The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women.All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing.The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1–3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2–4.2).Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism. Thrombosis is a dynamic balance between factors that promote clot formation, antithrombotic mechanisms, and fibrinolysis. Central to this balance is the thrombomodulin-protein C antithrombotic mechanism. Thrombomodulin forms a 1:1 complex with thrombin on the vascular endothelium, thereby inhibiting the procoagulant actions of thrombin and converting protein C to activated protein C -5. TheseTHBD) maps to chromosome 20p11.2, contains a single exon and no introns, and spans 4 kb (OMIM 188040, UniGene NM_000361, Locus Link 7056). The thrombomodulin protein is expressed primarily on the luminal surface of vascular endothelial cells and consists of 557 amino acids (aa) : an N-terminal lectin-like module (aa 1–154), a hydrophobic region (aa 155–222), six epidermal growth factor (EGF)-like modules (aa 223–462), a serine and threonine rich region (aa 463–497), a single transmembrane segment (aa 498–521), and a short cytoplasmic tail (aa 522–557) [The thrombomodulin gene  is a population-based case-control study that was initiated to examine risk factors for ischemic stroke in young women. In that study the term "population-based" means that cases and their comparison group were identified from the same defined population. The study area included all of Maryland (except the far Western panhandle), Washington DC, and the southern portions of both Pennsylvania and Delaware. Cases were female patients 15 to 44 years of age with a first cerebral infarction as identified by discharge surveillance at 59 regional hospitals and through direct referral by regional neurologists. The methods for discharge surveillance, chart abstraction, and case adjudication have been described previously ,13,14. TTHBD genotyping at the Ala455Val polymorphism for 141 cases and 210 control subjects. This included all case and control samples that were available at that time. Genotyping was performed blinded to case-control status. Genomic DNA was extracted from stored peripheral blood lymphocytes by using standard protocols (Gentra Systems, Minneapolis, MN). The THBD Ala455Val polymorphism was determined by pyrosequencing. The single-nucleotide polymorphism region of the gene was amplified by polymerase chain reaction (PCR) with the use of published primers [We performed  primers ,16. The THBD Ala455Val polymorphism and stroke: age, race, current cigarette smoking, hypertension, diabetes mellitus, history of angina or myocardial infarction (angina/MI), use of oral contraceptive pills (OCP) or hormone replacement therapy (HRT), sickle cell disease, and sickle cell trait. Age, race, current cigarette smoking status, use of OCP or HRT was determined by subject reports (or proxy report, if a participant was unable to answer). Hypertension and diabetes mellitus, sickle cell disease or sickle cell trait were determined by asking study participants (or a proxy) if a physician had ever told them that they had the condition.We assessed the following potential confounders of the association between the alleles of the We compared means by t tests and proportions by χ2 tests. The probability values presented are based on two-sided tests. Because of the low frequency of the V455 allele, we compared the frequency of the combined AV/VV genotype between cases and controls. Adjusted odds ratios derived from logistic regression were used to determine whether the presence of the Ala455Val test allele was associated with an increased risk for stroke after differences in age, race, current cigarette smoking, hypertension, and diabetes mellitus were controlled for. Additional analyses included: 1). adding ischemic heart disease (angina/MI) into the logistic regression model; 2). evaluation for interactions between genotype and OCP/HRT 3). an analysis excluding sickle cell trait, and 4). an analysis excluding cardioembolic strokes.Characteristics by case-control status are described in Table The distribution of genotypes was in Hardy Weinberg equilibrium for the pooled set of cases and controls, both in total and by race.Among control subjects, the prevalence of the AA genotype was 81% (59/73) for blacks and 68% (93/137) for whites. The relationship between the Ala455Val genotypes and selected stroke risk factors in control subjects is summarized in Table Table The strength of association between the AA genotype and stroke remained unchanged including history of angina or myocardial infarction in the logistic regression model (OR 1.9, 95% CI 1.1–3.3). Neither OCP/HRT use, nor sickle cell trait demonstrated an interaction with genotype and additional adjustment for these factors did not alter the association between the AA genotype and stroke.Among the 141 stroke patients, 70 (50%) had a least 1 probable cause, 30 (21%) had no probable cause but a least one possible cause, and 41 (29%) were indeterminate. Table A secondary analysis removing all probable (n = 16) or possible (n = 15) cardioembolic strokes was performed using the same adjusted model including age, race, smoking, hypertension, and diabetes. An increased association between non-cardioembolic stroke and the AA genotype was demonstrated (odds ratio 2.2, 95% CI 1.2–4.2).THBD Ala455Val polymorphism, the prevalence of the AA genotype among our control population was similar to that previously reported for the Atherosclerosis Risk in Communities (ARIC) Study population [In our study of the pulation . Our respulation . VasculaTHBD Ala455Val polymorphism and coronary artery disease (CAD) have yielded conflicting results. A Swedish case-control study found the alanine allele was associated with CAD [THBD Ala455Val polymorphism and CAD [THBD Ala455Val polymorphism, ours included, is due to population-stratification bias, a functionally neutral polymorphism that serves as a marker for a nearby functional mutation (linkage disequilibrium), or the true existence of different associations in the different study populations.Several recent studies evaluating the with CAD . In contwith CAD . A Briti and CAD . Consist and CAD , we obsePopulation-stratification bias is due to confounding by population admixture . An unidTHBD Ala455Val locus may be in linkage disequilibrium with an unobserved "high-risk" susceptibility locus. Linkage disequilibrium is a function of the history of the population, and thus true associations can occur in one population and not another.The THBD Ala455Val polymorphism, thereby defining a susceptibility locus for the disease. An important criterion for a true susceptibility locus is that the polymorphism is associated with a change in protein expression or function. The THBD Ala455Val polymorphism has not been associated with variation in soluble thrombomodulin concentrations [Our results are also consistent with a causal association between stroke and the trations , but soltrations ,8,20,21.trations . Furthertrations .Thrombomodulin has not previously been examined as a candidate gene for stroke susceptibility. We found that among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early-onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this association is due to population stratification, linkage to a nearby functional polymorphism, or variation in thrombomodulin expression or function.The author(s) declare that they have no competing interests.All authors certify that they participated in the conceptual design of this work, the analysis of the data, and the writing of the manuscript to take public responsibility for it. All authors reviewed the final version of the manuscript and approve it for publication. J.W.C., S.J.K., B.D.M., M.A.W. and R.F.M. participated in the writing of the initial draft. M.G., K.K.S., W.H.G. and S.C.R. participated in the genotyping. J.W.C., S.J.K., B.D.M., and L.J.R. participated in the data analysis. All authors provided critiques of the final manuscript.Dr. Cole's effort on this project was supported in part by an American Academy of Neurology Clinical Research Training Fellowship, by the National Institutes of Health Research Training in the Epidemiology of Aging (Grant T32-AG00262-04), and by the Department of Veterans Affairs, Baltimore, Office of Research and Development, Medical Research Service, and Stroke Research Enhancement Award Program. Dr. Kittner was supported in part by the Department of Veterans Affairs, Baltimore, Office of Research and Development, Medical Research Service, Geriatrics Research, Education and Clinical Center, and Stroke Research Enhancement Award Program; a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention; the National Institute of Neurological Disorders and Stroke and the NIH Office of Research on Women's Health; the National Institute on Aging Pepper Center Grant P60 12583; and the University of Maryland General Clinical Research Center (Grant M01 RR 165001), General Clinical Research Centers Program, National Center for Research Resources, NIH.The pre-publication history for this paper can be accessed here:


Micro computed tomography (micro CT) has been shown to provide exceptionally high quality imaging of the fine structural detail within urinary calculi. We tested the idea that micro CT might also be used to identify the mineral composition of urinary stones non-destructively.Micro CT x-ray attenuation values were measured for mineral that was positively identified by infrared microspectroscopy (FT-IR). To do this, human urinary stones were sectioned with a diamond wire saw. The cut surface was explored by FT-IR and regions of pure mineral were evaluated by micro CT to correlate x-ray attenuation values with mineral content. Additionally, intact stones were imaged with micro CT to visualize internal morphology and map the distribution of specific mineral components in 3-D.Micro CT images taken just beneath the cut surface of urinary stones showed excellent resolution of structural detail that could be correlated with structure visible in the optical image mode of FT-IR. Regions of pure mineral were not difficult to find by FT-IR for most stones and such regions could be localized on micro CT images of the cut surface. This was not true, however, for two brushite stones tested; in these, brushite was closely intermixed with calcium oxalate. Micro CT x-ray attenuation values were collected for six minerals that could be found in regions that appeared to be pure, including uric acid (3515 – 4995 micro CT attenuation units, AU), struvite (7242 – 7969 AU), cystine (8619 – 9921 AU), calcium oxalate dihydrate (13815 – 15797 AU), calcium oxalate monohydrate (16297 – 18449 AU), and hydroxyapatite (21144 – 23121 AU). These AU values did not overlap. Analysis of intact stones showed excellent resolution of structural detail and could discriminate multiple mineral types within heterogeneous stones.Micro CT gives excellent structural detail of urinary stones, and these results demonstrate the feasibility of identifying and localizing most of the common mineral types found in urinary calculi using laboratory CT. Clinical laboratory assessment of urinary stones is typically conducted using destructive methods of analysis -5 and isKnowing the mineral composition of a patient's stones has obvious value in determining a treatment plan, but stone structure may be important as well. It has long been appreciated that there is variability in stone fragility to shock waves in lithotripsy, that stones of a given mineral type do not all break the same . Stone fThe purpose of this report is to present micro computed tomography (micro CT) as a potential method for the analysis of urinary stone composition and morphology in a nondestructive manner at very high resolution. Micro CT, which has seen considerable use as a research tool in bone biology , has theHuman urinary stones were obtained following percutaneous nephrolithotomy procedures or from a stone analysis laboratory . A representative collection of urinary stones of pure and heterogeneous mineral content was selected for use in this study.Stones for this work had already been analyzed using conventional methods , with portion used here typically the half of the stone remaining intact after that analysis. For some stones, pre-CT analysis was completed on a cohort stone taken during the same surgical procedure. Compositions of the 11 stones used for combined micro CT and IR microspectroscopy included pure COM, pure calcium oxalate dihydrate (COD), 91% COD/9% COM, 99% COM/1% hydroxyapatite, 52% COM/48% uricite, pure uricite, pure struvite, two pure cystine stones, and two pure brushite stones.-1. Spectra for COM, COD, apatite, uric acid, struvite, cystine, and brushite were all easily identified and distinguishable from one another. Uricite and uric acid dihydrate could not be distinguished above the background noise of the spectra, and so regions are reported as uric acid.Stones were embedded within methyl methacrylate and sliced into 1–2 mm slabs using a diamond wire saw (Well Saw, Delaware Diamond Knives, DE). A Perkin-Elmer AutoImage infrared microscope interfaced to a Perkin-Elmer Spectrum 2000 fourier transform infrared (FT-IR) spectrometer (Perkin Elmer, Shelton, CT) was used to collect infrared spectra on the flat surface of the stone slices. The spectrometer directs infrared light onto the specimen through a microscope lens, and collects reflected light onto a cooled mercury-cadmium-telluride detector. Spectra were collected in grids of 200 × 200 μm intervals, averaging 16 individual scans on each spot, yielding spectral resolution of 4 cmThe same stone slices analyzed by FT-IR microspectroscopy were also scanned by micro CT, using a Scanco MicroCT 20 instrument  Figure . The sysThe FT-IR analysis yielded a 2-D map of mineral composition for a defined region of each stone slice. Regions of the 2-D map showing pure mineral were compared to the identical region on the micro CT image slice taken just below the cut surface  affords much greater spatial resolution than conventional single-detector helical CT. Williams et al. used four-row MDCT to show that some degree of internal structure can already be seen in urinary stones . Zarse aere used . Eight-rere used . Sixteenere used . Moreovein vitro imaging of urinary calculi for nondestructive stone analysis. Fine resolution coupled with the 2-D and 3-D reconstruction capabilities of micro CT yields an imaging diagnostic that offers excellent images of surface and internal stone structure. Mineral deposition pattern and regions of potential structural weakness, such as voids, were easily visible. Six common stone minerals were found to occupy non-overlapping ranges of attenuation value, which allows the identification of mineral types using micro CT alone. This technology carries the potential for immediate application to non-destructive analysis of stone structure and composition in clinical stone analysis laboratories. The demonstration that stone composition can be determined by micro CT is proof of concept and an important step toward the use of helical CT to provide similar analysis in patients.Micro CT provides high resolution The author(s) declare that they have no competing interests.CZ did the experimental work for calibrating the attenuation values, put together several of the figures, including the image stack movie, and drafted the manuscript. AJ performed the FT-IR analyses. EH did many of the micro CT scans and managed the library from which stones were chosen. SK and JL provided some of the stones from patients, and SK performed the 3-D imaging of cystine stone. JM, JL, and AE initiated much of the intellectual direction for the study. JM and AE also played important roles in the FT-IR analysis part of the study. JW performed the 3-D image construction in MacVol, drafted several of the figures, and performed the primary editing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Micro CT image stack through a urinary stone.MOV 6.61 MBClick here for file


These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.Together, these  In the present study, we investigated the hydrolysis of DMF to its most bioactive metabolite monomethylfumarate (MMF) and the stability of MMF, DMF and MEF in different environments representing various body compartments using this methodology.Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and infiltration of inflammatory cells into skin lesions. Anti-psoriatic therapies are mainly anti-inflammatory. Long-term use of many of these anti-psoriatic therapies is often hampered by serious adverse effects -5. In thDMF, MMF and MEF remained completely intact in a buffer of pH 1 mimicking the pH in the stomach Figure  and 1F. To further examine the pH-dependency of the hydrolysis of DMF to MMF, we measured concentrations of DMF and MMF in phosphate buffers (with pH ranging from 6.5–8) supplemented with DMF or the combination of DMF and MEF. The results revealed that the half-life of DMF dramatically decreased with increasing pH values and the maximal hydrolysis of DMF to MMF was seen at pH 8 . For example, at pH 7.4 the half-life of DMF amounted to 12.7 ± 1.0 hr (n = 3) Figure . In agreSince FAE must enter the circulation to exert their anti-psoriatic effects at the affected skin site , we deteTo find out which blood cell type(s) is (are) responsible for the hydrolysis of FAE in whole blood, hydrolysis of DMF in a buffer of pH 7.4 by purified blood cell fractions was analyzed. The results revealed that monocytes/lymphocytes Figure , but notin vitro pharmacokinetics of FAE. For example, no enzymes, e.g. esterases, are present in these buffers whereas they are in these body compartments. In this connection, Werdenberg and collegues [A major finding of the present study is that hardly any DMF was hydrolyzed in a buffer of pH ≤ 7.4, whereas at pH 8, resembling the pH of the small intestines, this FAE was effectively hydrolyzed to its active metabolite MMF. It should be noted that MMF (and MEF) remained stable in these buffers. We realize that using acidic or alkaline buffers to mimick the conditions in body compartments, like the stomach and the small intestines, is only a first attempt to investigate the ollegues  recentlyAnother important finding of this study is that the half-life of DMF in whole blood is considerably shorter than that in serum, although the pH of both blood and serum is 7.4. To explain this difference in hydrolysis of DMF in whole blood and serum we considered the possibility that blood cells also hydrolyze DMF to MMF. Using purified blood cell fractions resuspended in PBS (pH 7.4) we found that monocytes/lymphocytes, but not granulocytes and erythrocytes, at concentrations present in whole blood effectively hydrolyzed DMF to MMF. The rapid removal of DMF from PBS after addition of granulocytes and erythrocytes suggests that these blood cells bind DMF.® tablets [[et al., manuscript submitted; Litjens et al., unpublished data]. Our observation that the MMF is more rapidly removed from whole blood than from serum could indicate that MMF (and MEF) is taken up by blood cells and perhaps further metabolized into FA, which subsequently fuels the citric acid cycle, as suggested earlier by Joshi . The different interactions between FAE and blood cells may affect their functional activities, as has been reported earlier [It should be realized that MMF (and MEF) most likely enter the circulation of psoriasis patients in order to exert their antipsoriatic effects in the skin lesions. In agreement we detected MMF and MEF, but not DMF, in the circulation of healthy volunteers and psoriasis patients after oral intake of Fumaraat 120tablets [, Litjens earlier ,17-19, tin vitro data indicate that DMF is almost completely hydrolyzed to MMF at an alkaline pH, but not at an acidic pH, suggesting that this hydrolysis occurs mainly within the small intestines and not in the stomach. Most likely, MMF and MEF are then absorbed in the circulation where they interact with blood cells and perhaps cells in the psoriatic lesions. The different interactions between these FAE and the various cell types may explain the beneficial effects of FAE in psoriasis. Finally, these in vitro experimental data will be key to the pharmacokinetic analysis of oral FAE in human healthy volunteers and psoriasis patients.Together, these ®; TioFarma), containing 120 mg of DMF and 95 mg of calcium-MEF was investigated in this study.The following FAE were used: dimethylfumarate , calcium-monoethylfumarate , monomethylfumarate . In addition, the enteric-coated, magisterial manufactured tablet (named Fumaraat 120® tablet. In addition, to determine the release of the contents of a Fumaraat 120® tablet and the hydrolysis of DMF to MMF at pH 1 (0.1 N of HCl) and pH 8 (0.1 M of sodium phosphate buffer), the tablet was placed in these buffers and at various intervals samples were taken and prepared for measurement of the concentrations of DMF, MMF and MEF by high-performance liquid chromatography (HPLC) as described below.To investigate the stability of DMF, MMF and MEF and the hydrolysis of DMF to MMF in several environments representing various aspects of different body compartments, 0.1 N HCl with pH 1 and 0.1 M sodium phosphate buffer with pH 8 were spiked with 2 mg/L of DMF, MMF, MEF or the combination of 2 mg/L of DMF and 1.4 mg/L MEF, to resemble the ratio of these two components in the Fumaraat 120To further investigate the effect of the pH on the hydrolysis of DMF to MMF, 0.1 M sodium phosphate buffers with pH values ranging from 6.5–8 were spiked with DMF and the combination of DMF and MEF. At several intervals thereafter, samples were taken, and then prepared for measurement of the various FAE by HPLC.As the current buffers lack proteins, no extraction procedure was necessary and the concentrations of the various FAE in the samples could be directly quantified by HPLC (see below).As described above, serum and whole blood from 3 volunteers was spiked with 2 mg/L of DMF, MMF, MEF or the combination of 2 mg/L of DMF and 1.4 mg/L MEF. All volunteers were healthy as assessed by a full medical screening.At several intervals, samples were taken, and then prepared for measurement of the various FAE by HPLC. In short, serum and whole blood contained proteins known to interfere with the measurement of FAE. To overcome this problem, the various FAE were extracted from serum and whole blood samples and subsequently the concentrations were measured by HPLC (see below).6 monocytes and lymphocytes/mL PBS, 4 × 106 granulocytes/mL PBS, and 5 × 109 erythrocytes/mL PBS were spiked with 2 mg/L DMF. Again, at several intervals samples were taken and concentrations of the various FAE were measured as described below.The various blood cell fractions were obtained from blood of healthy volunteers using centrifugational techniques as described earlier ,19. In set al., submitted for publication). Briefly, after precipitation of serum proteins with acetonitrile, DMF in the samples was quantitated by HPLC. The sample preparation for MMF and MEF required a protein precipitation step with metaphosphoric acid followed by extraction with diethylether and additional pH-lowering to pH 0.5. Next, sodium chloride was added before centrifugation at 12,000 g. Thereafter, the ether layer was transferred to a glass vial and after evaporation the residue reconstituted in methanol: 0.1 M potassium phosphate buffer  supplemented with 5 mM tetrabutylammonium dihydrogen phosphate 1:1 (v/v).The concentrations of the various fumarates in serum samples were determined as described (Litjens Concentrations of DMF, MMF, and MEF were determined on a HPLC apparatus (Spectra SERIES P100, Thermo Separation Products, Breda, The Netherlands) equipped with an Alltima C18  column and an Alltima Guard C18 precolumn  using methanol:water 30:70 (v/v) as an eluent for DMF and methanol: potassium phosphate buffer supplemented with 5 mM tetrabutylammonium dihydrogen phosphate 20:80 (v/v) as eluent for MMF and MEF. The limit of detection for all three compounds amounted to 0.01 mg/L, the coefficient of variation for MMF, DMF and MEF was 7%, 8% and 9% at 0.5 mg/L, respectively (n = 4), and the recovery of MMF, DMF and MEF amounted to 75 ± 7%, 98 ± 3%, 67 ± 7% (n = 6). Standard curves constructed with purified FAE in buffers or human serum were used to quantify the concentrations of FAE in the various samples of these buffers and human serum or whole blood, respectively.NL participated in the design of the study, analysis of the data and drafted the manuscript. ES carried out the optimisation of the HPLC method and performed all HPLC analyses. CvG was responsible for the optimisation of the HPLC method and participated in the design of the study. HM participated in the design of the study and analysis of the data. JvD, HT and PN conceived of the study and participated in its design and coordination. All authors read and approved the final manuscript.


How did language develop and evolve? Here, linguists, cognitive scientists, behavioural ecologists, and theoretical biologists all offer their disparate views on this emerging field Language Evolution, a compilation of essays by a diverse group of respected researchers, is amongst the first books that try to tackle what is arguably one of the hardest scientific problems. The editors set themselves the ambitious target of creating an up-to-date book about this emerging field, and they have to be congratulated for their efforts. Linguists, cognitive scientists, behavioural ecologists, and theoretical biologists all offer their view on the origin of human language and, refreshingly, do not shy from pointing out the real or assumed weaknesses of the other approaches.A ban in the 1866s by the French Academy of Sciences on publications about the origin of human language must have been one of the strangest bans in the history of sciences. Yet it was highly effective. After the ban, scientists and interested laymen had to wait for more than a century to hold a textbook on language evolution in their hands. One of the main themes of the book is the evolutionary approach and the importance of biological structures and properties that were co-opted in the development of language (pre-adaptations). In one essay, Michael Studdert-Kenedy and Louis Goldstein propose that speech, as a motor function, draws on phylogenetically ancient mammalian oral capacities for sucking, licking, swallowing, and chewing. Thus, our hominid ancestors adopted an apparatus already divided neuroanatomically into discrete components. Complementing this evidence, Marc Hauser and Tecumseh Fitch compare human speech production and perception with that of nonhuman species. They conclude that many traits that were formerly thought to have evolved specifically for speech  are also present in other species.But perhaps the most interesting idea about pre-adaptation comes from the work of neuroscientist Michael Arbib on ‘mirror’ neurons in monkeys. These neurons are a subset of the grasp-related premotor neurons that discharge not only, as other premotor neurons do, when the monkey executes a certain class of actions, but also when the monkey observes more or less similarly meaningful hand movements made by the experimenter (or by another monkey). The area in which these grasp-related neurons are found is analogous with the Broca's area in human brains, which is involved in assessing the syntax of words. This observation serves as the basis for the mirror-system hypothesis, which postulates that Broca's area in humans evolved from a basic mechanism not originally related to communication but rather from the mirror system for grasping in the common ancestor of monkey and human. As a result, the mirror system provides a possible ‘neural link’ in the evolution of human language.There is still much debate about the selection pressures that led to the evolution of language. Observing the overabundance of potential selective scenarios for why language evolved, the linguist Derek Bickerton voices his scepticism: ‘The fact that these and similar explanations flourish side by side tells one immediately not enough constraints are being used to limit possible explanations.’ One frequent source of confusion, he notes, is equating language with speech by not distinguishing between modality, lexicon, and structure. Hauser and Fitch share Bickerton's scepticism and urge scientists to rely more on the traditional comparative approach, which was always the strength of Darwinian evolutionary theory.Primatologist Robin Dunbar, who originally proposed that grooming (group bonding) could have provided the stimulus for language, dismisses two other possible scenarios—hunting and tool-making—as potential ecological contexts for the evolution of human language. Gestural origins are also dismissed in his theory, because gestural languages do not seem to develop spontaneously and also require a line-of-sight contact making them useless at night.Interestingly, Steven Pinker rules out both Dunbar's theory of grooming and Geoffrey Miller's theory of sexual selection, whereas Bickerton rules out grooming, gossip, mating contract, and Machiavellian intelligence as likely contexts for the origin of human language.Also under fire in the book is the idea that the human brain is somehow equipped at birth with a ‘universal grammar’ out of which all human languages later develop. Several authors try to provide alternatives to innate predispositions, such as the importance of function to categorization (Michael Tomasello) and the importance of cultural transmission to the structure of language (Simon Kirby and Morton Christiansen). Arbib explicitly questions the traditional Chomskyan theory of innate linguistic predispositions and argues that what humans have and had in the past is ‘language readiness’ rather than a fixed universal grammar.Neuroscientist Terrence Deacon also puts an alternative theory forward. According to Deacon, many of the language universals reflect semiotic constraints inherent in the requirements for producing symbolic reference rather than innate predispositions. Thus, neither evolved innate predispositions nor culturally evolved and transmitted regularities can be considered as the ultimate source of language universals. He draws a parallel with mathematical operations (addition, subtraction, etc.) and with prime numbers. Symbolic reference, he argues, is constrained by the structure it refers to.The editors claim, in the light of this diversity, that ‘this book is intended to bring together, for the first time, all the major perspectives on language evolution’. We have two concerns with this aim. First, two books of the same organization and scope have been published in the past six years based on the material from language evolution conferences . AlthougOne of these missing themes is the selective advantage of early language. As discussed, many of the contributors express their scepticism towards the selective scenarios found in the literature—and indeed towards such constructions in general—but there is no review and no balanced evaluation of these selective scenarios. Since one of the key questions of language evolution is the selective advantage of early language, the lack of such a review is a major weakness. A balanced account could have been presented even if the editors and most of the contributors are frustrated by the plethora of selective scenarios.Related to the possible selective advantage of language is the issue of genetic background. Although there is mention of the so-called FOX genes—some mutations of which are associated with language disorders—there is no detailed discussion of our current knowledge of genetics related to language.Another lightly treated theme is the neural basis of language and language evolution. Understandably it is one of the most difficult issues concerning human language, and no one expects the editors or any of the contributors to come up with an answer to all the questions. What is missing again is a good survey outlining the problems and the current findings of the field.The weaknesses of the book come from its structure and organization. The editors, instead of outlining a structure and asking specialists to contribute to that structure, appear to have let every contributor write freely about their current ideas and current research without regard to the bigger picture. This definitely shows the interests of the contributors and outlines the current state of the art; it leaves gaps, however, in the coverage of crucial topics related to the evolution of human language.


With a growing trend for those with advanced cancer to die at home, there is a corresponding increase in need for primary medical care in that setting. Yet those with lower incomes and in rural regions are often challenged to have their health care needs met. This study examined the association between patient income and residence and the receipt of Family Physician (FP) home visits during the end-of-life among patients with cancer.Data Sources/Study Setting. Secondary analysis of linked population-based data. Information pertaining to all patients who died due to lung, colorectal, breast or prostate cancer between 1992 and 1997 (N = 7,212) in the Canadian province of Nova Scotia (NS) was extracted from three administrative health databases and from Statistics Canada census records. Study Design. An ecological measure of income ('neighbourhood' median household income) was developed using census information. Multivariate logistic regression was then used to assess the association of income with the receipt of at least one home visit from a FP among all subjects and by region of residency during the end-of-life. Covariates in the initial multivariate model included patient demographics and alternative health services information such as total days spent as a hospital inpatient. Data Extraction Methods. Encrypted patient health card numbers were used to link all administrative health databases whereas the postal code was the link to Statistics Canada census information.Over 45% of all subjects received at least one home visit (n = 3265). Compared to those from low income areas, the log odds of receiving at least one home visit was significantly greater among subjects who reside in middle to high income neighbourhoods . This association was found to be primarily associated with residency outside of the largest metropolitan region of the province.The likelihood of receiving a FP home visit during the end-of-life is associated with neighbourhood income particularly among patients living outside of a major metropolitan region. In the last ten years, more and more of those dying of cancer in Canada are doing so out of hospital. In NovaAs this trend has developed, it has become even more important for patients and families to have access to medical care in the community. Such first line medical care, in Canada, is generally provided by a family physician, usually previously known to the patient. Initially those with terminal illness will obtain their medical care in the office or out patient setting. As they become sicker, however, there will come a time when getting from the home to the clinic office will be too difficult. At such a time, access to home visiting by a physician becomes very important -11. ReseThere is evidence that those better off financially live longer and are in better health than poorer individuals,16. ReasWe wondered if access to terminal care home visiting by family physicians is better for those with higher incomes even in our publicly-funded health system. Therefore, the purpose of this study was to examine the association between income and the likelihood of receiving home visits by family physicians during the end-of-life among those with cancer. In addition, we examined the effect of regional residency, specifically residency in a major urban centre versus all other regions of NS .Data for this retrospective, population-based study were obtained through the linkage of individual-level information extracted from four administrative health databases: (1) the Nova Scotia Cancer Centre Oncology Information System (OPIS) which includes the Nova Scotia Cancer Registry (NSCR) and provincial vital statistics information, (2) the Nova Scotia Medical Services Insurance Physician Services (MSIPS), (3) the Nova Scotia Hospital Admissions / Separations (HAS) file, and (4) the Queen Elizabeth II Health Sciences Center Palliative Care Program (PCP). The MSIPS provides a record of all services provided by physicians to residents of Nova Scotia whereas the HAS contains information relating to all hospital inpatient and outpatient stays and procedures. Because individual-level income information is not available from these sources, the Postal Code Conversion File (PCCF) and 1996 Statistics Canada census data were used to develop an 'ecologic-level' proxy for household income, enumeration area median (EAM) income quintiles or 'neighbourhood income'. These aggregate measures are derived from census information grouped by provincial enumeration areas or 'neighbourhoods'. The resulting quintiles are based on the median income value of each enumeration area. Evidence suggests the use of such proxies in population-based studies is a valid alternative in situations where household level information in not available. It is, Encrypted patient health care numbers were used to link all four administrative health databases whereas the postal code was the link to the PCCF and Statistics Canada census information. Ethics approval for this project was provided by the Queen Elizabeth II Health Sciences Centre research ethics committee.th revision [ICD9-CM]) from 1992 to 1997 were included as subjects. These four cancers represent the most common causes of cancer death in Nova Scotia.All adults identified on death certificates in the NSCR database as having died due to lung, colorectal, breast or prostate cancer death , date of initial cancer diagnosis, year of death (1992–1997) cancer cause of death , and neighbourhood income categorized as provincial quintiles (lower, lower middle, middle, upper middle, upper). Almost 40% (39.5%) of Nova Scotia's population resides in the HRM which spans a primarily urban geographical region. Within HRM's boundaries are all of Nova Scotia's major tertiary health care centres, several community hospitals and many specialized care programs. Although regions outside of HRM also encompass many towns with regional and community health care facilities, they span a much larger, diverse, geographical area and may be considered to be relatively more rural than HRM.Health services information was limited to each subject's 'survival time'. In our end-of-life research we have defined 'end-of-life' as the last 180 days of life, or if of shorter duration, from the date of initial cancer diagnosis to death. This six month time period is commonly used in end-of-life studies -24.Total family physician home visits received during this survival time were counted and, due to the highly skewed distribution evidenced, also dichotomized to represent at least one home visit received or none. Additional health services of interest and potential covariates included the total number of ambulatory visits made to a family physicians by each subject, the total number of visits made by the subject to a specialist, the total number of days spent as a hospital inpatient, receipt of palliative radiotherapy, and whether or not the patient had been admitted to the PCP, a comprehensive palliative care program which has been operating since 1992. As an indirect measure of whether the patient was a resident of a long term care (LTC) facility during the end-of-life, a flag was created indicating whether a patient had received at least one family physician within a LTC centre.Following descriptive statistics and the application of nonparametric tests to assess median differences and cross-tabulations with chi-square analyses for association, regression techniques were employed to estimate the effect of neighbourhood income (EAM income quintile) on the receipt of family physician home visits. Our initial regression analysis retained the total number of home visits as a continuous dependent variable and involved negative binomial regression where differences in survival time were accounted for as an offset variable. This was followed by logistic regression techniques where the probability of receiving at least one FP home visit versus no home visits was assessed. For both forms of regression, unadjusted analyses were followed by multivariate where the initial model included neighbourhood income in addition to sex, year of death, age, cancer cause of death, region of residency, the number of visits made to a medical specialist, the receipt of palliative radiotherapy and admission to the PCP as covariates. To account for the possibility that the subject may not have been 'at home' during their 'survival time' and hence unable to receive a home visit, our LTC residency flag and the total days spent as a hospital inpatient were added to the model.To control for differences in 'survival time', the number of days from the initial cancer diagnosis date to death were categorized and added to the model. Subsequent modeling involved the sequential elimination of covariates and confounders found to no longer be significantly associated with the receipt of FP home visits in the multivariate model at the p = 0.05 level of significance.Since our administrative data do not provide the ability to make adjustments for regional differences such as the availability of alternative health services, physician density or community resources, as an alternative, we stratified each analysis by region of residency.All analyses were performed using SAS software.In total, 7212 adults were identified from death certificate information as having died from lung, colorectal, prostate or breast cancer between 1992 and 1997 in Nova Scotia. Over 94% of these advanced cancer patients had seen a family physician at least once during the end-of-life. In total, home visits accounted for 29% of all ambulatory visits provided by family physicians with 3265 (45.3%) patients receiving at least one FP home visit. The total number of FP home visits received varied widely, from 0 to 89 with an average number of 2 (standard deviation [SD] 4.2) and median of 0. Table Subject characteristics and health service utilization by receipt of at least one home visit are displayed in Table Regression results incorporating the total number of home visits using negative binomial regression and those derived from logistic techniques assessing the log odds of receiving at least one home visit compared to none proved similar. Therefore, for ease of presentation, we present the logistic regression results only.Displayed in Table Among all advanced cancer patients, additional factors predictive of receiving at least one FP home visit included a longer length of survival , admission to the QEII Palliative Care Program (PCP) (adjusted OR 2.25, 95%CI 1.97, 2.56), older age  and being female . Patients who were in LTC at some point during their survival period  and those who spent 32 or more days in hospital compared to none  tended to be less likely to receive at least one FP home visit. Over time, the likelihood of receiving a home visit tended to decline. However, after accounting for all other predictors in the model, year of death was not a major factor.Cancer cause of death, receipt of physician specialty visits and undergoing palliative radiation were not associated with home visit receipt in the final multivariate model.The neighbourhood income of those dying of cancer is associated with the likelihood of receiving a home visit during the end-of-life by a family physician in Nova Scotia. The association found, however, appears to be modified by region of residence for those who died of cancer. It appears that income plays less of a role in predicting home visits by a family physician for those who live in the larger, urban centre of Halifax Regional Municipality. Given the finding that patients followed by the QEII Palliative Care Program are also more likely to receive family physician home visits, we speculate that the urban centre may provide a collaborative 'team-care' advantage to cancer patients. The publicly-funded PCP may act to equalize the opportunity to stay at home and facilitate family physician home involvement in ways rural locations may not be able to. In previous work, income was not associated with location of death but region of residency was. We haveIn the United Kingdom, Aylin and colleagues found, fWe hypothesize that when it comes to routine home visits for brief, episodic illnesses, the home visiting trend may be as Aylin suggests. However, for those who are at home and looking to stay at home with advanced cancer, there are more substantial financial issues driving whether this is likely to happen or not. In Nova Scotia, as in many Canadian settings, there is access to home visiting nurses and some other health professionals through the publicly-funded health system. However, as disease progresses, the ability of a family to support death at home depends on many other factors. These include the presence of a family member who can stay at home, the ability of a family member to manage the medications and symptom assessment along with health professionals, the cost of drugs which are paid for in hospital but not in the home , the cost of equipment in the home, and possibly the cost of additional nursing or personal care workers in the home (variably covered by the public system, and only sometimes covered by private insurance). All of the critically enabling feature. Thus, the home visit is essential but not sufficient and without the rest of the support required, the patient will not be able to stay at home, thereby resulting in fewer home visits.The home visits provided by family physicians may therefore be a direct response to the other capacities of patients and families to stay at home rather than being Another interpretation is that those with lower incomes may actually make different choices about how they wish to receive health care and where they would like to spend their last days. Depending on the study cited, up to 80% of those with advanced cancer wish to spend their last days at home,28-30. GHome visiting has long been an element of continuity of care across settings  provided by family physicians. Some would argue that home visits may be influenced by the geography in which the physician operates daily. As a result, physician travel patterns to and from the office (when home visiting often occurs) may not take them through low income neighbourhoods, thus reducing the likelihood of a visit. The work of Aylin and McNiNew initiatives are underway in Canada which may provide more opportunities for the enhanced presence of a range of health professionals in the homes of the dying. In response to the Romanow Commission, the fedOur study has limitations. As we are using routinely collected data used for administrative and billing purposes there may be biases operating. The data reflect those family physicians who bill for the services they provide. It should also reflect the "shadow-billing" of those on alternate payment mechanisms (estimated to be less than five per cent of family physicians at the time of the study) but in reality, these physicians may have less incentive to capture these fee codes and so may under-report home visiting slightly.The data file used in this study was originally created for an alternate project looking at health service utilization among patients who died due to lung, colorectal, breast or prostate cancer. We were therefore limited to examining home visits provided to these patients only and are not able to report whether the use of family physician home services among those who died due to all other cancer causes is similar or different.We are unable to adjust for homecare utilization (data did not exist for the study years), family member caregiving status (no data available) or account for additional insurance coverage  which may have covered additional costs associated with drugs, home nursing, home equipment, etc. Our attempt to account for service availability by region is crude. HRM is more homogeneous with respect to services than our combination all other regions outside of HRM; however, the effect evidenced may, therefore, be a conservative estimate.And so, in conclusion, it appears that even in death those with fewer financial resources may be less likely to achieve the same access to health services as those better off. What does this mean for our care of the dying? We must examine carefully which elements are the cause of this inequality. If there is less desire among those with more financial barriers, we need to examine the origins of these desires. Is it fear of caring for those at home? Is it an established culture of caring to move loved ones to hospital at the end-of-life? These issues need identification if we are to support such families. If there truly are financial barriers to such things as drugs, equipment and personnel then we must redefine health policy to make these more accessible to those with fewer financial resources. And finally, we should attempt to understand whether or not there is any bias operating on the part of health professionals. All of these need further research if we are to ensure patients receive the care where they wish to as they approach death.The author(s) declare that they have no competing interests.FB and BL participated in the conceptualization and design of the project, the analysis and interpretation of the data, first-drafted the majority of the article, and incorporated co-author comments into the final draft. GJ participated in the interpretation of the data and the drafting and revising of the manuscript. All authors gave approval to this final version.The pre-publication history for this paper can be accessed here:


Student attitudes to mental health consumers were measured pre and post the program. All tutorial evaluation data was analysed using univariate statistics. Both tutors and students evaluated the teaching program using a 4 point rating scale. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test.Consumer tutors were successfully trained and accredited as tutors and able to sustain delivery of tutorials over a 4 year period. The study found that whilst the medical students started with positive attitudes towards consumers prior to the program, there was a general trend towards improved attitude across all measures. Other outcomes for tutors and students (both positive and negative) are described.Consumer tutors along with professional tutors have a place in the education of medical students, are an untapped resource and deliver largely positive outcomes for students and themselves. Further possible developments are described. Interview skills, while important in all areas of medicine, are a prime focus of educational endeavour in the teaching of psychiatry. The interview is the cornerstone of psychiatric investigation and the scene for the establishment of rapport and therapeutic engagement. The importance of effective skills training in interviewing for medical students was highlighted in the core curriculum in psychiatry published by The World Psychiatric Association and the World Federation for Medical Education . An addith year medical students in psychiatry. The idea is based on the belief that consumers have a legitimate experience to share and a rich skill base on which to draw. The purpose of this ongoing project is to contribute to the ultimate development of a workforce of medical practitioners with clinical assessment skills that are better tailored to the needs of mental health consumers. More immediate potential benefits are the promotion of an engaging curriculum in psychiatry for students, offering direct meaningful contact with mental health consumers.Moving beyond the traditional teaching of interview skills by psychiatrists in the "see one, do one, teach one" mode, we report the development of an innovative approach to the teaching of psychiatric interview skills. This approach began four years ago as a partnership between mental health consumers and academic psychiatry to examine the ongoing feasibility of training mental health consumers as tutors for 4Consumers and patients are not new to medical education, offering a unique perspective on their experiences with the health system. There are 3 levels of consumer participation in education. Consumers may be the subject of teaching tutorials (a demonstration), a visitor to a tutorial (sharing their experiences with few guidelines) or a paid trained tutor delivering an agreed curriculum (a 'consumer tutor'). Consumer tutors are distinct from 'professional tutors' (those with a career obligation to teach) a distinction that does not imply a lack of professionalism regarding the consumer tutor. The issue of language is not trivial: the local user support network was committed to the term 'consumer' rather than other common labels like client or patient. The language used was chosen for the perception of action and autonomy and to reflect respect for the role and to make it clear to students and staff that these people were a committed part of the teaching workforce, not visitors only present to tell of their (often negative) experiences.This work drew on the Partners in Arthritis project  that demth year medical students in effective approaches to interviewing. There was commitment to evaluate the effectiveness of the teaching in terms of (i) changing student attitudes towards consumers, (ii) preparing students for a common examination in psychiatry, (iii) monitoring consumer tutor involvement and feedback.In summary this project set out to train and support mental health consumers as consumer tutors for the delivery of a jointly developed curriculum for 4The project was set in a medical school (University of Sydney) undergoing transition to graduate entry, with adult self-directed and problem based learning models providing an opportunity to students keen to explore new ways of learning. This environment of educational change added to student and staff enthusiasm to trial new ideas. There was recognition that carers and consumers required the same respect and courtesy as professional tutors, and inequities such as only being paid travel expenses were unsatisfactory . ConsumeThe Academic Unit of Psychological Medicine approached consumers from the local mental health consumer network seeking expressions of interest to join a steering committee to oversee the project. Consumers were involved at all stages including planning, development, implementation and evaluation. The steering committee met weekly to determine an approach to consumer tutor recruitment and training, and to author the student curriculum for delivery.Consumer tutors were recruited, trained in small group methods and assessed. The assessment task was a nine-item quiz. Typical questions included "List three strengths of working in small groups" and "List three strategies to get a discussion going amongst students". Those who wished to teach were then allocated in pairs to a consistent student group of six to eight students for weekly tutorials over seven weeks. Consumer tutors conducted the planned curriculum, provided feedback on each tutorial and contributed to curriculum review.Evaluation of the content of the curriculum, the quality of the teaching and handouts was measured using a 4-point Likert scale (4 = excellent, 3 = good, 2 = fair, 1 = poor) followed by an open comment item. After each tutorial consumer tutors were debriefed by academic staff and arrangements for the following tutorials confirmed. An expedient payment method was established. Over time, consumer tutors and academic staff periodically reviewed tutor and student feedback and decided on tutorial modification.The steering committee comprised six consumers, three with previous teaching experience at secondary or tertiary level. Professional approaches were adopted for recruitment, training, assessment, graduation and payment. Academic staff drafted a structure for consumer tutor training completed by the committee. The committee determined the priorities for the student curriculum and each oversaw the writing of a tutorial in conjunction with academic staff. Consumer input was central and meaningful rather than at the level of editing academic staff work. The committee were paid regular sitting rates for committee attendance. The steering committee met during the first trial to review progress, an overseeing role replaced later by the consumer tutors themselves.Expressions of interest from potential consumer tutors were sought through the consumer network against selection criteria. These included the essential criteria of being a current consumer of mental health services and having an interest in the development of medical student interviewing skills. Desirable criteria included previous experience in teaching. Applications were reviewed by the steering committee and all applications for training were accepted. Payment for training and tutoring was set at the current university casual tutor rates appropriate to qualifications.Recruitment resulted in a cross section of consumers including several 'marginalised consumers' who are usually under represented in such activities Three training cycles have occurred with 20 consumers (12 women, 8 men) commencing training and 18 consumers graduating from training. Fifteen consumer tutors have taught over the four years, whilst three decided after graduation that they did not wish to teach. Drop out occurred because of illness, disinterest or realising that tutoring was more difficult than first imagined.The tutor training program comprised six weekly, one and a half hour tutorials delivered by academic staff encouraging discussion, controversy and practice in a supportive environment. See Table Students in one of four teaching centres of the University of Sydney participated in the consumer tutor-led tutorials. Students were oriented by academic staff and completed a pre-participation measure. This measured student attitudes to mental health consumers adapted from work on the 'hated patient' . Five stStudents were then introduced to their consumer tutors and participated in an 'ice breaker' session involving an interactive board game designed to sensitise medical students to the experience of being a mental health consumer. This was followed by six tutorials which both consumer tutors and medical students evaluated using the same measure. Students repeated the attitude measure at the end of the program and completed assessment tasks as per the university requirements. Students also participated in a seminar series (including didactic teaching on interview content) with professional tutors similar to that delivered in the other teaching centres. All tutorial evaluation data was analysed using univariate statistics. The pre and post attitude measure was compared using term group means (as completion was anonymous) using an independent samples t-test. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test.The student curriculum was developed as six one-hour tutorials . The curriculum and written materials underwent several revisions in response to feedback aimed at improving interactivity and clarity. Consumer tutors used the ground rules set out in training for dealing with absences. Reserve tutors were introduced at the start of the term so they were familiar to students if required. Tutor pairs were able to support each other and compensate for ebbs and flows in performance.The consumer tutors debriefed following each tutorial with academic staff. These meetings were an important opportunity for tutors to give positive and constructive feedback to each other as well as addressing ways to improve their delivery of the tutorials. They discussed problems and obstacles and brainstormed effective solutions. The larger consumer tutor group contributed to successfully resolving most conflict. Discussions were frank. Formal mediation was used to resolve a conflict between two tutors, in dispute over matters beyond teaching. Mediation was successful in terms of allowing ongoing involvement in teaching for both people. Academic staff informally debriefed the students during other tutorials. While a few students complained about the whole experience of being taught by a consumer, most students were positive. Indeed many reported they used the consumer tutors as a sounding board for other interview-related experiences during the week, seeking advice about alternative styles and approaches.Like all tutors, the consumer tutors required support, stimulation and refreshment. This happened in the tutorial debriefs outlined and in occasional workshops to review feedback, revise curriculum and refresh skills. Consumer tutors were encouraged to present reports of their experiences at appropriate meetings and received a national award for consumer research. Consumer tutors' motivation particularly increased when clinical mental health staff asked them about their teaching experiences and recognised that the individual had made many gains since the last episode of acute care.Consumer and professional tutors were commonly concerned about intervening illness and the impact on teaching. Some consumer tutors became acutely unwell during the term and required care. As a result they developed an agreement to postpone their involvement in the tutoring whilst they received necessary treatment. Consumer tutors and students were understanding of this and students had a rare experience of the longitudinal patterns of an illness and the person.Out of a total cohort of 104 medical students, students completed the pre (n = 72) and post (n = 68) attitudes questionnaire using a 5 point scale (5 = strongly agree, 4 = agree, 3 = uncertain, 2 = disagree, 1 = strongly agree). A comparison of mean scores on 3 items reflecting student attitudes towards consumers was conducted using an independent samples t-test. Results showed that prior to the program the medical students began with positive attitudes towards learning from consumers (n = 57, x = 3.89, s.d. = .865) and working with mental health clients (n = 72, x = 3.68, s.d. = 747). Whilst there was a general trend towards further improvement in their attitudes, their mean scores pre and post the program were not significantly different. However, the medical students did show a significant improvement in their belief that "clients in psychiatric units give reliable histories" (n = 72, x = 3.07, s.d. = .657, p < .005)  were returned on 452 occasions. Analysis of the mean scores of students on the quality of the 'teaching' and 'content' of the program revealed favourable ratings . Whereas, tutors tended to rate the program even higher . A comparison of the mean scores of students and tutors using an independent samples t-test showed that this difference was statistically significant (p < 0.001), see Table All medical students who participated in the consumers as tutors program passed the university wide assessment of an observed psychiatric interview rated against defined criteria.th year medical students in effective approaches to interviewing. Training and delivery has continued requiring modest maintenance, perhaps in keeping with sustaining professional tutors. Consumer tutors have shown themselves to be reliable, professional in approach and amenable to feedback. Benefits for students  included the extended experience of working with a consumer of health services, the development of a clearer perspective regarding consumer views and an opportunity to see people with mental illness in recovery. Students were at least as well prepared as their peers for a structured assessment in interviewing . Students largely reported positive experiences, found the curriculum and delivery acceptable and saw tutor experience and knowledge as legitimate and valuable. Ideally it would have been useful to follow up medical students over a longer term to assess their psychiatric interviewing skill, however, this was not practically possible within this study.This project established the feasibility of training and supporting mental health consumers as tutors for delivery of a jointly developed curriculum for 4The attempt to measure attitudes deserves discussion. Attitudes are recognised as an important component of curriculum development yet remain the personal business of each of us. It would be reasonable to see education as a means of working past one's own attitudes rather than seeking to refine or replace student attitudes. Guidelines for working with consumers in health care assume that "for consumer participation to be effective, all participants in the process need to respect the different skills and expertise of the other participants" . In thisBenefits for consumer tutors  included enhanced self esteem and financial reward for work done. Consumer tutor curriculum development was novel such as utilising an art therapy vehicle to experience a non-pharmaceutical therapeutic device. Most consumer tutors have continued to teach, with appropriate breaks, and have mentored new tutors. Some have used this experience to step further into paid employment and to rehabilitate previous work skills. Consumer tutors have remained resilient and episodes of relapse appear to be multifactorial in origin (with teaching perhaps one of the factors). This robustness was also found in a study of psychological impact on consumers working in a peer support role in an acute care setting . ConsumeBenefits for the health system included the placement of consumers in a 'professional' light. Consumer tutors shared the staff tearoom, were paid as other casual tutors and were seen as well contributors rather than being in the sick role. Professional tutors were aware of the consumer tutor teaching and perhaps viewed it as 'politically correct' rather than educationally effective. Dissemination of findings via service and conference presentations has helped address this common view.Tutoring medical students is a skilful and potentially stressful role, and is not suitable for all mental health consumers. Following the training program some trained tutors realised that teaching was not their interest or strength . This was anticipated and should be factored into training plans. Some consumer tutors realised their tolerance level was insufficient to manage student junior skill level and found it hard to resist retelling their 'war stories' of difficult clinical encounters. This was a common theme in debriefing and required active refocusing on the curriculum of effective and ineffective interview techniques. The occasional protesting student required gentle persuasion to see that ongoing participation was a way of exploring contact with consumers. Like most education programs this approach did not run itself. Tutors required sustenance; feedback needed action and materials needed review. New tutors needed to be trained to add to the growing pool of available people. Despite these issues, our experience was that this was manageable and in keeping with maintenance of quality teaching by professional tutors.We believe this model is another valuable option in a range of consumer involvement programs and could be replicated in health, emergency services and support agency education. Discussions have occurred with carers about possible involvement. At this stage it was decided to invite carers to speak about specific topics in the mainstream program as consumers see their expertise as fundamentally different to that of a carer. Despite the potential for use with other groups, our attempt to use this experience in refreshing interview skills in general practitioners was unsuccessful. Notwithstanding the diligent work by all parties, local general practitioners held fast to the view that consumer tutors would lack the emotional robustness to survive teaching. They were welcome to come and talk of their experience but were not seen as competent to deliver a curriculum. This may well have been shorthand for more complex issues of concerns about confidentiality, power and autonomy. This example reminds us, however, that health education is in change and that new strategies are required to engage today's students in experiences that will produce clinicians skilled to support effective consumer participation in healthcare.We have detailed a feasibility study which demonstrates a new level of consumer participation in the design, implementation and evaluation of a medical student training program. The effort has been sustained over four years with appropriate maintenance. Largely positive outcomes were seen for students, consumer tutors and the health care system. These included raising the profile of consumers as 'legitimate teachers' in medical education and contributing to an improvement in the attitude of medical students towards mental health consumers. Together the joint partners in the program were able to manage obstacles, such as, pessimistic attitudes towards the involvement of consumers and difficulties adhering to the curriculum. Adopting a continuous review of the feedback from both medical students and consumer tutors has helped to further refine our ability to deliver the curriculum and better support the participants. Lastly, our experience has been that consumer tutors are an untapped resource offering a richness of experience and a professional approach to teaching that deserves closer examination in other health settings.Pfizer funded the initial pilot in the first year of the study.CO conceived of the study, participated in the design of both the consumer tutor curriculum and medical student curriculum and performed the data analysis. CO and RR participated in the training of consumers, monitored the implementation and evaluation phases and coordinated the program. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The manifestation of primary hyperparathyroidism with acute pancreatitis is a rare event. Ectopic paraesophageal parathyroid adenomas account for about 5%–10% of primary hyperparathyroidism and surgical resection results in cure of the disease.99mTc sestamibi scintigraphy. The tumor was resected via a cervical collar incision and calcium and parathormone tumor levels returned to normal within 48 hours.A 71-year-old woman was presented with acute pancreatitis and hypercalcaemia. During the investigation of hypercalcemia, a paraesophageal ectopic parathyroid mass was detected by computerized tomography (CT) scan and 99mTc sestamibi scintigraphy and CT scan of the neck and chest allows successful surgical treatment.Acute pancreatitis associated with hypercalcaemia should pose the suspicion of primary hyperparathyroidism. Accurate preoperative localization of an ectopic parathyroid adenoma, by using the combination of  Acute pancreatitis occurring secondary to hypercalcemia is rare. Most of the time adenomas are located in the neck. However, in 10–20% cases the parathyroid adenomas are found to be located within the mediastinum . ParaesoWe present a case of paraesophageal parathyroid adenoma clinically presenting as acute pancreatitis and successfully managed surgically by the collaboration of thoracic and general surgeons, via a cervical incision.3), increased serum levels of amylase (1,100 IU/L), LDH (550 IU/L) and calcium (14.8 mg/dl). On ultrasonography of the upper abdomen a non homogeneous appearance of the head of the pancreas was noted with a common bile duct diameter of 8.5 mm. CT scan of the abdomen confirmed the diagnosis of acute exudative pancreatitis. Acute pancreatitis subsided within 72 hours after conservative treatment. Further laboratory investigation of the hypercalcaemia revealed increased 24-hours urine calcium (465 mg), decreased serum phosphorus levels at 1.3 mg/dl, increased serum parathyroid hormone levels (771 pg/ml), normal levels of serum free T3 (FT3), free T4 (FT4), thyroid stimulating hormone (TSH), calcitonine, carcino embryonic antigen (CEA), carcinoma antigen (CA) 15-9, CA 125, alpha feto protein (AFP). Ultrasonography of the thyroid gland and the neck showed a suspicious prevertebral mass. CT scan of the thorax and neck detected a paraesophageal mediastinal mass close to the thoracic inlet.  which failed to show bile duct lithiasis. With a diagnosis of parathyroid adenoma, resection of the parathyroid adenoma via a collar cervical incision was carried out. The tumor was easily separated from the surrounded structures (vertebra, trachea, and esophagus) by blunt dissection and the feeding vessels were found and ligated anteriorly. Figure  The patiet al found significantly elevated serum calcium levels to be of major importance in the development of pancreatitis in patients with primary hyperparathyroidism [Recurrent episodes of acute pancreatitis secondary to hypercalcemia are an uncommon presentation of primary hyperparathyroidism -7. AcuteIncreased levels of serum calcium at the first episode of acute pancreatitis should pose the suspicion of primary hyperparathyroidism. In patients with a history of cholecystectomy (as in the presented case), where the main cause of an episode of acute pancreatitis is bile duct lithiasis, the diagnosis could be missed if serum calcium levels ranged within normal values. The main causes of primary hyperparathyroidism are single or double parathyroid adenoma (80%), hyperplasia of all four or more existing parathyroid glands 15–20%) and rarely cancer of the parathyroid gland (2%) 5–20% and.et al reported 5%–10% of the parathyroid glands to be located in the posterior mediastinum, 20% are found substernally within the thymic tissue in the anterior mediastinum (1–2%) while 1% of the glands are located in the carotid sheath and 5% into the thyroid gland. [99mTc sestamibi scintigraphy). The frequency of this occurrence at the moment is uncertain [Richards d gland. . By revid gland. . Parathy99mTc sestamibi scintigraphy and CT scan of the chest and neck gives important information to proceed with surgery and to minimize the risk of re-operation for recurrent hyperparathyroidism in the future [99mTc scintigraphy includes eutopic parathyroid disease, ectopic parathyroid disease, solitary, double or multiple parathyroid adenoma, cystic adenoma, lipoadenoma, multiple endocrine neoplasia, entities with atypical washout and non-parathyroid entities that take up 99mTc sestamibi  [99mTc sestamibi scintigraphy gives more information to the surgeon, concerning the depth of the lesion in atypical sites [Many investigators advocate the need for the concordance of at least two diagnostic modalities before surgical excision. The combination of e future ,16,18,19d tumor) . The addal sites .et al for preoperative detection and localization of parathyroid adenomas; high cost and limited availability of the scanners restrict its use as first-line examination in primary hyperparathyroidism [CT scan with intravenously injected contrast material has a low overall sensitivity of 45%–55% in primary hyperparathyroidism, but it is helpful mainly in the detection of ectopic mediastinal parathyroid adenomas ,3. Magneyroidism .Paraesophageal mediastinal adenomas are resected via a cervical incision in the majority of cases ,2,16,26.An ectopic paraesophageal parathyroid adenoma may be manifested with an episode of acute pancreatitis. Preoperative investigation for exact localization of an adenoma should include two imaging studies, preferably Tc-99m sestamibi scintigraphy or sestamibi-SPECT scintigraphy of the neck and chest and CT scan of the neck and chest. Resection of an ectopic paraesophageal adenoma is easily accomplished via a cervical incision and blunt mobilization of the tumor.The author(s) declare that they have no competing interests.CNF has made contribution to the conception, design and drafting of the article, was involved in the critical revision of the article.S R has made contribution to the conception, design and drafting of the article.C L has made contribution to the conception and design of the article.D K has made contribution to the conception and design of the article.G K has made contribution to the conception and design of the article, was involved in the critical revision of the article.AL has made contribution to the conception and design of the article, was involved in the critical revision of the article.All the authors have read and approved the final version of the manuscript.