Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

The role of long-term parenteral support in patients with underlying benign conditions who do not have intestinal failure (IF) is contentious, not least since there are clear benefits in utilising the oral or enteral route for nutritional support. Furthermore, the risks of long-term home parenteral nutrition (HPN) are significant, with significant impacts on morbidity and mortality. There has, however, been a recent upsurge of the use of HPN in patients with conditions such as gastro-intestinal neuromuscular disorders, opioid bowel dysfunction, disorders of gut-brain interaction and possibly eating disorders, who do not have IF. As a result, the European Society of Clinical Nutrition and Metabolism (ESPEN), the European Society of Neuro-gastroenterology and Motility (ESNM) and the Rome Foundation for Disorders of Gut Brain Interaction felt that a position statement is required to clarify - and hopefully reduce the potential for harm associated with - the use of long-term parenteral support in patients without IF. Consensus opinion is that HPN should not be prescribed for patients without IF, where the oral and/or enteral route can be utilised. On the rare occasions that PN commencement is required to treat life-threatening malnutrition in conditions such as those listed above, it should only be prescribed for a time-limited period to achieve nutritional safety, while the wider multi-disciplinary team focus on more appropriate biopsychosocial holistic and rehabilitative approaches to manage the patient's primary underlying condition.

Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

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Gastrointestinal dysmotility: A qualitative exploration of the journey from symptom onset to diagnosis.

BACKGROUND: Gastrointestinal dysmotility (GID) covers a spectrum of disorders disrupting enteric neuromuscular co-ordination which, when severe, causes intractable gastrointestinal symptoms and malnutrition and is a recognized cause of chronic intestinal failure. To date, no study has provided an in-depth account of the experiences of patients with severe GID and their psychosocial needs. This study aimed to explore patients' experiences from symptom onset and the process of seeking and receiving a diagnosis. It specifically explored the psychological effect of this process and the effect on relationships. METHODS: Participants (n = 20, mean age = 47.9, female n = 16, parenteral nutrition = 13) were recruited from a UK center with tertiary Neurogastroenterology and Intestinal Failure services. A qualitative exploratory design with semi-structured in-depth interviews was used. Data were analyzed using thematic analysis. KEY RESULTS: Significant delays were experienced in obtaining a diagnosis. Participants reported having their mental health questioned and felt that they had to fight to prove their symptoms had a physical basis to access appropriate treatment. Although a diagnosis helped legitimize symptoms, the condition remained poorly understood by participants themselves, relatives, and health professionals. Participants discussed the impact that "feeling delegitimized" and the "lack of coherent understanding of GID" had on their relationships and mental health. CONCLUSIONS & INFERENCES: The distressing experience of GID symptoms are compounded by a delay in validating symptoms and lack of coherent understanding. More knowledge of GID is needed by health professionals to speed up diagnosis and offer more coherent information. The psychological impact of a GID diagnosis should be acknowledged early to help facilitate adjustment.

Reduced 30-day gastrostomy placement mortality following the introduction of a multidisciplinary nutrition support team: a cohort study.

BACKGROUND: Percutaneous endoscopic gastrostomy feeding allows patients with dysphagia to receive adequate nutritional support, although gastrostomy insertion is associated with mortality. A nutrition support team (NST) may improve a gastrostomy service. The present study aimed to evaluate the introduction of a NST for assessment and follow-up of patients referred for gastrostomy. METHODS: We included adult inpatients referred for gastrostomy insertion consecutively between 1 October 2010 and 31 March 2013. During the first 6 months, a multidisciplinary NST assessment service was implemented. Patient characteristics, clinical condition, referral appropriateness and follow-up were documented prospectively. We compared the frequencies of appropriate referrals, 30-day mortality and mental capacity/consent assessment time spent between the 6 months implementation phase and 2 years following establishment of the assessment service ('established phase'). RESULTS: In total, 309 patients were referred for gastrostomy insertion and 199 (64%) gastrostomies placed. The percentage of appropriate referrals rose from 72% (61/85) during the implementation phase to 87% (194/224) during the established phase (P = 0.002). Thirty-day mortality reduced from 10% (5/52) to 2% (3/147) (P = 0.01), whereas time allocated to assessment of mental capacity and attainment of informed consent rose from mean 3 days (limits of normal variation 0-7) to mean 6 (0-13) days. CONCLUSIONS: The introduction of a NST to assess and select patients referred for gastrostomy placement was associated with a rise in the frequency of appropriate referrals and a decrease in 30-day mortality following gastrostomy insertion. Concomitantly, time spent on patient assessment and attainment of informed consent increased.

Outcome of intestinal failure after bariatric surgery: experience from a national UK referral centre.

BACKGROUND/OBJECTIVES: Bariatric surgery for morbid obesity provides sustained weight loss. Complications of bariatric surgery include severe nutritional decline, but minimal data describing occurrence and outcome of intestinal failure (IF) exist. SUBJECTS/METHODS: All patients referred to one of the UK's National IF units (IFU) are prospectively entered onto a database; case notes were assessed for bariatric surgery details, IF onset, outcomes, resulting intestinal anatomy, mortality and catheter-related bloodstream infections (CRBSIs). RESULTS: A total of six patients (mean referral age 54.0 years; 95% confidence interval (CI): 44.6-63.4; 5 female) were identified with IF after bariatric surgery from 457 patients (total cohort) managed on home parenteral nutrition (HPN) at the IFU between 2008 and 2014. In all, 6/6 had Roux-en-Y gastric bypass bariatric surgery. Median (range) time from index bariatric surgery to IF development was 28.7 months (1.7-106). IF aetiology was internal herniation (4/6), ischaemia (1/6) and anastomotic leak (1/6); all patients required HPN for a median of 26.4 months (15.3-34.7). CRBSI occurred on 7 occasions in 3 patients, equivalent to 1.5/1000 catheter days in these 6 compared with 0.32/1000 in the 451 IFU HPN patients during this time period. In all, 0/6 patients died, 6/6 had continuity restored in a median of 16.5 months (6.5-32.5) after IF diagnosis and 3/6 (50%) were weaned from PN by a median of 2.2 months (0.6-12.8). CONCLUSIONS: Bariatric surgery, an increasingly common operation, can be associated with IF necessitating long-term HPN. The cohort presented had a higher CRBSI compared with other HPN patients; more stringent approaches to catheter care may be required in this patient group, although more collective data are required.

Quality and safety impact on the provision of parenteral nutrition through introduction of a nutrition support team.

BACKGROUND/OBJECTIVES: Parenteral nutrition (PN) should be provided to the malnourished patient if enteral feeding is insufficient or unsafe. A nutrition support team (NST) may improve PN services. We compared the use and complications of hospital PN before and after the implementation of an NST. SUBJECTS/METHODS: All inpatients referred for PN outside of the intensive care unit and the intestinal failure unit were prospectively included from 2009 to 2012. The NST was introduced in 2010. Quality improvement methodology was applied. RESULTS: In 2009, a mean of 16 (limits of normal variation 4-28) patients were referred for PN each month. After introduction of the NST, this rose to 26 (10-42) referrals per month. The percentage of referrals where PN was not initiated increased from 5.3% in 2009 to 10.1% in 2012 (P=0.03). This increase was restricted to teams that infrequently referred for PN, and enteral nutrition could replace PN in 31 of 51 patients (61%) as compared with 8 of 32 (25%) patients referred from teams that frequently referred for PN (P=0.001). The frequency of PN started owing to an insufficient oral or enteral intake decreased from 11% to 3% (P=0.01). The catheter-related bloodstream infection rate dropped from 6.7 to 0.7 episodes per 1000 catheter days (P<0.001). CONCLUSIONS: Introduction of an NST increased both the total PN use and the percentage of referrals where enteral nutrition could replace PN. Medical specialty influenced the referral pattern and the likelihood that a referral resulted in PN being initiated. Safety of PN catheters improved significantly following NST introduction.

Psychophysiological responses to visceral and somatic pain in functional chest pain identify clinically relevant pain clusters.

BACKGROUND: Despite chronic pain being a feature of functional chest pain (FCP) its experience is variable. The factors responsible for this variability remain unresolved. We aimed to address these knowledge gaps, hypothesizing that the psychophysiological profiles of FCP patients will be distinct from healthy subjects. METHODS: 20 Rome III defined FCP patients (nine males, mean age 38.7 years, range 28-59 years) and 20 healthy age-, sex-, and ethnicity-matched controls (nine males, mean 38.2 years, range 24-49) had anxiety, depression, and personality traits measured. Subjects had sympathetic and parasympathetic nervous system parameters measured at baseline and continuously thereafter. Subjects received standardized somatic (nail bed pressure) and visceral (esophageal balloon distension) stimuli to pain tolerance. Venous blood was sampled for cortisol at baseline, post somatic pain and post visceral pain. KEY RESULTS: Patients had higher neuroticism, state and trait anxiety, and depression scores but lower extroversion scores vs controls (all p < 0.005). Patients tolerated less somatic (p < 0.0001) and visceral stimulus (p = 0.009) and had a higher cortisol at baseline, and following pain (all p < 0.001). At baseline, patients had a higher sympathetic tone (p = 0.04), whereas in response to pain they increased their parasympathetic tone (p ≤ 0.008). The amalgamating the data, we identified two psychophysiologically distinct 'pain clusters'. Patients were overrepresented in the cluster characterized by high neuroticism, trait anxiety, baseline cortisol, pain hypersensitivity, and parasympathetic response to pain (all p < 0.03). CONCLUSIONS & INFERENCES: In future, such delineations in FCP populations may facilitate individualization of treatment based on psychophysiological profiling.

Review article: the assessment and management of chronic severe gastrointestinal dysmotility in adults.

BACKGROUND: The characterisation and management of chronic severe gastrointestinal (GI) dysmotility are challenging. It may cause intestinal failure requiring home parenteral nutrition (HPN). AIMS: To review the presentation, aetiology, characterisation, management and outcome of chronic severe GI dysmotility, and to suggest a pragmatic management algorithm. METHODS: PubMed search was performed up to December 2012 using appropriate search terms, restricted to human articles and reviewed for relevance. Segmental dysmotility, acute ileus, functional syndromes and non-English articles were excluded. Evidence and recommendations were evaluated using the GRADE system. RESULTS: In total, 721 relevant articles were reviewed. A coherent and definitive picture is hampered by overlapping classification systems using multi-modal characterisation methods, subject to pitfalls and some requiring further validation. The literature is confined to case series with no randomised trials. Fewer than 20% undergo full thickness jejunal biopsy, which are otherwise labelled idiopathic. However, in studies with up to 80% biopsy rates, neuromuscular abnormalities may be found in 90%. Between 14% and 50% will require HPN, comprising 8-14% of all HPN patients, of which 2/3 are primary/idiopathic and 1/3 secondary, with scleroderma being the leading secondary cause. Ten-year  mortality ranges from 13% to 35% and is worst in elderly scleroderma patients. Management includes limited treatments for secondary causes, prokinetics, symptom palliation, psychological support, nutrition, hydration and judicious surgery. CONCLUSIONS: Severe dysmotility often remains idiopathic. It is rarely possible to alter disease trajectory; consequently, prognosis may be poor. Multi-disciplinary teams in a specialist setting can improve outcomes. Graded recommendations are enumerated and a pragmatic algorithm is suggested.

The autonomic response to human esophageal acidification and the development of hyperalgesia.

BACKGROUND: Distal esophageal acidification induces variable hyperalgesia in the non-acid exposed proximal esophagus. As the autonomic nervous system (ANS) modulates nociception, the aim was to determine whether autonomic reactivity to acid infusion predicted inter-individual differences in hyperalgesia. METHODS: In 25 healthy volunteers (18 women, age range 22-58, mean 36.5 years), using a double-blind, placebo-controlled crossover design, pain thresholds to electrical stimulation were determined in the proximal esophagus and foot (control) pre and post a 30-min distal esophageal infusion of 0.15 mol L(-1) HCl or saline with autonomic monitoring. Sympathetic Cardiac Sympathetic Index and Skin Conductance Response and parasympathetic Cardiac Vagal Tone and Cardiac Sensitivity to Baroreflex measures were derived. Plasma cortisol was measured pre and post infusion as were anxiety and unpleasantness. KEY RESULTS: Acid infusion reduced group pain threshold in the proximal esophagus (adjusted mean change -5.0 mA vs saline +3.4 mA, P < 0.001), and raised sympathetic measures (Cardiac Sympathetic Index, Skin Conduction Response) and cortisol levels, but reduced parasympathetic measures (cardiac vagal tone and cardiac sensitivity to Baroreflex) (all P < 0.05). Acid infusion also increased anxiety and unpleasantness scores (both P < 0.05). In 16 acid-sensitizers, the degree of hyperalgesia correlated with increasing heart rate (r = -0.66, P = 0.005), and fall in cardiac vagal tone (r = 0.54, P = 0.03) and Cardiac Sensitivity to Baroreflex (r = 0.54, P = 0.03). CONCLUSIONS & INFERENCES: Acid-induced esophageal hyperalgesia correlated with reduced parasympathetic tone, suggesting that the parasympathetic nervous system may have anti hyperalgesic properties. Additional studies on the autonomic modulation of esophageal hyperalgesia are required.

Personality differences affect brainstem autonomic responses to visceral pain.

Brainstem autonomic nuclei integrate interoceptive inputs including pain, with descending modulation, to produce homeostatic and defence outputs. Cardiac Vagal Control is especially implicated in psychophysiological processes for both health and disease and is indexed non-invasively by heart rate variability. The study aim was to determine the nature of psychophysiological response profiles for visceral pain. Nineteen healthy subjects had electrocardiographic recordings at rest and during 10 painful oesophageal balloon distensions. Cardiac Vagal Control originating from nucleus ambiguus (CVC(NA)) was determined by polynomial filter application to the electrocardiogram inter-beat interval series. Heart rate and 'Cardiac Sympathetic Index (CSI)' were also determined. Psychological state and trait, including neuroticism and extroversion, were assessed. Subjects who increased CVC(NA) to pain were more neurotic, anxious and sensory sensitive than those who decreased CVC(NA.) Cluster analysis identified two psychophysiological groups: Group 1 (n = 11) demonstrated lower baseline CVC(NA) (P = 0.0001), higher heart rate (P = 0.02) and CSI (P = 0.015), pain tolerance at lower balloon volumes (P = 0.04), but attenuated heart rate response to pain (P = 0.01). Group 2 (n = 8) had the converse profile. Neuroticism scores were higher (P = 0.0004) and extroversion lower (P = 0.01) for group 1 than group 2. Two distinct psychophysiological response profiles to visceral pain exist that are influenced by personality. These may reflect different psychobiological bases for active and passive defence repertoires. Prevalence and clinical relevance of these endophenotypes as vulnerability factors for pain and emotion disorders warrant further exploration.

Assessing the temporal reproducibility of human esophageal motor-evoked potentials to transcranial magnetic stimulation.

BACKGROUND: Although the electrophysiological properties and reproducibility of somatic limb motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) are well characterized, little is known about the reproducibility of MEPs for viscerosomatic structures such as the esophagus. AIM: To determine the temporal reproducibility of esophageal MEPs to TMS. METHODS: MEPs to TMS were recorded from the proximal esophagus, using a swallowed catheter housing a pair of electrodes, in eight healthy subjects at five stimulus intensities (SI) (motor threshold [MT] to 20% above MT). For each SI, 20 consecutive TMS stimuli at 5-second intervals were delivered over a single scalp site (dominant hemisphere at site exhibiting MT at lowest SI) and repeated 40 and 80 minutes thereafter. MEP amplitudes and latencies were measured, and means were sequentially calculated for each SI and then log-transformed. The repeatability coefficients (RC) for the three time points were calculated across each set of 20 stimuli and presented as an exponential ratio. RESULTS: Best RC (amplitude/latency) were achieved at 120% SI relative to MT, being 1.8/1.2 (optimal = 1.0). For lower intensities of 115%, 110%, 105%, and 100% SI, the RC were 2.1/1.2, 2.1/1.1, 2.4/1.2, and 2.6/1.4, respectively. For all SI, the greatest reductions in RC occurred over the first 10 stimuli, with little additional gain beyond this number. CONCLUSIONS: Latencies of esophageal MEP to TMS across intensities are highly reproducible, whereas amplitudes are more stimulus intensity-dependent, being most reliable and reproducible at the highest stimulus strengths. SIGNIFICANCE: Using careful parameters, TMS can be used reliably in future studies of viscerosomatic structures, although the size of the response variability needs to be taken into account when assessing changes in cortico-fugal activity.

Gender role attitudes and other determinants of breast feeding intentions in Brazilian women.

This study of 230 Brazilian mothers examined the associations of several sociodemographic variables, maternal attitudes and perceptions with intended breast feeding duration. The usual relationships of sociodemographic variables such as mother's age, education, smoking, parity and infant birth weight with intended breast feeding duration were not found. However, mother's intentions were related to gender role attitudes with both the least and the most traditional women intending to breast feed longer than women with moderately traditional gender role attitudes. Mother's attitude toward breast feeding, help with household tasks, and the attitudes of friends and relatives toward breast feeding were also very significantly related to intended breast feeding duration. Women who did not work outside the home intended to breast feed significantly longer than those who were employed.

A domain distinct from nucleoplasmin's nuclear localization sequence influences its transport.

We constructed mutants of the prototypical, nuclear-accumulating protein nucleoplasmin and used them in both in vivo and in vitro nuclear transport assays to search for transport-influencing domains distinct from this protein's recognized nuclear localization sequence. We identified the polyglutamic acid tract on the amino flank of the nuclear localization sequence as being involved in two stages of nuclear transport. This poly-glu tract is required for the facilitated translocation of nucleoplasmin through the nuclear pore complex, and it also enhances the subsequent binding of nucleoplasmin within the nucleus.

Distinct phosphorylation sites differentially influence facilitated transport of an NLS-protein and its subsequent intranuclear binding.

We measured the nuclear transport of radiolabeled fusion proteins consisting of variants of the Simian Virus 40 large T antigen's nuclear localization sequence region linked to beta-galactosidase, itself a cytoplasmic protein. We microinjected the fusion protein variants into the cytoplasm of living Xenopus oocytes or supplied them to the surface of oil-isolated oocyte nuclei via paired beads or cytoplasm. Presence of the cdc2 kinase site (124T) on the amino flank of the nuclear localization sequence (126PKKKRKV132) greatly enhances facilitated transport through the nuclear pore complex; additional presence of the casein kinase II site (112S) enhances subsequent intranuclear binding.

Intranuclear binding of nucleoplasmin.

Many proteins--including not only structural proteins, but also enzymes, hormone receptors, and other transcription factors--accumulate to much higher nuclear than cytoplasmic concentrations. Nuclear localization sequences or signals (NLSs) within their primary structures entrain specific transport of these proteins through the nuclear pore complexes. This transport process is energy-dependent, but evidence for a true active transport mechanism is not conclusive. An alternative mechanism--facilitated transport of NLS proteins followed by their intranuclear binding--has been implicated by experiments with oil-isolated nuclei. However, there has been no agreement as to a role for binding in the in vivo nuclear accumulation of NLS-containing proteins. We demonstrate herein that a prototypical NLS protein, nucleoplasmin (Np), binds within the nucleus of the living Xenopus oocyte and that this binding accounts for its nuclear accumulation.

Nucleoplasmin associates with and is phosphorylated by casein kinase II.

Nucleoplasmin is a phosphorylated nuclear-accumulating protein. We report herein that the kinetics of its cytoplasm-->nucleus transport are affected by its degree of phosphorylation. Therefore, we sought to identify any protein kinase which specifically associates with nucleoplasmin. We discovered that nucleoplasmin co-isolates by two independent methods (immunoabsorption and chromatography) in a complex including a kinase which phosphorylates nucleoplasmin. The co-purifying kinase is casein kinase II-like because: (i) it phosphorylates casein; (ii) its phospho-transferase activity can be competed out by GTP; (iii) it is stimulated by polylysine; and (iv) it is inhibited by heparin. Moreover, a polyclonal antibody to the alpha (38 kDa) and alpha' (36 kDa) catalytic subunits of casein kinase II specifically recognizes 38 and 36 kDa polypeptides in the nucleoplasmin-complex, and a specific inhibitor of casein kinase II inhibits nucleoplasmin's nuclear transport. Additionally, we found that phosphorylation of nucleoplasmin by its associated casein kinase II is strongly inhibited by histones and that, in addition to nucleoplasmin, another protein (p100) in the nucleoplasmin-complex is phosphorylated by casein kinase II.