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1.  Between Celiac Disease and Irritable Bowel Syndrome: The “No Man’s Land” of Gluten Sensitivity 
The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.
PMCID: PMC3480312  PMID: 19455131
2.  Protein phosphatase 5 protects neurons against amyloid β toxicity 
Journal of neurochemistry  2009;111(2):391-402.
Amyloid β (Aβ) is thought to promote neuronal cell loss in Alzheimer’s disease (AD), in part through the generation of reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) pathways. Protein phosphatase 5 (PP5) is a ubiquitously expressed serine/threonine phosphatase which has been implicated in several cell stress response pathways and shown to inactivate MAPK pathways through key dephosphorylation events. Therefore we examined whether PP5 protects dissociated embryonic rat cortical neurons in vitro from cell death evoked by Aβ. As predicted, neurons in which PP5 expression was decreased by siRNA treatment were more susceptible to Aβ toxicity. In contrast, overexpression of PP5, but not the inactive PP5 mutant, H304Q, prevented MAPK phosphorylation and neurotoxicity induced by Aβ. PP5 also prevented cell death caused by direct treatment with H2O2, but did not prevent Aβ-induced production of ROS. Thus, the neuroprotective effect of PP5 requires its phosphatase activity and lies downstream of Aβ-induced generation of ROS. In summary, our data indicate that PP5 plays a pivotal neuroprotective role against cell death induced by Aβ and oxidative stress. Consequently, PP5 might be an effective therapeutic target in AD and other neurodegenerative disorders in which oxidative stress is implicated.
PMCID: PMC3044491  PMID: 19686245
PP5; protein phosphatase 5; amyloid β; Alzheimer’s disease; neuroprotection; oxidative stress
3.  In the psychiatrist's chair: how neurologists understand conversion disorder 
Brain  2009;132(10):2889-2896.
Conversion disorder (‘hysteria’) was largely considered to be a neurological problem in the 19th century, but without a neuropathological explanation it was commonly assimilated with malingering. The theories of Janet and Freud transformed hysteria into a psychiatric condition, but as such models decline in popularity and a neurobiology of conversion has yet to be found, today's neurologists once again face a disorder without an accepted model. This article explores how today's neurologists understand conversion through in-depth interviews with 22 neurology consultants. The neurologists endorsed psychological models but did not understand their patients in such terms. Rather, they distinguished conversion from other unexplained conditions clinically by its severity and inconsistency. While many did not see this as clearly distinct from feigning, they did not feel that this was their problem to resolve. They saw themselves as ‘agnostic’ regarding non-neuropathological explanations. However, since neurologists are in some ways more expert in conversion than psychiatrists, their continuing support for the deception model is important, and begs an explanation. One reason for the model's persistence may be that it is employed as a diagnostic device, used to differentiate between those unexplained symptoms that could, in principle, have a medical explanation and those that could not.
PMCID: PMC2759333  PMID: 19321463
conversion disorder; hysteria; malingering; deception; factitious disorder
4.  Metabolic and Mitochondrial Dysfunction in Early Mouse Embryos Following Maternal Dietary Protein Intervention1 
Biology of Reproduction  2009;80(4):622-630.
Dietary supply of nutrients, both periconception and during pregnancy, influence the growth and development of the fetus and offspring and their health into adult life. Despite the importance of research efforts surrounding the developmental origins of health and disease hypothesis, the biological mechanisms involved remain elusive. Mitochondria are of major importance in the oocyte and early embryo, particularly as a source of ATP generation, and perturbations in their function have been related to reduced embryo quality. The present study examined embryo development following periconception exposure of females to a high-protein diet (HPD) or a low-protein diet (LPD) relative to a medium-protein diet (MPD; control), and we hypothesized that perturbed mitochondrial metabolism in the mouse embryo may be responsible for the impaired embryo and fetal development reported by others. Although the rate of development to the blastocyst stage did not differ between diets, both the HPD and LPD reduced the number of inner cell mass cells in the blastocyst-stage embryo. Furthermore, mitochondrial membrane potential was reduced and mitochondrial calcium levels increased in the 2-cell embryo. Embryos from HPD females had elevated levels of reactive oxygen species and ADP concentrations, indicative of metabolic stress and, potentially, the uncoupling of oxidative phosphorylation, whereas embryos from LPD females had reduced mitochondrial clustering around the nucleus, suggestive of an overall quietening of metabolism. Thus, although periconception dietary supply of different levels of protein is permissive of development, mitochondrial metabolism is altered in the early embryo, and the nature of the perturbation differs between HPD and LPD exposure.
The supply of high (25%) or low (9%) levels of dietary protein to the female mouse prior to conception is permissive of embryo development but has differential effects on the metabolism and mitochondria of 2-cell embryos.
PMCID: PMC2849812  PMID: 19129514
embryo; metabolism; mitochondria; nutrition
5.  Limits to truth-telling: Neurologists’ communication in conversion disorder 
Patient Education and Counseling  2009;77(2):296-301.
Neurologists face a dilemma when communicating with their conversion disorder patients – whether to be frank, and risk losing the patient's trust, or to disclose less, in the hope of building a therapeutic relationship. This study reports how neurologists in the UK described dealing with this dilemma in their practice.
Practicing consultant neurologists from an NHS region were recruited by snowball sampling. Twenty-two of 35 consultants in the region were interviewed in depth, and the interviews qualitatively analysed.
The neurologists were reluctant to disclose conversion disorder as a differential diagnosis until they were certain. They were guided by the receptivity of their patients as to how psychological to make their eventual explanations, but they did not discuss their suspicions about feigning. They described their communications as much easier now than they had seen in training.
Neurologists adapt their disclosure to their patients, which facilitates communication, but imposes some limits on truth-telling. In particular, it may sometimes result in a changed diagnosis.
Practice implications
An optimum strategy for communicating diagnoses will need to balance ethical considerations with demonstrated therapeutic benefit.
PMCID: PMC2773836  PMID: 19560894
Conversion disorder; Factitious disorder; Malingering; Hysteria; Truth-telling; Deception; Neurology
6.  A Method of External Fixation to Offload and Protect the Foot Following Reconstruction in High-Risk Patients: The SALSAstand 
Eplasty  2009;9:e21.
Introduction: The course of wound healing in high-risk patients with diabetes, particularly those with peripheral arterial disease and renal failure, is often prolonged and fraught with complications. Traditional methods of offloading the posterior foot or holding correction in place following diabetic foot reconstruction include various padded and bolstering devices. Methods: In this article, we describe a method (SALSAstand) to effectively elevate, offload, and protect the foot with an external fixation device, while also promoting flap healing, maintaining tendon correction, and limiting the tendon retraction and contracture that is commonly seen following a foot-salvage procedure in high-risk patients. Results: Not applicable. Discussion: The SALSAstand device has been successfully utilized on many patients in our service to accomplish the aforementioned goals in this most challenging patient population.
PMCID: PMC2697004  PMID: 19578534
7.  The Diabetic Rapid Response Acute Foot Team: 7 Essential Skills for Targeted Limb Salvage 
Eplasty  2009;9:e15.
Objective: People with diabetes are prone to develop lower-extremity ulcerations and infections, both of which serve as major risk factors for limb amputation. The development of lower-extremity complications of diabetes is associated with increased morbidity and mortality. Recently, there has been increasing interest in the development of interdisciplinary teams to manage the myriad factors that complicate the treatment of high-risk patients, particularly in the perihospitalization period. Methods: This article presents 7 essential skills that necessarily allow the limb salvage team to appropriately manage the most common presenting comorbidities in patients with diabetes, including vasculopathy, infection, and deformity. Results: Seven essentials skills have been demonstrated to promote the greatest salvage outcomes, and these are the ability to (1) perform hemodynamic and anatomic vascular assessment with revascularization, as necessary; (2) perform neurologic workup; (3) perform site-appropriate culture technique; (4) perform wound assessment and staging/grading of infection and ischemia; (5) perform site-specific bedside and intraoperative incision and debridement; (6) initiate and modify culture-specific and patient-appropriate antibiotic therapy; and (7) perform appropriate postoperative monitoring to reduce risk of reulceration and infection. Conclusions: Utilization of these 7 essential skills as the core basis for interdisciplinary limb salvage team models will provide clinicians guidance when establishing such teams. Interdisciplinary teams have been demonstrated to improve quality and efficiency of patient care, thus improving overall outcomes and reducing amputation rates.
PMCID: PMC2680239  PMID: 19436764
8.  Hydrodebridement of wounds: effectiveness in reducing wound bacterial contamination and potential for air bacterial contamination 
The purpose of this study was to assess the level of air contamination with bacteria after surgical hydrodebridement and to determine the effectiveness of hydro surgery on bacterial reduction of a simulated infected wound.
Four porcine samples were scored then infected with a broth culture containing a variety of organisms and incubated at 37°C for 24 hours. The infected samples were then debrided with the hydro surgery tool (Versajet, Smith and Nephew, Largo, Florida, USA). Samples were taken for microbiology, histology and scanning electron microscopy pre-infection, post infection and post debridement. Air bacterial contamination was evaluated before, during and after debridement by using active and passive methods; for active sampling the SAS-Super 90 air sampler was used, for passive sampling settle plates were located at set distances around the clinic room.
There was no statistically significant reduction in bacterial contamination of the porcine samples post hydrodebridement. Analysis of the passive sampling showed a significant (p < 0.001) increase in microbial counts post hydrodebridement. Levels ranging from 950 colony forming units per meter cubed (CFUs/m3) to 16780 CFUs/m3 were observed with active sampling of the air whilst using hydro surgery equipment compared with a basal count of 582 CFUs/m3. During removal of the wound dressing, a significant increase was observed relative to basal counts (p < 0.05). Microbial load of the air samples was still significantly raised 1 hour post-therapy.
The results suggest a significant increase in bacterial air contamination both by active sampling and passive sampling. We believe that action might be taken to mitigate fallout in the settings in which this technique is used.
PMCID: PMC2694772  PMID: 19426486
9.  An implementation research agenda 
In October 2006, the Chief Medical Officer (CMO) of England asked Professor Sir John Tooke to chair a High Level Group on Clinical Effectiveness in response to the chapter 'Waste not, want not' in the CMOs 2005 annual report 'On the State of the Public Health'. The high level group made recommendations to the CMO to address possible ways forward to improve clinical effectiveness in the UK National Health Service (NHS) and promote clinical engagement to deliver this. The report contained a short section on research needs that emerged from the process of writing the report, but in order to more fully identify the relevant research agenda Professor Sir John Tooke asked Professor Martin Eccles to convene an expert group – the Clinical Effectiveness Research Agenda Group (CERAG) – to define the research agenda. The CERAG's terms of reference were 'to further elaborate the research agenda in relation to pursuing clinically effective practice within the (UK) National Health Service'. This editorial presents the summary of the CERAG report and recommendations.
PMCID: PMC2671479  PMID: 19351400
10.  Nonlinear modeling of venous leg ulcer healing rates 
BMC Dermatology  2009;9:2.
The purpose of this manuscript was to determine whether the change in wound surface area over time could be described through nonlinear mathematics.
We studied 3,588 serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized trial of two topical wound treatments.
A majority (72%) of VLUs exhibited surface area reduction via an exponential decay model, particularly during the early stages of healing. These results were consistent with the mechanics of wound contraction and epithelial cell proliferation, supported by the higher frequency at which exponential surface area reduction associated with full wound closure (35% of wounds that fit the exponential model healed vs. 21% of wounds that did not fit the exponential model completely healed during the study period, p = 0.018). Goodness-of-fit statistics suggested that much of the individual variation in healing could be described as nonlinear variation from the exponential model.
We believe that parameter estimates from a mathematical model may provide a more accurate quantification of wound healing rates, and that similar models may someday reach routine use in comparing the efficacy of various treatments in routine practice and in product registration trials.
PMCID: PMC2672927  PMID: 19335882
11.  CMOS Image Sensors for High Speed Applications 
Sensors (Basel, Switzerland)  2009;9(1):430-444.
Recent advances in deep submicron CMOS technologies and improved pixel designs have enabled CMOS-based imagers to surpass charge-coupled devices (CCD) imaging technology for mainstream applications. The parallel outputs that CMOS imagers can offer, in addition to complete camera-on-a-chip solutions due to being fabricated in standard CMOS technologies, result in compelling advantages in speed and system throughput. Since there is a practical limit on the minimum pixel size (4∼5 μm) due to limitations in the optics, CMOS technology scaling can allow for an increased number of transistors to be integrated into the pixel to improve both detection and signal processing. Such smart pixels truly show the potential of CMOS technology for imaging applications allowing CMOS imagers to achieve the image quality and global shuttering performance necessary to meet the demands of ultrahigh-speed applications. In this paper, a review of CMOS-based high-speed imager design is presented and the various implementations that target ultrahigh-speed imaging are described. This work also discusses the design, layout and simulation results of an ultrahigh acquisition rate CMOS active-pixel sensor imager that can take 8 frames at a rate of more than a billion frames per second (fps).
PMCID: PMC3280755  PMID: 22389609
Active-pixel-sensor; biomedical imaging; CCD; CMOS; high-speed; image-sensor; photodetectors; smart-pixel

Results 1-11 (11)