Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community.

There is limited research which examines health concerns of individuals with osteogenesis imperfecta (OI). Discussion groups with leaders of the adult OI community identified a broad range of medical priorities beyond fractures and brittle bones. Our work underscores the need to include patient-reported outcomes in rare bone disease research. INTRODUCTION: Osteogenesis imperfecta (OI) is a rare genetic disorder affecting collagen protein leading to brittle bones and a number of other medical complications. To date, there is limited research which examines the life-long process of aging with this rare disease, much less the perspective of individuals with OI. METHODS: In order to explore and prioritize health concerns that adults with OI feel have been inadequately addressed in health care and research, investigators held discussions with leaders from the global adult OI community. The meetings were held in August 2017 at the 13th International Conference on OI in Oslo, Norway as part of the preconference seminar "Patient Participation in OI Research". Investigators were part of the Brittle Bone Disease Consortium (BBDC), a multicenter research program devoted to the study of OI, and their focus was on patient-reported outcomes (PRO). RESULTS: Participants noted that while fractures and brittle bones are the most common feature of OI, a number of body systems are under-studied in this disorder. They particularly emphasized breathing, hearing, and the effects of aging as primary concerns that researchers and physicians may not fully understand or address. Other areas included pain, gastrointestinal problems, mental health, nutrition, menopause/pregnancy, and basilar invagination. Participants also emphasized that they must be informed of study results. They underscored that outcome measures incorporated into future drug trials must look beyond fractures and consider the whole patient. CONCLUSIONS: This work will help guide the incorporation of PROs into the next phase of the BBDC Natural History Study of OI and underscores the importance of including PROs in the study of rare diseases.

Patient recollections of perioperative anaesthesia risks.

There is widespread variation as to the method of presentation of informed anaesthetic consent with little empirical data on the nature of communication and how much information is retained. At a dedicated anaesthesia pre-admission clinic, 149 patients undergoing elective surgery under general anaesthesia were both verbally informed and shown written information about four major and three minor anaesthesia risks. The major risks were death, pneumonia, heart attack and stroke. The minor risks were dental damage, nausea and vomiting. On the day of scheduled surgery, retention of information about these anaesthetic risks was examined. Thirty-eight patients (26%) could not recall any anaesthesia risks, 55 patients (37%) could not recall any major risks and 126 patients (84%) could not recall any minor risks. Our findings indicate that patients should receive a second explanation on the day of surgery, even if informed consent was provided only two weeks earlier.

Modelling the way that dentists use information: an audit tool for capability and competency.

Information, and the use of computers to provide that information, is becoming an increasingly important part of all aspects of clinical practice including dentistry. In 2003, a survey of English dental practices found nearly a quarter of practices were not using computers at all. Dental practices, whether NHS or private, can use information technology to provide significant benefits to patients and practices alike. In this article, a model is described for the maturity of information usage in dental practices. The model uses an approach successfully deployed previously in a range of applications in healthcare and other domains. The approach audits current maturity of usage and staff competency to help develop improvement plans for dental practices. The article describes how the model has been made freely available to dental practices over the Internet.

The use of ketamine as rescue analgesia in the recovery room following morphine administration--a double-blind randomised controlled trial in postoperative patients.

In some patients, control of postoperative pain can be difficult with morphine alone. This double-blind randomised controlled trial was designed to evaluate whether a small bolus dose of ketamine could improve pain scores in those patients who had inadequate relief of their postoperative pain after two standard doses of morphine. Forty-one patients with uncontrolled postoperative pain were randomly assigned to receive either morphine (M) alone, or morphine plus 0.25 mg/kg ketamine (K) in the recovery room. No other analgesics were to be given. The study had adequate power to detect a 25% difference in pain scores. There was no statistically significant difference in verbal rating scale pain scores between the two groups either in the recovery room (K = 5.16, M = 6.28, P = 0.065), or at a later time on the ward. There was no apparent difference between groups in sedation, morphine consumption, postoperative nausea and vomiting, quality of recovery or need for rescue analgesia. We could not demonstrate an effective role for ketamine in the management of problematic postoperative pain at the dose studied.

Models of the subthalamic nucleus. The importance of intranuclear connectivity.

A coherent set of models is presented that provide novel and testable predictions about the functional role of the subthalamic nucleus (STN) in the basal ganglia. The STN is emerging as an important target for novel therapeutic strategies for the alleviation of Parkinsonian type symptoms [Lancet 345 (1995) 91; Science 249 (1990) 1436]. Computational and mathematical models based on the properties of the STN and its interactions are reviewed. These models focus on core anatomical and physiological data that span many levels. By assessing models of anatomy, dynamic network models, and a detailed model of a recent pharmacological experiment, we can expose the primary modes of STN function and highlight their underlying properties. We show that the presence of functional interactions between STN projection neurons is critical in defining its behaviour and how it interacts with other basal ganglia nuclei. Pulses or switch-like activity patterns emerge in the models as a consequence of these local interactions. Furthermore, the models demonstrate that this behaviour can break down under abnormal conditions resulting in low frequency bursting oscillations. Such oscillations may play a role in symptoms of Parkinson's disease.

Arm position and blood pressure: a risk factor for hypertension?

The objective of this study was to re-evaluate the effect of arm position on blood pressure (BP) measurement with auscultatory and oscillometric methods including ambulatory blood pressure monitoring (ABPM). The setting was the hospital outpatient department and the subjects chosen were normotensive and hypertensive. The effect of lowering the arm from heart level on indirect systolic BP (SBP) and diastolic BP (DBP) measurement as well as the importance of supporting the horizontal arm were measured. In the sitting position, lowering the supported horizontal arm to the dependent position increased BP measured by a mercury device from 103+/-10/60+/-7 to 111+/-14/67+/-10 mmHg in normotensive subjects, a mean increase of 8/7 mmHg (P<0.01). In hypertensive subjects, a similar manoeuvre increased BP from 143+/-21/78+/-17 to 166+/-29/88+/-20 mmHg, an increase of 23/10 mmHg (P<0.01). Combined results from normotensive and hypertensive subjects demonstrate a direct and proportional association between BP (SBP and DBP) and the increase produced by arm dependency. Similar changes and associations were noted with oscillometric devices in the clinic situation. However, supporting the horizontal arm did not alter BP. Of particular interest, analysis of 13 hypertensive subjects who underwent ABPM on two occasions, once with the arm in the 'usual' position and once with the arm held horizontally for BP measurement during waking hours, demonstrated changes comparable to the other devices. The mean 12-hour BP was 154+/-19/82+/-10 mmHg during the former period and significantly decreased to 141+/-18/74+/-9 mmHg during the latter period (P<0.01). Regression analysis of the change in SBP and DBP with arm position change again demonstrated a close correlation (r(2)=0.8113 and 0.7273; P<0.001) with the artefact being larger with higher systolic and diastolic pressures. In conclusion, arm movements lead to significant artefacts in BP measurement, which are greater, the higher the systolic or diastolic pressure. These systematic errors occur when using both auscultatory and oscillometric (clinic and ABPM) devices and might lead to an erroneous diagnosis of hypertension and unnecessary medication, particularly in individuals with high normal BP levels. Since clinical interpretations of heart level vary, the horizontal arm position should be the unambiguous standard for all sitting and standing BP auscultatory and oscillometric measurements.

Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy.

Pulmonary alveolar proteinosis is a rare condition traditionally requiring treatment with whole lung lavage. The case is presented of a young man who obtained complete remission following treatment with granulocyte-macrophage colony stimulating factor, a new treatment option.

Assessing and improving the quality of information for health evaluation and promotion.

Studies by the author based upon a sample of over 1.1 million patients in the North West of England have shown that the introduction of computers cannot be demonstrated to produce significant improvements in health promotion activity. Other studies have revealed error rates in healthcare information systems in excess of 50%. This paper considers the reasons for these findings and demonstrate that there is a level of maturity of information management required before information systems can make a significant contribution to health promotion and evaluation. With the advent of locality commissioning and a re-affirmation of the emphasis upon health promotion activity set out in Health of the Nation and Our Healthier Nation [8], the role of information management has become even more significant. The paper presents a maturity model developed by the author, known as General Practice Information Maturity Model (GPIMM) that provides a strategic framework to improve the use of information by practices and to improve practice to enable viable sharing of accurate information. The paper will show the model can be used as a basis for the development of training and information strategies. The model identifies computerised practices as being in one of five stages of maturity: (1) Computerised, (2) Computerised PHC Team, (3) Coded, (4) Bespoke, (5) Paperless. The model specifically leads practices to a point in their development where they are able to carry out health evaluation, promotion and audit activities as a routine activity. Once these activities form part of practice activity they are then extended to encompass a group of practices such as a Primary Care Group. Finally, a case study is presented to show how the model was used to enable two very different but geographically neighbouring practices to work together towards the establishment of a common dataset. This dataset will be used to enable health promotion and evaluation activity to be provided for a total population of over 20,000 patients.

Computational models of the basal ganglia.

Computer simulation studies and mathematical analysis of models of the basal ganglia are being used increasingly to explore theories of basal ganglia function. We review the implications of these new models for a general understanding of basal ganglia function in normal as well as in diseased brains. The focus is on their functional similarities rather than on the details of mathematical methodologies and simulation techniques. Most of the models suggest a vital role for the basal ganglia in learning. Although this interest in learning is partly driven by experimental results associating the acute firing of dopamine cells with reward prediction in monkeys, some of the models have preceded the electrophysiological results. Another common theme of the models is selection. In this case, the striatum is seen as detecting and selecting cortical contexts for access to basal ganglia output. Although the behavioral consequences of this selection are hard to define, the models provide frameworks within which to explore these ideas empirically. This provides a means of refining our understanding of basal ganglia function and to consider dysfunction within the new logical frameworks.

Conservation genetics of bush mango from central/west Africa: implications from random amplified polymorphic DNA analysis.

Genetic variation was assessed in the two bush mango species, Irvingia gabonensis and I. wombolu, valuable multipurpose fruit trees from central and west Africa that are currently undergoing domestication. A total of 130 individuals sampled from Cameroon, Nigeria and Gabon were analysed using 74 random amplified polymorphic DNAs (RAPDs). Significant genetic integrity was found in the two morphologically similar species (among-species analysis of molecular variance [AMOVA] variance component 25.8%, P < 0.001), with no evidence of hybridization, even between individuals from areas of sympatry where hybridization was considered probable. Results suggest that large-scale transplantation of either species into new habitats will probably not lead to genetic introgression from or into the other species. Therefore, subsequent cultivation of the two species should not be hindered by this consideration, although further studies on the potential for hybridization/introgression between these species would be prudent. Significant genetic differentiation of both species (among-countries within species, nested AMOVA variance component 9.8%, P < 0.001) was observed over the sampled regions, and genetic similarity of samples decreased significantly with increasing geographical distance, according to number of alleles in common (NAC) analysis. 'Hot spots' of genetic diversity were found clustered in southern Nigeria and southern Cameroon for I. wombolu, and in southern Nigeria, southern Cameroon and central Gabon for I. gabonensis. The possible reasons for this distribution of genetic variation are discussed, but it may reflect evolutionary history, as these populations occur in areas of postulated Pleistocene refugia. The application of these results to domestication programmes and, in the light of extensive deforestation in the region, conservation approaches, is discussed.

Genetic diversity in mesoamerican populations of mahogany (Swietenia macrophylla), assessed using RAPDs

Swietenia macrophylla King, a timber species native to tropical America, is threatened by selective logging and deforestation. To quantify diversity within the species and monitor the impact of selective logging, populations were sampled across Mesoamerica, from Mexico to Panama, and analysed for RAPD DNA variation. Ten decamer primers generated 102 polymorphic RAPD bands and pairwise distances were calculated between populations according to Nei, then used to construct a radial neighbour-joining dendrogram and examine intra- and interpopulation variance coefficients, by analysis of molecular variation (AMOVA). Populations from Mexico clustered closely together in the dendrogram and were distinct from the rest of the populations. Those from Belize also clustered closely together. Populations from Panama, Guatemala, Costa Rica, Nicaragua and Honduras, however, did not cluster closely by country but were more widely scattered throughout the dendrogram. This result was also reflected by an autocorrelation analysis of genetic and geographical distance. Genetic diversity estimates indicated that 80 percent of detected variation was maintained within populations and regression analysis demonstrated that logging significantly decreased population diversity (P=0.034). This study represents one of the most wide-ranging surveys of molecular variation within a tropical tree species to date. It offers practical information for the future conservation of mahogany and highlights some factors that may have influenced the partitioning of genetic diversity in this species across Mesoamerica.(Au)

Hospital blood pressure measurement: staff and device assessment.

Evaluation of the ability of clinical staff to measure blood pressure as well as the functional state of hospital sphygmomanometers has consistently demonstrated marked deficiencies. In this study, the working order of all sphygmomanometers (manual and automated) in a teaching hospital was evaluated. Nursing staff were tested on their knowledge and use of such devices and were also asked to estimate the blood pressure from videotape. The accuracy of a commonly used automated device, Dinamap 8100, was also measured. Of 543 manual sphygmomanometers, 14% were in perfect working order although portable devices were more likely to be functional (47% of 36 units). In contrast, all 135 automated portable devices were in perfect working order although service requirements were seldom met. The mean time since last service was 18 months. There appeared to be an inverse correlation between the availability of automated and manual devices and the maintenance of wall-mounted bedside sphygmomanometers. Staff knowledge about manual devices was adequate as was their ability to accurately measure blood pressure using standardised videotape. Forty-two per cent of 31 nurses who completed the test were correct in 9 of 12 blood pressures. A comparison of this result with a comparable group of nurses tested in 1990 did not detect a significant change in competence. Direct evaluation of the commonly used Dinamap 8100 in 47 hospital patients demonstrated a poor correlation with a mercury sphygmomanometer with a D grade (fail) for systolic and a C grade for diastolic pressure. In summary, maintenance of manual sphygmomanometers was very poor, probably due to their lack of use by clinical staff. This was particularly true for units attached to bedside walls. Nursing staff demonstrated significant deficiencies in manual sphygmomanometer use although their skills were similar to those measured several years earlier. Because of the demonstrated inaccuracy of the Dinamap 8100 automated device, the strong trend towards the use of automated devices instead of manual sphygmomanometers within hospitals cannot be supported.

Antihypertensive drug treatment: a comparison of usual care with self blood pressure measurement.

Blood pressure self-measurement is increasing in most communities and yet its role in the management of hypertension is poorly understood. This study was devised to evaluate the behaviour of doctors in general practice when treating patients with poorly controlled essential hypertension who use self-measurement. Patients, most of whom were already taking antihypertensive medications were commenced on perindopril or indapamide at their doctor's discretion and were randomly allocated to self-measurement (SM) using an OMRON HEM706 oscillometric device or a continuation of their usual care (UC) over an 8-week period. This was an observational study without any specific or set treatment goals for the doctor to follow. Sixty of 62 subjects completed the study and the two groups were equally matched for age, body mass index, gender, and blood pressure (BP). While additional perindopril or indapamide produced a significant fall in BP in both groups over the study period, the systolic pressure remained significantly higher in the SM group (sitting 148 +/- 3 compared with 142 +/- 3; 145 +/- 3 compared with 138 +/- 3 mm Hg respectively; P < 0.05). Twenty-four hour and daytime ambulatory monitor systolic pressures were also significantly higher in the SM group. Differences in diastolic BP were not statistically significant. Furthermore, SM patients were less likely to have their medications increased and more likely to have them reduced or ceased. Doctors and patients found self-measurement convenient and useful. This study suggests that doctors prescribing decisions are influenced by evidence from self-measurement of BP with consequential increases in office BP related to reduced drug use. While self-BP measurement can offer reassurance about adequacy of control when away from a physicians office, our best evidence of understanding target blood pressures comes from large randomised studies using office blood pressures as an end-point. There is an urgent need for further study to provide arbitration between self-measurement and office blood pressures although each measurement must contribute to the management of hypertension.

Genetic diversity in mesoamerican populations of mahogany (Swietenia macrophylla), assessed using RAPDs.

Swietenia macrophylla King, a timber species native to tropical America, is threatened by selective logging and deforestation. To quantify genetic diversity within the species and monitor the impact of selective logging, populations were sampled across Mesoamerica, from Mexico to Panama, and analysed for RAPD DNA variation. Ten decamer primers generated 102 polymorphic RAPD bands and pairwise distances were calculated between populations according to Nei, then used to construct a radial neighbour-joining dendrogram and examine intra- and interpopulation variance coefficients, by analysis of molecular variation (AMOVA). Populations from Mexico clustered closely together in the dendrogram and were distinct from the rest of the populations. Those from Belize also clustered closely together. Populations from Panama, Guatemala, Costa Rica, Nicaragua and Honduras, however, did not cluster closely by country but were more widely scattered throughout the dendrogram. This result was also reflected by an autocorrelation analysis of genetic and geographical distance. Genetic diversity estimates indicated that 80% of detected variation was maintained within populations and regression analysis demonstrated that logging significantly decreased population diversity (P = 0.034). This study represents one of the most wide-ranging surveys of molecular variation within a tropical tree species to date. It offers practical information for the future conservation of mahogany and highlights some factors that may have influenced the partitioning of genetic diversity in this species across Mesoamerica.

A massively connected subthalamic nucleus leads to the generation of widespread pulses.

A composite model of the subthalamic nucleus is developed from physiological and anatomical considerations. First, study of a geometric model of the anatomical arrangements of projection neurons within the nucleus indicates that they form a massively connected network. Second, given the excitatory nature of these neurons, their threshold and peak firing rates, a simple model of neuron responses reveals that large regions of this highly interconnected nucleus can respond to excitatory input in the form of a wide-spread uniform pulse. Such widespread pulses of activity may act as a braking signal that resets the major basal ganglia output nuclei.

Effect of diuretics on sodium and chloride permeability in the rat papillary collecting duct.

While in vivo data suggests that diuretics such as furosemide and hydrochlorothiazide alter inner medulla collecting duct (IMCD) cell electrolyte transport, this has not been confirmed by in vivo studies nor have the mechanisms been evaluated. This study evaluated the direct effect of these diuretics as well as amiloride on sodium and chloride unidirectional permeability in the isolated perfused rat IMCD. In the absence of diuretics, the permeability of sodium was lower than that of chloride (0.63 +/- 0.05 compared with 0.83 +/- 0.08 micrometer/s), although both were relatively impermeable when compared to water. Furosemide (10(-4)) and hydrochlorothiazide (10(-3)) both increased the diffusional permeability of chloride by approximately 30% (0.80 +/- 0.06 to 1.04 +/- 0.09 micrometer/s, p < 0.01, and 0.74 +/- 0.09 to 0.98 +/- 0.10 micrometer/s, p < 0.02, respectively). However, sodium permeability was unaltered. Inhibition of Na+, K+-ATPase by ouabain or cooling (4 degrees C) inhibited basal sodium but not chloride permeability while a maximal antidiuretic AVP concentration did not alter sodium or chloride permeability. However, increasing the lumen and bath sodium chloride concentration from 150 to 300 and 600 mM significantly increased both sodium and particularly chloride conductance. In contrast, amiloride (10(-4)) significantly reduced both sodium and chloride permeability. These studies support a direct effect of furosemide and hydrochlorothiazide on the IMCD and suggest that their in vivo effect is primarily mediated by facilitating the passive movement of chloride into the lumen via a favourable electrochemical gradient. These results also demonstrate that amiloride inhibits both sodium and chloride unidirectional permeability by mechanisms separate to that of the sulphonamide-related diuretics.

Numerical chromosomal aberrations in Hodgkin's disease detected by in situ hybridisation on routine paraffin sections.

AIMS: To visualise directly numerical chromosomal aberrations and polyploidy in both Hodgkin and Reed Sternberg (HRS) cells and background cells from cases of Hodgkin's disease using in situ hybridisation. METHODS: Non-isotopic DNA in situ hybridisation was applied to interphase cell nuclei of Hodgkin's disease within routine paraffin embedded tissue sections. Two a satellite DNA probes, specific for chromosomes 3 and 12, were used to evaluate the feasibility of this approach. Double labelling with immunocytochemical detection of the CD30 antigen was used to identify HRS cells. Cytogenetic normal diploid and triploid placental tissue served as controls. RESULTS: The eight cases of Hodgkin's disease investigated displayed frequent polysomy, while the majority of background cells showed disomy signals. CONCLUSIONS: Numerical chromosomal aberrations were detected in HRS cells from eight cases of Hodgkin's disease by in situ hybridisation. These data show that in Hodgkin's disease HRS cells frequently display polyploidy compared with background cells and are, therefore, probably the only neoplastic component in this disease. Correlations between polysomy and tumour type or grade could not be made from these data owing to the limited number of cases examined and to problems with interpreting data from truncated nuclei.