Reliability and Confidence of Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) Rating Among Research and Clinical Speech Pathologists Before and After Implementation of a Training Manual: A Multi-site Study.

DIGEST is a validated, open-source method to grade the severity of pharyngeal dysphagia from the modified barium swallow (MBS) study. Dissemination and implementation of DIGEST is rising, making it critical to understand reliability and facilitators of accurate implementation among users. The aim was to assess reliability of the tool among speech-language pathology (SLP) raters practicing at multiple sites before and after review of a DIGEST training manual and evaluate confidence of DIGEST use pre-and post-training. Thirty-two SLPs from 5 sites participated in a blinded longitudinal DIGEST rating study. Raters were provided a standardized training set of MBS (n = 19). Initial SLP ratings (round 1, R1) were followed by a 2-4 week break before raters rated a re-keyed MBS set (round 2, R2). A minimum 4-8 week wash-out period then preceded self-study of the DIGEST training manual which was followed by a final rating (round 3, R3) and a post-manual survey afterwards. Baseline reliability (R1) of overall DIGEST was on average k = 0.70, reflecting agreement in the substantial range. Seventy-five percent of raters (24/32) demonstrated reliability ≥ 0.61 in the substantial to almost perfect range prior to training. Inter-rater reliability significantly improved from R1 to R3 after review of the DIGEST manual, with the largest change in DIGEST-Efficiency (mean change: DIGEST k = .04, p = .009, DIGEST-Safety k = .07, p = 0.03, and DIGEST-Efficiency k = .14, p = 0.009). Although DIGEST reliability at baseline was adequate in the majority of raters, self-study of the DIGEST training manual significantly improved inter-rater reliability and rater confidence using the DIGEST method, particularly when assigning DIGEST-Efficiency grade. These early data show promise that provider training may be useful to aid in fidelity of DIGEST implementation among SLP clinical users with varying DIGEST experience.

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

HIV and viral hepatitis coinfection analysis using surveillance data from 15 US states and two cities.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

UT-B Urea Transporter Localization in the Bovine Gastrointestinal Tract.

Facilitative UT-B urea transporters play an important role in the urea nitrogen salvaging process that occurs in the gastrointestinal tract of mammals, particularly ruminants. Gastrointestinal UT-B transporters have previously been reported in various ruminant species-including cow, sheep and goat. In this present study, UT-B transporter localization was investigated in tissues throughout the bovine gastrointestinal tract. RT-PCR analysis showed that UT-B2 was the predominant UT-B mRNA transcript expressed in dorsal, ventral and cranial ruminal sacs, while alternative UT-B transcripts were present in other gastrointestinal tissues. Immunoblotting analysis detected a strong, glycosylated ~50 kDa UT-B2 protein in all three ruminal sacs. Immunolocalization studies showed that UT-B2 protein was predominantly localized to the plasma membrane of cells in the stratum basale layer of all ruminal sac papillae. In contrast, other UT-B protein staining was detected in the basolateral membranes of the surface epithelial cells lining the abomasum, colon and rectum. Overall, these findings confirm that UT-B2 cellular localization is similar in all ruminal sacs and that other UT-B proteins are located in epithelial cells lining various tissues in the bovine gastrointestinal tract.

Excessive gestational weight gain over multiple pregnancies and the prevalence of obesity at age 40.

OBJECTIVE: Although several studies have found an association between excessive gestational weight gain (GWG) and obesity later in life, to the best of our knowledge, no studies have explored the role of GWG events across the life course. DESIGN AND METHODS: We describe how the prevalence of midlife obesity (BMI⩾30 at age 40 or 41) among women varies by life course patterns of GWG (using 2009 IOM guidelines) in the USA's National Longitudinal Survey of Youth 1979 cohort. RESULTS: Among women who reported 1-3 births before age 40, the prevalence of midlife obesity increased with a rising number of excessive GWG events: from none (23.4%, n=875) to one (37.6%, n=707), from none (23.4%, n=875) to two (46.8%, n=427) and from none (23.4%, n=875) to three (54.6%, n=108), P<0.00005 for trend. Obesity prevalence was similar for the same number of excessive GWG events, regardless of parity. No clear pattern emerged for the sequencing of excessive GWG event(s) and later obesity. CONCLUSIONS: In our descriptive exploratory study, excessive GWG events appear to be associated with increased prevalence of obesity for parous women, suggesting the importance of preventive interventions regardless of timing of pregnancy-related weight changes over the life course.

MRI characteristics of nodular fasciitis of the musculoskeletal system.

OBJECTIVE: To evaluate MRI imaging appearances of nodular fasciitis in a pathologic-proven series of 29 patients. MATERIALS AND METHODS: Review of the orthopedic oncology and pathology databases yielded 51 cases of histologically proven nodular fasciitis. MR imaging was available in 29 patients. Three musculoskeletal radiologists retrospectively reviewed all cases in consensus. Imaging features evaluated included location in the body, size, compartmental localization, relationship to fascia, signal characteristics, enhancement pattern, transcompartmental extension, and osseous and intra-articular involvement. RESULTS: There were 15 male and 14 female patients. Mean age was 33 years (range, 16-59 years). Lesions ranged in size from 1.6 to 9 cm with 84 % of lesions measuring less than 4 cm. Twenty-three lesions were located in the upper arm or shoulder girdle. Nine lesions were subcutaneous in location, nine were intra-muscular, and 11 were inter-muscular. Lesions were consistently ovoid in shape with broad fascial contact. They exhibited internal homogenous low T1 and heterogeneous intermediate T2 signal with surrounding edema and slightly inhomogeneous enhancement. Twelve lesions exhibited central non-enhancing areas. Trans-compartmental spread was demonstrated in nine lesions. Osseous changes were seen in five cases and included extrinsic cortical saucerization, medullary edema, and transcortical osseous invasion. Two lesions demonstrated intra-articular extension. CONCLUSIONS: MR imaging features of nodular fasciitis are generally non-specific and can be mistaken for a soft tissue sarcoma. This series, the largest MRI series of musculoskeletal cases in the literature, confirms the predilection of nodular fasciitis for the upper extremity in young adults but also demonstrates that aggressive imaging features such as transcompartmental spread, and osseous and intra-articular involvement may be seen in association with this benign soft tissue lesion.

Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior.

A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.

Oxidative stress, glutamate, and neurodegenerative disorders.

There is an increasing amount of experimental evidence that oxidative stress is a causal, or at least an ancillary, factor in the neuropathology of several adult neurodegenerative disorders, as well as in stroke, trauma, and seizures. At the same time, excessive or persistent activation of glutamate-gated ion channels may cause neuronal degeneration in these same conditions. Glutamate and related acidic amino acids are thought to be the major excitatory neurotransmitters in brain and may be utilized by 40 percent of the synapses. Thus, two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain. The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.

Methylazoxymethanol treatment of fetal rats results in abnormally dense noradrenergic innervation of neocortex.

A single injection of methylazoxymethanol in pregnant rats at 15 days of gestation results in severe cortical atrophy in the offspring. In the adult offspring, the neurochemical markers for the cortical gamma-aminobutyric acid-containing neurons are severely reduced, whereas the noradrenergic markers are minimally altered. Immunohistofluorescence microscopy demonstrates a marked increase in the density of noradrenergic axons which have an abnormal pattern of distribution in the atrophic cortex. The results suggest that the central noradrenergic neurons determine the number of axons to be formed early in brain development, but local factors in the terminal field regulate the ultimate distribution of the noradrenergic axons.

Major innervation of newborn rat cortex by monoaminergic neurons.

A major monoaminergic innervation in infant rat neocortex, predominantly in layer IV, has been demonstrated by ultrastructural and biochemical studies after the administration of exogenous catecholamine precursors and congeners. One-third of all cortical synapses have an uptake-storage mechanism for catecholamines. In newborn cortex, the storage capacity for catecholamines is tenfold greater than the endogenous levels, and the uptake-storage mechanism matures earlier than the ability to synthesize neurotransmitter.

Antiparkinsonian drugs: inhibition of dopamine uptake in the corpus striatum as a possible mechanism of action.

A variety of antiparkinsonian drugs are potent, noncompetitive inhibitors of dopamine uptake into synaptosomes in homogenates of rat corpus striatum. Inhibition of dopamine uptake may potentiate the synaptic actions of dopamine in the striatum and could explain the antiparkinsonian effects of these drugs. This hypothesis accounts for several clinical features of Parkinson's disease and predicts compounds which may be new therapeutic agents.

Selective destruction of neurons by a transmitter agonist.

Microinjection of nanomole amounts of kainic acid, a heterocyclic analog of glutamate, into the cerebellums of adult hamsters and rats causes rapid degeneration of Purkinje, basket, stellate, and Golgi II cells, neurons that receive synaptic input from granule cells, whereas the granule cells themselves are spared. This selectivity is consistent with the evidence that glutamate is the granule cell transmitter and supports the hypothesis that kainic acid exerts its neurotoxic effects through glutamate receptors.

Alzheimer's disease: a disorder of cortical cholinergic innervation.

Great emphasis is being placed on identification of neurotransmitter systems involved in the symptomatic manifestations of neurological and psychiatric disorders. In the case of Alzheimer's disease, which now seems to be one of the most common causes of mental deterioration in the elderly, compelling evidence has been developed that acetylcholine-releasing neurons, whose cell bodies lie in the basal forebrain, selectively degenerate. These cholinergic neurons provide widespread innervation of the cerebral cortex and related structures and appear to play an important role in cognitive functions, especially memory. These advances reflect a close interaction between experimental and clinical neuroscientists in which information derived from basic neurobiology is rapidly utilized to analyze disorders of the human brain.

Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.

Recent evidence indicates that the nucleus basalis of Meynert, a distinct population of basal forebrain neurons, is a major source of cholinergic innervation of the cerebral cortex. Postmortem studies have previously demonstrated profound reduction in the presynaptic markers for cholinergic neurons in the cortex of patients with Alzheimer's disease and senile dementia of the Alzheimer's type. The results of this study show that neurons of the nucleus basalis of Meynert undergo a profound (greater than 75 percent) and selective degeneration in these patients and provide a pathological substrate of the cholinergic deficiency in their brains. Demonstration of selective degeneration of such neurons represents the first documentation of a loss of a transmitter-specific neuronal population in a major disorder of higher cortical function and, as such, points to a critical subcortical lesion in Alzheimer's patients.

Unintended changes in cognition, mood, and behavior arising from cell-based interventions for neurological conditions: ethical challenges.

The prospect of using cell-based interventions (CBIs) to treat neurological conditions raises several important ethical and policy questions. In this target article, we focus on issues related to the unique constellation of traits that characterize CBIs targeted at the central nervous system. In particular, there is at least a theoretical prospect that these cells will alter the recipients' cognition, mood, and behavior-brain functions that are central to our concept of the self. The potential for such changes, although perhaps remote, is cause for concern and careful ethical analysis. Both to enable better informed consent in the future and as an end in itself, we argue that early human trials of CBIs for neurological conditions must monitor subjects for changes in cognition, mood, and behavior; further, we recommend concrete steps for that monitoring. Such steps will help better characterize the potential risks and benefits of CBIs as they are tested and potentially used for treatment.

PRES (posterior reversible encephalopathy syndrome), a rare complication of tacrolimus therapy.

With increasing numbers of solid organ and hematopoietic stem cell transplantations being performed, there have been significant increases in the use of immunosuppressive agents such as cyclosporine and tacrolimus. Posterior reversible encephalopathy syndrome (PRES) is a serious complication of immunosuppressive therapy use following solid organ or stem cell transplants. Clinical findings including headache, mental status changes, focal neurological deficits, and/or visual disturbances. Associated with these are characteristic imaging features of subcortical white matter lesions on computed tomography (CT) or magnetic resonance imaging (MRI). The changes in the subcortical white matter are secondary to potentially reversible vasogenic edema, although conversion to irreversible cytotoxic edema has been described. These imaging findings predominate in the territory of the posterior cerebral artery. Many studies have shown that the neurotoxicity associated with tacrolimus may occur at therapeutic levels. In most cases of PRES, the symptom complex is reversible by reducing the dosage or withholding the drug for a few days. While PRES is an uncommon complication, it is associated with significant morbidity and mortality if it is not expeditiously recognized. MRI represents the most sensitive imaging technique for recognizing PRES. This report highlights the value of MRI in prompt recognition of this entity, which offers the best chance of avoiding long-term sequelae.

Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress.

Glutamate binds to both excitatory neurotransmitter binding sites and a Cl(-)-dependent, quisqualate- and cystine-inhibited transport site on brain neurons. The neuroblastoma-primary retina hybrid cells (N18-RE-105) are susceptible to glutamate-induced cytotoxicity. The Cl(-)-dependent transport site to which glutamate and quisqualate (but not kainate or NMDA) bind has a higher affinity for cystine than for glutamate. Lowering cystine concentrations in the cell culture medium results in cytotoxicity similar to that induced by glutamate addition in its morphology, kinetics, and Ca2+ dependence. Glutamate-induced cytotoxicity is directly proportional to its ability to inhibit cystine uptake. Exposure to glutamate (or lowered cystine) causes a decrease in glutathione levels and an accumulation of intracellular peroxides. Like N18-RE-105 cells, primary rat hippocampal neurons (but not glia) in culture degenerate in medium with lowered cystine concentration. Thus, glutamate-induced cytotoxicity in N18-RE-105 cells is due to inhibition of cystine uptake, resulting in lowered glutathione levels leading to oxidative stress and cell death.

A two phased study on health care professionals' perceptions of single or multi-use of intermittent catheters.

AIMS: This two phase study aimed to explore health care professionals' teaching and prescribing practice related to intermittent catheterisation and to identify their perceptions about the possible implementation of a mixed (single and multi-use) package for intermittent catheterization. INTRODUCTION: Single-use intermittent catheters are the norm in the UK although multi-use is common in some other countries. A recent Cochrane review found no difference in complications, including urinary tract infection rates, between those using single or multi-use catheters. A flexible option of both multi-use and single use intermittent catheters could provide users with more flexible choices in self-care. However, understanding health care professionals' perspectives is one of the keys to developing a multi-use intervention. DESIGN: A qualitative research framework using in-depth interviews to inform an on line survey. METHOD: In-depth interviews were conducted with health care professionals based in the UK who prescribe catheters, teach intermittent catheterisation or manage an intermittent catheterisation service. The interviewees were selected to represent a range of clinical areas, experience and professions - continence advisors, urology, multiple sclerosis (MS) and spinal cord injury specialist nurses, and General Practitioners. Following framework analysis the themes and factors identified were used to develop an on-line survey which was disseminated through health care professional networks whose members saw patients who use intermittent catheters. RESULTS: Nineteen health care professionals participated in the telephone interviews; 206 completed the survey. A wide range of professionals in terms of experience and specialty afforded rich information regarding the contextual issues around the teaching and prescribing of intermittent catheters. The primary finding was that health care professionals were concerned about 'minimising health risk' and maximising 'normalcy' for those using intermittent self-catheterisation. Health care professionals who worked in the acute setting or had no experience of re-use were most resistant to the re-use of catheters. Professionals requested evidence that a multi-use package would not increase the risk of developing a urinary tract infection or increase the burden of use to a patient before a mixed package would be considered. CONCLUSIONS: For multi-use to be acceptable, evidence based guidelines must be available for healthcare professionals and cleaning methods must be acceptable and safe for intermittent catheter users. Further evidence may be required to establish that a mixed catheter package is equivalent to single use only, particularly for outcomes such as urinary tract infection, urethral injury and quality of life. RELEVANCE TO CLINICAL PRACTICE: This paper highlights that if multi-use catheters are to be successfully introduced into clinical practice, the ease of use, safety and effectiveness of the cleaning technique will need to be convincingly demonstrated by a range of well-defined users.