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2.  A Family Medicine Health Technology Strategy for Achieving the Triple Aim for US Health Care 
Family medicine  2015;47(8):628-635.
Health information technology (health IT) and health technology, more broadly, offer tremendous promise for connecting, synthesizing, and sharing information critical to improving health care delivery, reducing health system costs, and achieving personal and community health. While efforts to spur adoption of electronic health records (EHRs) among US practices and hospitals have been highly successful, aspirations for effective data exchanges and translation of data into measureable improvements in health outcomes remain largely unrealized. There are shining examples of health enhancement through new technologies, and the discipline of family medicine is well poised to take advantage of these innovations to improve patient and population health. The Future of Family Medicine led to important family medicine health IT initiatives over the past decade. For example, the American Academy of Family Physicians (AAFP) Center for Health Information Technology and the Robert Graham Center provided important leadership for informing health IT policy and standard-setting, such as the Centers for Medicare and Medicaid Services EHR incentives programs (often referred to as “meaningful use.”). As we move forward, there is a need for a new and more comprehensive family medicine strategy for technology. To inform the Family Medicine for America’s Health (FMAHealth) initiative, this paper explores strategies and tactics that family medicine could pursue to improve the utility of technology for primary care and to help primary care become a leader in rapid development, testing, and implementation of new technologies. These strategies were also designed with a broader stakeholder audience in mind, intending to reach beyond the work being done by FMAHealth. Specific suggestions include: a shared primary care health IT center, meaningful primary care quality measures and capacity to assess/report them, increased primary care technology research, a national family medicine registry, enhancement of family physicians’ technology leadership, and championing patient-centered technology functionality.
PMCID: PMC4926766  PMID: 26382121
3.  The impact of routine surveillance screening with magnetic resonance imaging (MRI) to detect tumour recurrence in children with central nervous system (CNS) tumours: protocol for a systematic review and meta-analysis 
Systematic Reviews  2016;5(1):143.
The aim of this study is to assess the impact of routine MRI surveillance to detect tumour recurrence in children with no new neurological signs or symptoms compared with alternative follow-up practices, including periodic clinical and physical examinations and the use of non-routine imaging upon presentation with disease signs or symptoms.
Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases have been searched, and further citation searching and reference checking will be employed. Randomised and non-randomised controlled trials assessing the impact of routine surveillance MRI to detect tumour recurrence in children with no new neurological signs or symptoms compared to alternative follow-up schedules including imaging upon presentation with disease signs or symptoms will be included.
The primary outcome is time to change in therapeutic intervention. Secondary outcomes include overall survival, surrogate survival outcomes, response rates, diagnostic yield per set of images, adverse events, quality of survival and validated measures of family psychological functioning and anxiety. Two reviewers will independently screen and select studies for inclusion. Quality assessment will be undertaken using the Cochrane Collaboration’s tools for assessing risk of bias. Where possible, data will be summarised using combined estimates of effect for time to treatment change, survival outcomes and response rates using assumption-free methods. Further sub-group analyses and meta-regression models will be specified and undertaken to explore potential sources of heterogeneity between studies within each tumour type if necessary.
Assessment of the impact of surveillance imaging in children with CNS tumours is methodologically complex. The evidence base is likely to be heterogeneous in terms of imaging protocols, definitions of radiological response and diagnostic accuracy of tumour recurrence due to changes in imaging technology over time. Furthermore, the delineation of tumour recurrence from either pseudo-progression or radiation necrosis after radiotherapy is potentially problematic and linked to the timing of follow-up assessments. However, given the current routine practice of MRI surveillance in the follow-up of children with CNS tumours in the UK and the resource implications, it is important to evaluate the cost-benefit profile of this practice.
Systematic review registration
PROSPERO CRD42016036802
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0318-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5006428  PMID: 27577246
Children; Central nervous system tumours; Surveillance; Recurrent disease; Magnetic resonance imaging (MRI); Systematic review
4.  The effectiveness and safety of proton beam radiation therapy in children with malignant central nervous system (CNS) tumours: protocol for a systematic review 
Systematic Reviews  2016;5:124.
The aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT).
Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre-specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy.
The evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy.
Systematic review registration
PROSPERO CRD42015029583
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0285-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4962509  PMID: 27460473
Children; Central nervous system tumours; Proton beam RT; Conventional photon RT; Systematic reviews
5.  A Mannose Family Phosphotransferase System Permease and Associated Enzymes Are Required for Utilization of Fructoselysine and Glucoselysine in Salmonella enterica Serovar Typhimurium 
Journal of Bacteriology  2015;197(17):2831-2839.
Salmonella enteric serovar Typhimurium, a major cause of food-borne illness, is capable of using a variety of carbon and nitrogen sources. Fructoselysine and glucoselysine are Maillard reaction products formed by the reaction of glucose or fructose, respectively, with the ε-amine group of lysine. We report here that S. Typhimurium utilizes fructoselysine and glucoselysine as carbon and nitrogen sources via a mannose family phosphotransferase (PTS) encoded by gfrABCD (glucoselysine/fructoselysine PTS components EIIA, EIIB, EIIC, and EIID; locus numbers STM14_5449 to STM14_5454 in S. Typhimurium 14028s). Genes coding for two predicted deglycases within the gfr operon, gfrE and gfrF, were required for growth with glucoselysine and fructoselysine, respectively. GfrF demonstrated fructoselysine-6-phosphate deglycase activity in a coupled enzyme assay. The biochemical and genetic analyses were consistent with a pathway in which fructoselysine and glucoselysine are phosphorylated at the C-6 position of the sugar by the GfrABCD PTS as they are transported across the membrane. The resulting fructoselysine-6-phosphate and glucoselysine-6-phosphate subsequently are cleaved by GfrF and GfrE to form lysine and glucose-6-phosphate or fructose-6-phosphate. Interestingly, although S. Typhimurium can use lysine derived from fructoselysine or glucoselysine as a sole nitrogen source, it cannot use exogenous lysine as a nitrogen source to support growth. Expression of gfrABCDEF was dependent on the alternative sigma factor RpoN (σ54) and an RpoN-dependent LevR-like activator, which we designated GfrR.
IMPORTANCE Salmonella physiology has been studied intensively, but there is much we do not know regarding the repertoire of nutrients these bacteria are able to use for growth. This study shows that a previously uncharacterized PTS and associated enzymes function together to transport and catabolize fructoselysine and glucoselysine. Knowledge of the range of nutrients that Salmonella utilizes is important, as it could lead to the development of new strategies for reducing the load of Salmonella in food animals, thereby mitigating its entry into the human food supply.
PMCID: PMC4524042  PMID: 26100043
6.  Aminoaciduria in the prediction of ifosfamide-induced tubulopathy after childhood cancer: a feasibility study 
Ifosfamide, an alkylating agent used widely in the treatment of childhood malignancy, can cause many side effects including a proximal tubulopathy. Studies suggest that aminoaciduria is seen most commonly of all the biochemical abnormalities of ifosfamide-induced tubulopathy. A recent systematic review has found a paucity of data regarding the value of early markers indicating clinically significant tubulopathy. We undertook a pilot study to determine the feasibility of examining whether patients can be risk-stratified on the basis of aminoaciduria for the development of future significant ifosfamide-induced tubulopathy, to allow the evolution of appropriate follow-up strategies. We also aimed to define accrual rates, costs and clinical demands for a future larger study.
This observational study recruited 21 patients from the Leeds Paediatric Oncology service. The medical notes of each patient were reviewed for demographic and clinical data. Simultaneous samples of blood and urine were obtained.
The investigations in the feasibility study were acceptable to patients and were minimally demanding on both clinical and laboratory staff. Financially, the cost per patient was minimal. This study was not powered to detect significant associations with TmP/GFR (ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate), growth and electrolyte supplementation. However, all patients with minimal aminoaciduria (≤2 elevated urinary amino acids) had normal TmP/GFR and no need for electrolyte supplementation.
This pilot study has shown that a larger study is feasible and may provide clinically useful data to change current practice. This should aim to establish whether the number of abnormal amino acids or the degree of abnormality is most significant in predicting clinically significant proximal tubulopathy.
PMCID: PMC5154030  PMID: 27965825
Ifosfamide; Oncology; Renal damage; Long-term follow-up
7.  States Can Transform Their Health Care Workforce 
The United States faces the simultaneous challenges of improving health care access and balancing the specialty and geographic distribution of physicians. A 2014 Institute of Medicine report recommended significant changes in Medicare graduate medical education (GME) funding, to incentivize innovation and increase accountability for meeting national physician workforce needs. Annually, nearly $4 billion of Medicaid funds support GME, with limited accountability for outcomes. Directing these funds toward states' greatest health care workforce needs could address health care access and physician maldistribution issues and make the funding for resident education more accountable. Under the proposed approach, states would use Medicaid funds, in conjunction with Medicare GME funds, to expand existing GME programs and establish new primary care and specialty programs that focus on their population's unmet health care needs.
PMCID: PMC4477589  PMID: 26140143
8.  Critical Review of Clinical Practice Guidelines for Fertility Preservation in Teenagers and Young Adults with Cancer 
Purpose: The 5-year survival of teenagers and young adults (TYAs; 13–24 years old) with cancer has continued to rise, but as a result more patients experience late effects of treatment, such as infertility. Advice regarding fertility preservation in relation to cancer is provided in numerous clinical practice guidelines, but the rigor of their development is unclear.
Methods: A systematic search was undertaken for clinical practice guidelines regarding fertility preservation in TYAs with cancer. All guidelines were reviewed according to the Appraisal of Guidelines for Research and Evaluation (AGREE-II) criteria. Five out of 13 identified guidelines scored over 75% in the “rigor of development” section and were further appraised. Content, scope, and consistencies between recommendations were also examined.
Results: All five of the reviewed guidelines encouraged oncologists to have discussions with their patients about potential fertility issues associated with treatment and available fertility preservation methods. The cryopreservation of sperm, oocytes, and embryos were all recommended as first-line interventions in postpubertal patients. Recommendations surrounding pre- or peripubescent adolescents were few, with many techniques only recommended as part of a clinical trial. The risk of subfertility associated with different treatment regimens was poorly described.
Conclusions: The methodology and development of guidelines describing fertility preservation in TYA cancer patients varied greatly. Methodological quality did not clearly influence key recommendations. Those involved with the development of guidelines are encouraged to clearly define their development methods to allow users to be confident of the quality.
PMCID: PMC4270154  PMID: 25538859
AGREE-II; fertility; guidelines; preservation
10.  Current and Future Treatment of Hypertension in the SPRINT Era 
Based on the SPRINT trial, it is highly likely that new SPRINT-era guidelines will establish a blood pressure (BP) goal of < 130/80 mm Hg for those aged 50 or older who are at high risk for a cardiovascular event. In this group, SPRINT demonstrated that assignment to an intensive-treatment systolic BP (SBP) goal of < 120 mm Hg significantly reduced cardiovascular events and mortality compared to those assigned to a standard-treatment SPB goal of < 140 mm Hg. This review critically assesses current hypertension guidelines and presents predictions for SPRINT-era guidelines in the elderly, African Americans, and patients with uncomplicated essential hypertension, diabetes, chronic kidney disease, cardiovascular disease, and coronary artery disease. Specific attention is paid to BP goals and preferred pharmacological antihypertensive therapy in these populations, and an algorithm that incorporates the SPRINT trial results is presented. Inhibitors of the renin-angiotensin-aldosterone system as well as calcium channel blockers are universally accepted as first-line therapy in uncomplicated hypertension, but controversy exists over the role of thiazide diuretics and beta blockers. This review also discusses a physiologically and outcomes-based approach to combination therapy for treatment of hypertension.
PMCID: PMC4814005  PMID: 27057288
blood pressure; guidelines; masked hypertension; essential hypertension; SPRINT study
11.  Dynamic High-Cadence Cycling Improves Motor Symptoms in Parkinson’s Disease 
Individuals with Parkinson’s disease (PD) often have deficits in kinesthesia. There is a need for rehabilitation interventions that improve these kinesthetic deficits. Forced (tandem) cycling at a high cadence improves motor function. However, tandem cycling is difficult to implement in a rehabilitation setting.
To construct an instrumented, motored cycle and to examine if high cadence dynamic cycling promotes improvements in motor function.
This motored cycle had two different modes: dynamic and static cycling. In dynamic mode, the motor maintained 75–85 rpm. In static mode, the rider determined the pedaling cadence. UPDRS Motor III and Timed Up and Go (TUG) were used to assess changes in motor function after three cycling sessions.
Individuals in the static group showed a lower cadence but a higher power, torque and heart rate than the dynamic group. UPDRS score showed a significant 13.9% improvement in the dynamic group and only a 0.9% improvement in the static group. There was also a 16.5% improvement in TUG time in the dynamic group but only an 8% improvement in the static group.
These findings show that dynamic cycling can improve PD motor function and that activation of proprioceptors with a high cadence but variable pattern may be important for motor improvements in PD.
PMCID: PMC4557094  PMID: 26388836
movement disorders; exercise; rehabilitation; neuroplasticity; bradykinesia; motor function
12.  Electronic health record functionality needed to better support primary care 
Electronic health records (EHRs) must support primary care clinicians and patients, yet many clinicians remain dissatisfied with their system. This article presents a consensus statement about gaps in current EHR functionality and needed enhancements to support primary care. The Institute of Medicine primary care attributes were used to define needs and meaningful use (MU) objectives to define EHR functionality. Current objectives remain focused on disease rather than the whole person, ignoring factors such as personal risks, behaviors, family structure, and occupational and environmental influences. Primary care needs EHRs to move beyond documentation to interpreting and tracking information over time, as well as patient-partnering activities, support for team-based care, population-management tools that deliver care, and reduced documentation burden. While stage 3 MU's focus on outcomes is laudable, enhanced functionality is still needed, including EHR modifications, expanded use of patient portals, seamless integration with external applications, and advancement of national infrastructure and policies.
PMCID: PMC4147605  PMID: 24431335
Primary Care; Electronic Health Records; Meaningful Use
13.  Symbiotic Bacterial Metabolites Regulate Gastrointestinal Barrier Function via the Xenobiotic Sensor PXR and Toll-like Receptor 4 
Immunity  2014;41(2):296-310.
Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is as a ligand for PXR in vivo, and IPA down-regulated enterocyte TNF–α while up-regulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2−/−) mice showed a distinctly “leaky” gut physiology coupled with up-regulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2−/−Tlr4−/− mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway which involves luminal sensing and signaling by TLR4.
PMCID: PMC4142105  PMID: 25065623
14.  Organization of Vagal Afferents in Pylorus: Mechanoreceptors Arrayed for High Sensitivity and Fine Spatial Resolution? 
The pylorus is innervated by vagal mechanoreceptors that project to gastrointestinal smooth muscle, but the distributions and specializations of vagal endings in the sphincter have not been fully characterized. To evaluate their organization, the neural tracer dextran biotin was injected into the nodose ganglia of rats. Following tracer transport, animals were perfused, and their pylori and antra were prepared as whole mounts. Specimens were processed to permanently label the tracer, and subsets were counterstained with Cuprolinic blue or immunostained for c-Kit. Intramuscular arrays (IMAs) in the circular muscle comprised the principal vagal afferent innervation of the sphincter. These pyloric ring IMAs were densely distributed and evidenced a variety of structural specializations. Morphometric comparisons between the arbors innervating the pylorus and a corresponding sample of IMAs in the adjacent antral circular muscle highlighted that sphincter IMAs branched profusely, forming more than twice as many branches as did antral IMAs (means of 405 vs. 165, respectively), and condensed their numerous neurites into compact receptive fields (~48% of the area of antral IMAs) deep in the circular muscle (~6 μm above the submucosa). Separate arbors of IMAs in the sphincter interdigitated and overlapped to form a 360° band of mechanoreceptors encircling the pyloric canal. The annulus of vagal IMA arbors, putative stretch receptors tightly intercalated in the sphincter ring and situated near the lumen of the pyloric canal, creates an architecture with the potential to generate gut reflexes on the basis of pyloric sensory maps of high sensitivity and fine spatial resolution.
PMCID: PMC4058399  PMID: 24656895
antrum; gastric emptying; gastroduodenal sphincter; interstitial cells of Cajal; nodose ganglion; pyloric canal; pyloric reflex
15.  Systematic Review and Meta-Analysis of Outcomes after Cardiopulmonary Arrest in Childhood 
PLoS ONE  2015;10(6):e0130327.
Cardiopulmonary arrest in children is an uncommon event, and often fatal. Resuscitation is often attempted, but at what point, and under what circumstances do continued attempts to re-establish circulation become futile? The uncertainty around these questions can lead to unintended distress to the family and to the resuscitation team.
To define the likely outcomes of cardiopulmonary resuscitation in children, within different patient groups, related to clinical features.
Data Sources
MEDLINE, MEDLINE in-Process & Other non-Indexed Citations, EMBASE, Cochrane database of systematic reviews and Cochrane central register of trials, Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment database, along with reference lists of relevant systematic reviews and included articles.
Study Eligibility Criteria
Prospective cohort studies which derive or validate a clinical prediction model of outcome following cardiopulmonary arrest.
Participants and Interventions
Children or young people (aged 0 – 18 years) who had cardiopulmonary arrest and received an attempt at resuscitation, excluding resuscitation at birth.
Study Appraisal and Synthesis Methods
Risk of bias assessment developed the Hayden system for non-randomised studies and QUADAS2 for decision rules. Synthesis undertaken by narrative, and random effects meta-analysis with the DerSimonian-Laird estimator.
More than 18,000 episodes in 16 data sets were reported. Meta-analysis was possible for survival and one neurological outcome; others were reported too inconsistently. In-hospital patients (average survival 37.2% (95% CI 23.7 to 53.0%)) have a better chance of survival following cardiopulmonary arrest than out-of-hospital arrests (5.8% (95% CI 3.9% to 8.6%)). Better neurological outcome was also seen, but data were too scarce for meta-analysis (17% to 71% ‘good’ outcomes, compared with 2.8% to 3.2%).
Lack of consistent outcome reporting and short-term neurological outcome measures limited the strength of conclusions that can be drawn from this review.
Conclusions and Implications of Key Findings
There is a need to collaboratively, prospectively, collect potentially predictive data on these rare events to understand more clearly the predictors of survival and long-term neurological outcome.
Systematic Review Registration Number
PROSPERO 2013:CRD42013005102
PMCID: PMC4479568  PMID: 26107958
16.  Health Information Technology Needs Help from Primary Care Researchers 
While health information technology (HIT) efforts are beginning to yield measurable clinical benefits, more is needed to meet the needs of patients and clinicians. Primary care researchers are uniquely positioned to inform the evidence-based design and use of technology. Research strategies to ensure success include engaging patient and clinician stakeholders, working with existing practice-based research networks, and using established methods from other fields such as human factors engineering and implementation science. Policies are needed to help support primary care researchers in evaluating and implementing HIT into everyday practice, including expanded research funding, strengthened partnerships with vendors, open access to information systems, and support for the Primary Care Extension Program. Through these efforts, the goal of improved outcomes through HIT can be achieved.
PMCID: PMC4450103  PMID: 25957361
17.  The use of nutrient-optimizing/cost-minimizing software to develop ready-to-use therapeutic foods for malnourished pregnant women in Mali 
Food Science & Nutrition  2015;3(2):110-119.
Malnutrition affects people of all ages in many countries in the developing world. One treatment for malnutrition is the intervention involving ready-to-use therapeutic foods (RUTFs). This study developed RUTFs for pregnant women in Mali using formulation computer software and largely local, plant-based ingredients. Mali has the world's second highest birth rate and infant mortality rate. Nutrient profiles of possible ingredients and their prices from 2004 to 2009 were entered into the software. Computer-selected ingredients included peanuts, cowpeas, and millet as well as rice or barley koji (sources of α-amylase and ingredients). Components of the six selected formulations were milled, hydrolyzed with koji α-amylase, and heated at 121°C for 15 min. The contents of protein, fat, ash, fiber, carbohydrates, amino acid, and energy of dehydrated products were determined and compared with software-predicted values. Actual and predicted values were comparable: the protein content was 1.45–2.04% higher, and ash content was 0.60–0.89% higher than the predicted values, while the fat content was 0.18–0.88% lower, the lysine content was 0.17–0.25% lower, and fiber content was 0.16% lower to 2.06% higher than the predicted values. The difference in actual and predicted energy levels were 14.8–22.2%. The amount of RUTF needed to meet the requirement of most limiting nutrients, lysine and energy, ranged from 2620 to 3002 g. The costs for producing the RUTFs were substantially lower than importing commercial RUTFs even with increased ingredient prices in Mali from 2004 to 2009.
PMCID: PMC4376405  PMID: 25838889
Linear programming; malnutrition; ready-to-use therapeutic foods
18.  Regioselective Nitration of Nα,N1-Bis(trifluoroacetyl)-L-Tryptophan Methyl Ester: Efficient Synthesis of 2-Nitro and 6-Nitro-N-Trifluoroacetyl-L-Tryptophan Methyl Ester 
Nitration of Nα,N1-bis(trifluoroacetyl)-L-tryptophan methyl ester with HNO3 in acetic anhydride at 0° C provides Nα-trifluoroacetyl-2-nitro-L-tryptophan methyl ester in 67% yield, whereas nitration in trifluoroacetic acid at 0° C gives Nα-trifluoroacetyl-6-nitro-L-tryptophan methyl ester in 69% yield.
PMCID: PMC4335804  PMID: 18851915
19.  Sympathetic axonopathies and hyperinnervation in the small intestine smooth muscle of aged Fischer 344 rats 
Autonomic neuroscience : basic & clinical  2013;179(0):10.1016/j.autneu.2013.09.002.
It is well documented that the intrinsic enteric nervous system of the gastrointestinal (GI) tract sustains neuronal losses and reorganizes as it ages. In contrast, age-related remodeling of the extrinsic sympathetic projections to the wall of the gut is poorly characterized. The present experiment, therefore, surveyed the sympathetic projections to the aged small intestine for axonopathies. Furthermore, the experiment evaluated the specific prediction that catecholaminergic inputs undergo hyperplastic changes. Jejunal tissue was collected from 3-, 8-, 16-, and 24-month-old male Fischer 344 rats, prepared as whole mounts consisting of the muscularis, and processed immunohistochemically for tyrosine hydroxylase, the enzymatic marker for norepinephrine, and either the protein CD163 or the protein MHCII, both phenotypical markers for macrophages. Four distinctive sympathetic axonopathy profiles occurred in the small intestine of the aged rat: (1) swollen and dystrophic terminals, (2) tangled axons, (3) discrete hyperinnervated loci in the smooth muscle wall, including at the bases of Peyer's patches, and (4) ectopic hyperplastic or hyperinnervating axons in the serosa/subserosal layers. In many cases, the axonopathies occurred at localized and limited foci, involving only a few axon terminals, in a pattern consistent with incidences of focal ischemic, vascular, or traumatic insult. The present observations underscore the complexity of the processes of aging on the neural circuitry of the gut, with age-related GI functional impairments likely reflecting a constellation of adjustments that range from selective neuronal losses, through accumulation of cellular debris, to hyperplasias and hyperinnervation of sympathetic inputs.
PMCID: PMC3844004  PMID: 24104187
CD163; Gastrointestinal; MHCII; Muscularis; Myenteric; Resident Macrophages
20.  Architecture of Vagal Motor Units Controlling Striated Muscle of Esophagus: Peripheral Elements Patterning Peristalsis? 
Autonomic neuroscience : basic & clinical  2013;179(0):10.1016/j.autneu.2013.08.069.
Little is known about the architecture of the vagal motor units that control esophageal striated muscle, in spite of the fact that these units are necessary, and responsible, for peristalsis. The present experiment was designed to characterize the motor neuron projection fields and terminal arbors forming esophageal motor units. Nucleus ambiguus compact formation neurons of the rat were labeled by bilateral intracranial injections of the anterograde tracer dextran biotin. After tracer transport, thoracic and abdominal esophagi were removed and prepared as whole mounts of muscle wall without mucosa or submucosa. Labeled terminal arbors of individual vagal motor neurons (n = 78) in the esophageal wall were inventoried, digitized and analyzed morphometrically. The size of individual vagal motor units innervating striated muscle, throughout thoracic and abdominal esophagus, averaged 52 endplates per motor neuron, a value indicative of fine motor control. A majority (77%) of the motor terminal arbors also issued one or more collateral branches that contacted neurons, including nitric oxide synthase-positive neurons, of local myenteric ganglia. Individual motor neuron terminal arbors co-innervated, or supplied endplates in tandem to, both longitudinal and circular muscle fibers in roughly similar proportions (i.e., two endplates to longitudinal for every three endplates to circular fibers). Both the observation that vagal motor unit collaterals project to myenteric ganglia and the fact that individual motor units co-innervate longitudinal and circular muscle layers are consistent with the hypothesis that elements contributing to peristaltic programming inhere, or are “hardwired,” in the peripheral architecture of esophageal motor units.
PMCID: PMC3844123  PMID: 24044976
deglutition; enteric; motor neuron; myenteric plexus; NOS neurons; peristalsis; swallowing
22.  Protocol for a systematic review of reductions in therapy for children with low-risk febrile neutropenia 
Systematic Reviews  2014;3:119.
Febrile neutropenia is a common complication of therapy in children with cancer. Some patients are at low risk of complications, and research has considered reduction in therapy for these patients. A previous systematic review broadly considered whether outpatient treatment and oral antibiotics were safe in this context and concluded that this was likely to be the case. Since that review, there has been further research in this area. Therefore, we aim to provide a more robust answer to these questions and to additionally explore whether the exact timing of discharge, including entirely outpatient treatment, has an impact on outcomes.
The search will cover MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CDSR, CENTRAL, LILACS, HTA and DARE. A full search strategy is provided. Key conference proceedings and reference lists of included papers will be hand searched. Prominent authors/clinicians in the field will be contacted. We will include randomised and quasi-randomised controlled trials along with prospective single-arm studies that examine the location of therapy and/or the route of administration of antibiotics in children or young adults (aged less than 18 years) who attend paediatric services with fever and neutropenia due to treatment for cancer and are assessed to be at low risk of medical complications. Studies will be screened and data extracted by one researcher and independently checked by a second. All studies will be critically appraised using tools appropriate to the study design. Data from randomised controlled trials (RCTs) will be combined to provide comparative estimates of treatment failure, safety and adequacy. Information from quasi-randomised trials and single-arm studies will provide further data on the safety and adequacy of regimes. Random effects meta-analysis will be used to combine studies. A detailed analysis plan, including assessment of heterogeneity and publication bias, is provided.
This study will aim to specifically define the features of a low-risk strategy that will maintain levels of safety and adequacy equivalent to those of traditional treatments. This will both inform the development of services and provide patients and families with data to help them make an informed decision about care.
Systematic review registration
PROSPERO CRD42014005817
PMCID: PMC4234526  PMID: 25336249
Fever; Neutropenia; Cancer; Children; Outpatient
23.  Vagal Afferent Innervation of the Lower Esophageal Sphincter 
To supply a fuller morphological characterization of the vagal afferents innervating the lower esophageal sphincter (LES), specifically to label vagal terminals in the tissues forming the LES in the gastroesophageal junction, the present experiment employed injections of dextran biotin into the nodose ganglia of rats. Four types of vagal afferents innervated the LES. Clasp and sling muscle fibers were directly and prominently innervated by intramuscular arrays (IMAs). Individual IMA terminals subtended about 16° of arc of the esophageal circumference, and, collectively, the terminal fields were distributed within the muscle ring to establish a 360° annulus of mechanoreceptors in the sphincter wall. 3D morphometry of the terminals established that, compared to sling muscle IMAs, clasp muscle IMAs had more extensive arbors and larger receptive fields. In addition, at the cardia, local myenteric ganglia between smooth muscle sheets and striated muscle bundles were innervated by intraganglionic laminar endings (IGLEs), in a pattern similar to the innervation of the myenteric plexus throughout the stomach and esophagus. Finally, as previously described, the principle bundle of sling muscle fibers that links LES sphincter tissue to the antropyloric region of the lesser curvature was innervated by exceptionally long IMAs as well as by unique web ending specializations at the distal attachment of the bundle. Overall, the specialized varieties of densely distributed vagal afferents innervating the LES underscore the conclusion that these sensory projections are critically involved in generating LES reflexes and may be promising targets for managing esophageal dysfunctions.
PMCID: PMC3749274  PMID: 23583280
antrum; cardia; GERD; lesser curvature; mechanoreceptor; nodose ganglion; pylorus; visceral afferent
24.  Effects of hydrostatic pressure on the conformational equilibrium of tryptophan synthase from Salmonella typhimurium 
A wide range of parameters influence allosteric communications between the α- and β-subunits of the Trp synthase α2β2 multienzyme complex with L-Ser, including monovalent cations, pH, temperature, ligands, organic solvents, and hydrostatic pressure. The conformational change from closed to open can be monitored either by absorbance at 423 nm or fluorescence at 495 nm from the pyridoxal-5′-phosphate-L-Ser complex. Pressure perturbation was used to quantify the effects of monovalent cations, ligands, and mutations on the conformational equilibrium of Trp synthase. P-jump kinetics in the presence of Na+, NH4+, and Na+ together with benzimidazole were also examined. The plots of lnk versus P are nonlinear and require a compressibility (β‡o) term to obtain a good fit. β‡o is positive for the Na+ enzyme but negative for NH4+ and Na+ with benzimidazole. These results suggest that there is a large contribution of solvation to the kinetics of the conformational change of Trp synthase. The relaxation kinetics are also different if the P-jumps are made by increasing or decreasing pressure, suggesting that the enzyme conformations are ensembles of microstates.
PMCID: PMC4156104  PMID: 20233374
tryptophan synthase; allostery; pyridoxal-5′-phosphate; compressibility; solvation
25.  Alpha-synuclein expression patterns in the colonic submucosal plexus of the aging Fischer 344 rat: Implications for biopsies in aging and neurodegenerative disorders? 
This experiment assessed normative expression patterns of alpha-synuclein (SYNC), including ganglionic remodeling and development of SYNC pathologies, in the submucosal plexus (SMP) of the colon during healthy aging. The observations address age-associated changes in bowel function and are relevant to evaluations of SMP-containing colonic biopsies for SYNC or synucleinopathies associated with aging and peripheral neurodegenerative diseases.
Colonic submucosal whole mounts from groups of virgin male Fischer 344 rats (n ≥ 8 per group) at 4, 8, 16 and 24 months of age were processed immunohistochemically for SYNC and the pan-neuronal marker HuC/D. Additionally, macrophages immunoreactive for MHCII were examined. Stereological protocols were used to generate unbiased estimates of neuron density, neurons per ganglion, neurons per ganglionic area, and neuron size.
Key Results
The protein SYNC was expressed in a subpopulation of SMP neurons, in both nucleus and cytoplasm. The general age-associated pattern across different cell counts was an increase in the number of SYNC+ neurons between 4 and 8 months of age, with progressively decreasing numbers of both SYNC+ and SYNC− neurons over the remaining lifespan. The soma size of SYNC+ neurons increased progressively with age. Aggregated SYNC occurred in the aging SMP, and macrophages with alternatively activated profiles were located adjacent to pathological SYNC deposits, consistent with ongoing phagocytosis.
Conclusions & Inferences
Changes in SYNC expression with age, including a baseline of accumulating synucleopathies in the healthy aging SMP, need to be considered when interpreting either functional disturbances or biopsies of the aging colon.
PMCID: PMC3735646  PMID: 23809578
Colon; Enteric; MHCII; Calbindin; Parkinson's disease

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