, I propose an alternative set of guidelines that offer a more constructive way to devise and compare theories

Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting

We present an analytical method to quantify clustering in super-resolution localization images of static surfaces in two dimensions. The method also describes how over-counting of labeled molecules contributes to apparent self-clustering and how the effective lateral resolution of an image can be determined. This treatment applies to clustering of proteins and lipids in membranes, where there is significant interest in using super-resolution localization techniques to probe membrane heterogeneity. When images are quantified using pair correlation functions, the magnitude of apparent clustering due to over-counting will vary inversely with the surface density of labeled molecules and does not depend on the number of times an average molecule is counted. Over-counting does not yield apparent co-clustering in double label experiments when pair cross-correlation functions are measured. We apply our analytical method to quantify the distribution of the IgE receptor (Fc{\epsilon}RI) on the plasma membranes of chemically fixed RBL-2H3 mast cells from images acquired using stochastic optical reconstruction microscopy (STORM) and scanning electron microscopy (SEM). We find that apparent clustering of labeled IgE bound to Fc{\epsilon}RI detected with both methods arises from over-counting of individual complexes. Thus our results indicate that these receptors are randomly distributed within the resolution and sensitivity limits of these experiments.Comment: 22 pages, 5 figure

Urinary C-Peptide of Insulin as a Non-Invasive Marker of Nutritional Status: Some Practicalities

Nutritional status is a critical element of many aspects of animal ecology, but has proven difficult to measure non-invasively in studies of free-ranging animals. Urinary C-peptide of insulin (UCP), a small polypeptide cleaved in an equimolar ratio from proinsulin when the body converts it to insulin, offers great promise in this regard, and recent studies of several non-human primate species have utilized it with encouraging results. Despite this, there are a number of unresolved issues related to the collection, processing, storage and transport of samples. These include: contamination of samples on collection (most commonly by dirt or faeces), short-term storage before returning to a field station, differences in processing and long-term storage methods (blotting onto filter paper, freezing, lyophilizing), and for frozen samples, transportation while keeping samples frozen. Such issues have been investigated for urine samples in particular with respect to their effects on steroid hormone metabolites, but there has been little investigation of their effects on UCP measurement. We collected samples from captive macaques, and undertook a series of experiments where we systematically manipulated samples and tested the effects on subsequent UCP measurements. We show that contamination of urine samples by faeces led to a decrease in UCP levels by >90%, but that contamination with dirt did not have substantial effects. Short-term storage (up to 12 hours) of samples on ice did not affect UCP levels significantly, but medium-term storage (up to 78 hours) did. Freezing and lyophilization for long-term storage did not affect UCP levels, but blotting onto filter paper did. A transportation simulation showed that transporting frozen samples packed in ice and insulated should be acceptable, but only if it can be completed within a period of a few days and if freeze-thaw can be avoided. We use our data to make practical recommendations for fieldworkers

On the universality of thermodynamics and η/s ratio for the charged Lovelock black branes

Abstract: We investigate general features of charged Lovelock black branes by giving a detailed description of geometrical, thermodynamic and holographic properties of charged Gauss-Bonnet (GB) black branes in five dimensions. We show that when expressed in terms of effective physical parameters, the thermodynamic behaviour of charged GB black branes is completely indistinguishable from that of charged Einstein black branes. Moreover, the extremal, near-horizon limit of the two classes of branes is exactly the same as they allow for the same AdS2 × R3, near-horizon, exact solution. This implies that, although in the UV the associated dual QFTs are different, they flow in the IR to the same fixed point. The calculation of the shear viscosity to entropy ratio η/s confirms these results. Despite the GB dual plasma has in general a non-universal temperature-dependent η/s, it flows monotonically to the universal value 1/4π in the IR. For negative (positive) GB coupling constant, η/s is an increasing (decreasing) function of the temperature and the flow respects (violates) the KSS bound

Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression.

The recent questioning of the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) is partly based on the observation that approximately half of company-sponsored trials have failed to reveal a significant difference between active drug and placebo. Most of these have applied the Hamilton depression rating scale to assess symptom severity, the sum score for its 17 items (HDRS-17-sum) serving as effect parameter. In this study, we examined whether the negative outcomes of many SSRI trials may be partly caused by the use of this frequently questioned measure of response. We undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline or fluoxetine, and including in total 6669 adults with major depression, the aim being to assess what the outcome would have been if the single item depressed mood (rated 0-4) had been used as a measure of efficacy. In total, 32 drug-placebo comparisons were reassessed. While 18 out of 32 comparisons (56%) failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons (9%) were negative when depressed mood was used as an effect parameter (

Methane emission by Camelids

Methane emissions from ruminant livestock have been intensively studied in order to reduce contribution to the greenhouse effect. Ruminants were found to produce more enteric methane than other mammalian herbivores. As camelids share some features of their digestive anatomy and physiology with ruminants, it has been proposed that they produce similar amounts of methane per unit of body mass. This is of special relevance for countrywide greenhouse gas budgets of countries that harbor large populations of camelids like Australia. However, hardly any quantitative methane emission measurements have been performed in camelids. In order to fill this gap, we carried out respiration chamber measurements with three camelid species (Vicugna pacos, Lama glama, Camelus bactrianus; n = 16 in total), all kept on a diet consisting of food produced from alfalfa only. The camelids produced less methane expressed on the basis of body mass (0.3260.11 L kg21 d21) when compared to literature data on domestic ruminants fed on roughage diets (0.5860.16 L kg21 d21). However, there was no significant difference between the two suborders when methane emission was expressed on the basis of digestible neutral detergent fiber intake (92.7633.9 L kg21 in camelids vs. 86.2612.1 L kg21 in ruminants). This implies that the pathways of methanogenesis forming part of the microbial digestion of fiber in the foregut are similar between the groups, and that the lower methane emission of camelids can be explained by their generally lower relative food intake. Our results suggest that the methane emission of Australia’s feral camels corresponds only to 1 to 2% of the methane amount produced by the countries’ domestic ruminants and that calculations of greenhouse gas budgets of countries with large camelid populations based on equations developed for ruminants are generally overestimating the actual levels

Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure

BACKGROUND: Since only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation. METHODS: White male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks) to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC) and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β(1)- and β(2)-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping. RESULTS: In doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity. CONCLUSION: BMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure

Berberine Attenuates Experimental Autoimmune Encephalomyelitis in C57 BL/6 Mice

Berberine, an isoquinoline derivative alkaloid, has a wide range of pharmacological properties and is considered to have anti-inflammatory and neuroprotective effects. However, there are no reports about the effects and mechanisms of berberine in experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS).Female C57 BL/6 mice immunized with myelin oligodendrocyte glycoprotein 35–55 amino acid peptide were treated with berberine at the day of disease onset and medication was administered daily until mice were sacrificed. Blood–brain barrier (BBB) permeability and the alteration of matrix metalloproteinase-2 (MMP-2, 72 kDa) and matrix metalloproteinase-9 (MMP-9, 92 kDa) in the brain and cerebrospinal fluid (CSF) of EAE mice were detected by quantitative measurement for Evan's blue (EB) content, Western blot and gelatin zymography respectively. The results showed that berberine attenuated clinical and pathological parameters of EAE, reduced the permeability of BBB, inhibited the activity and expression of MMP-9 but not MMP-2 in the CSF and brain of EAE mice.These findings suggest that berberine is effective to attenuate the clinical severity of EAE in C57 BL/6 mice by reducing the permeability of BBB, decreasing the expression and activity of MMP-9, and decreasing the inflammatory infiltration. We think that berberine might be a potential therapeutic agent for MS

What "best practice" could be in Palliative Care: an analysis of statements on practice and ethics expressed by the main Health Organizations

<p>Abstract</p> <p>Background</p> <p>In palliative care it would be necessary to refer to a model. Nevertheless it seems that there are no official statements which state and describe that model. We carried out an analysis of the statements on practice and ethics of palliative care expressed by the main health organizations to show which dimensions of end-of-life care are taken into consideration.</p> <p>Methods</p> <p>The official documents by the most representative health organisations committed to the definition of policies and guidelines for palliative and end-of-life care had been considered. The documents were analysed through a framework of the components of end-of-life care derived from literature, which was composed of 4 main "areas" and of 12 "sub-areas".</p> <p>Results</p> <p>Overall, 34 organizations were identified, 7 international organisations, and 27 organisations operating on the national level in four different countries (Australia, Canada, UK and United States). Up to 56 documents were selected and analysed. Most of them (38) are position statements. Relevant quotations from the documents were presented by "areas" and "sub-areas". In general, the "sub-areas" of symptoms control as well as those referring to relational and social issues are more widely covered by the documents than the "sub-areas" related to "preparation" and to "existential condition". Indeed, the consistency of end-of-life choices with the patient's wishes, as well as completion and meaningfulness at the end of life is given only a minor relevance.</p> <p>Conclusions</p> <p>An integrated model of the best palliative care practice is generally lacking in the documents. It might be argued that the lack of a fixed and coherent model is due to the relevance of unavoidable context issues in palliative care, such as specific cultural settings, patient-centred variables, and family specificity. The implication is that palliative care staff have continuously to adapt their model of caring to the specific needs and values of each patient, more than applying a fixed, although maybe comprehensive, care model.</p