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Heparan sulfate is a highly modified O -linked glycan that performs diverse physiological roles in animal tissues. Though quickly modified, it is initially synthesised as a polysaccharide of alternating β- d -glucuronosyl and N -acetyl-α- d -glucosaminyl residues by exostosins. These enzymes generally possess two glycosyltransferase domains (GT47 and GT64)—each thought to add one type of monosaccharide unit to the backbone. Although previous structures of murine exostosin-like 2 (EXTL2) provide insight into the GT64 domain, the rest of the bi-domain architecture is yet to be characterised; hence, how the two domains co-operate is unknown. Here, we report the structure of human exostosin-like 3 (EXTL3) in apo and UDP-bound forms. We explain the ineffectiveness of EXTL3’s GT47 domain to transfer β- d -glucuronosyl units, and we observe that, in general, the bi-domain architecture would preclude a processive mechanism of backbone extension. We therefore propose that heparan sulfate backbone polymerisation occurs by a simple dissociative mechanism. Heparan sulphate (HS)—a common cell surface decoration—is a carbohydrate of alternating sugars assembled by bi-domain enzymes such as EXTL3. Here, authors present the structure of EXTL3, explain EXTL3 lost activity, and propose that HS extension is distributive.

Study design: Cross-sectional questionnaire study. Objectives: To develop and validate a symptom-based score for neurogenic bowel dysfunction (NBD): NBD score. Setting: University Hospital of Aarhus, Denmark. Methods: A questionnaire including questions about background parameters ( n =8), faecal incontinence ( n =10), constipation ( n =10), obstructed defecation ( n =8), and impact on quality of life (QOL) ( n =3) was sent to 589 Danish spinal cord injured (SCI) patients. The reproducibility and validity of each item was tested in 20 and 18 patients, respectively. Associations between items and impact on QOL were determined by logistic regression analysis. The NBD score was constructed from items with acceptable reproducibility and validity that were significantly associated with impact on QOL. Based on odds ratios for associations between items and impact on QOL, each item was given a corresponding number of points in the NBD score. Results: A total of 424 SCI patients responded. The following 10 items met the criteria above: frequency of bowel movements (0–6 points), headache, perspiration or discomfort before or during defecation (0–2 points), tablets and drops against constipation (0–2 points each), time used for each defecation (0–7 points), frequency of digital stimulation or evacuation (0–6 points), frequency of faecal incontinence (0–13 points), medication against faecal incontinence (0–4 points), flatus incontinence (0–2 points) and perianal skin problems (0–3 points). Differences in NBD score among patients reporting no, little, some or major impact on QOL were statistically significant (all P <0.001). Conclusion: Based on valid and reproducible questions, we have constructed a score for NBD that is correlated to impact on QOL.

Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10 % DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3β and HIF-1α, with more interleukin-1β and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer’s disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3β and HIF-1α play a prominent role.

Study design: Randomized, controlled clinical trial. Objectives: Bladder and bowel management may cause serious autonomic dysreflexia (AD) in subjects with high spinal cord injury (SCI). We aimed at investigating autonomic responses to digital rectal evacuation (DE), transanal irrigation (TAI) with 500 ml and filling cystometry (FC) in SCI. Setting: Aarhus University Hospital, Denmark. Methods: Eight subjects with SCI (AIS A) at or above T6 (high SCI) and a previous history of AD were compared with three subjects with SCI (AIS A) between T10 and L2 (low SCI). In randomized order, DE, TAI and FC were performed. AD was defined as an acute rise in systolic blood pressure (sBP) of ⩾30 mm Hg above baseline. Blood levels of norepinephrine and epinephrine were determined before and shortly after the procedures. Results: During all three procedures, AD occurred in all patients with high SCI but not in those with low SCI. In high SCI subjects, DE increased median sBP from 127 (range: 86–154) to 188 (range: 140–206) mm Hg ( P <0.02), TAI from 126 (range: 91–146) to 163 (range: 130–188) mm Hg ( P <0.02) and FC from 125 (range: 106–149) to 200 (range: 179–220) mm Hg ( P <0.01). The sBP increase was lower during TAI than during DE ( P <0.05) or FC ( P <0.02). In high SCI subjects, the blood levels of norepinephrine, but not those of epinephrine, increased significantly during all three stimuli (all P <0.05). Conclusion: Bowel and bladder management caused AD in high SCI. The response is less severe during TAI than during FC or DE.

Background Irritable bowel syndrome (IBS) is a very common condition worldwide. Treatment options for severe IBS are few. Sacral neuromodulation (SNM) for patients with IBS has been shown to reduce symptoms and improve quality of life in the medium term. This study aimed to evaluate the long-term effectiveness and safety of SNM in diarrhoea-predominant and mixed IBS. Methods A prospective cohort of patients with IBS treated with SNM were evaluated 1, 3, 5, and 10 years after implantation. The primary end-point was a change in the Gastrointestinal Symptom Rating Scale–Irritable Bowel Syndrome version questionnaire (GSRS-IBS) from baseline to 10-year follow-up (FU). Secondary end-points were change in the GSRS-IBS score from baseline to 5-year FU and change in the Irritable Bowel Syndrome–Impact Scale questionnaire (IBS-IS) from baseline to 5- and 10-year FU. Adverse events following SNM were observed. Results Of 36 patients treated with SNM, 23 were eligible for 5-year FU and 13 for 10-year FU. The GSRS-IBS score was significantly reduced at both 5-year ( p  < 0.0001) and 10-year ( p  = 0.0007) FU. The IBS-IS score was also significantly improved at both 5 years ( p  < 0.0001) and 10 years ( p  = 0.0002). Fifty-six adverse events were registered. Five patients were explanted because of adverse events. Conclusion SNM seems to offer an effective and safe treatment option for highly selected patients with diarrhoea-predominant and mixed IBS. Clinical trial registration The present study has not been registered. The latest founding study was registered at ClinicalTrials.gov, NCT01948973.

Study design: International expert working group. Objectives: To revise the International Spinal Cord Injury (SCI) Bowel Function Basic Data Set as a standardized format for the collecting and reporting of a minimal amount of information on bowel function in clinical practice and research. Setting: Working group appointed by the American Spinal injury association (ASIA) and the International Spinal Cord Society (ISCoS). Methods: The draft prepared by the working group was reviewed by the International SCI Data Set Committee and later by members of the ISCoS Executive and Scientific Committees and the ASIA board. The revised data set was posted on the ASIA and ISCoS websites for 1 month to allow further comments and suggestions. Changes resulting from a Delphi process among experts in children with SCI were included. Members of ISCoS Executive and Scientific Committees and the ASIA board made a final review and approved the data set. Results: The International SCI Bowel Function Basic Data Set (Version 2.0) consists of the following 16 items: date of data collection, gastrointestinal and anal sphincter dysfunction unrelated to SCI, surgical procedures on the gastrointestinal tract, defecation method and bowel-care procedures, average time required for defecation, frequency of defecation, uneasiness, headache or perspiration during defecation, digital stimulation or evacuation of the anorectum, frequency of fecal incontinence, flatus incontinence, need to wear pad or plug, oral laxatives and prokinetics, anti-diarrheal agents, perianal problems, abdominal pain and discomfort and the neurogenic bowel dysfunction score. Conclusion: The International SCI Bowel Function Basic Data Set (Version 2.0) has been developed.

Study design: Review article. Objectives: To provide a consensus expert review of the treatment modality for transanal irrigation (TAI). Methods: A consensus group of specialists from a range of nations and disciplines who have experience in prescribing and monitoring patients using TAI worked together assimilating both the emerging literature and rapidly accruing clinical expertise. Consensus was reached by a round table discussion process, with individual members leading the article write-up in the sections where they had particular expertise. Results: Detailed trouble-shooting tips and an algorithm of care to assist professionals with patient selection, management and follow-up was developed. Conclusion: This expert review provides a practical adjunct to training for the emerging therapeutic area of TAI. Careful patient selection, directly supervised training and sustained follow-up are key to optimise outcomes with the technique. Adopting a tailored, stepped approach to care is important in the heterogeneous patient groups to whom TAI may be applied. Sponsorship: The review was financially supported by Coloplast A/S.

Study design: Longitudinal study with postal survey. Objectives: To describe changes in the patterns of neurogenic bowel dysfunction and bowel management in a population of people with spinal cord injury (SCI) followed for two decades. Setting: Members of the Danish SCI Association. Methods: In 1996, a validated questionnaire on bowel function was sent to the members of the Danish SCI Association ( n =589). The same questionnaire was sent to all the surviving members in 2006 ( n =284) and in 2015 ( n =178). A total of 109 responded to both the 1996 and 2015 questionnaires. Results: Comparing data from 2015 with those from the exact same participants in 1996, the proportion of respondents needing more than 30 min for each defaecation increased from 21 to 39% ( P <0.01), the use of laxatives increased ( P <0.05) and the proportion considering themselves very constipated increased from 19 to 31% ( P <0.01). In contrast, the proportion suffering from faecal incontinence remained stable at 18% in 1996 and 19% in 2015. During the 19-year period, there had been no significant change in the methods for bowel care, but 22 (20%) had undergone surgery for bowel dysfunction, including 11 (10%) who had some form of stoma. Conclusion: Self-assessed severity of constipation increased but quality of life remained stable in a cohort of people with SCI followed prospectively for 19 years. Methods for bowel care remained surprisingly stable but a large proportion had undergone stoma surgery.

Red blood cell distribution width (RDW) and visual assessments of anisocytosis assess variability in erythrocyte size. Veterinary studies on the correlation between the two methods and on observer agreement are scarce. The objectives were to assess the correlation of the grading of anisocytosis by means of conventional microscopy of canine blood smears to RDW, and to assess intra- and inter-observer variation in assessing the degree of anisocytosis. The study included 100 canine blood samples on which blood smear examination and RDW measurement were performed. RDW was measured on the Advia 2120i analyzer. The degree of anisocytosis was based on a human grading scheme assessing the ratio between the size of the representative largest red blood cell and that of the representative smallest red blood cell (1+ if <2x, 2+ if 2–3x, 3+ if 3–4x, and 4+ if >4x). Three observers participated and assessed the blood smears by conventional microscopy twice, 3 weeks apart by each observer. The correlation was assessed for each observer on each occasion using Kendahl-tau-b analysis. Intra-observer agreement was assessed using quadratically weighted kappa. Inter-observer agreement was assessed using free-marginal multi-rater kappa. Anisocytosis graded on blood smears correlated significantly with RDW values as assessed by Kendahl-tau-b ranging between 0.37 and 0.51 ( p < 0.0001). Intra-observer agreement ranged from weak to moderate with resulting kappa-coefficients being 0.58, 0.68, and 0.75, respectively. Inter-observer agreement was weak (Kappa-values 0.44). The weak to moderate observer agreement in the visual assessment of anisocytosis indicates that the more precise and more repeatable RDW measurement should be used for clinical decision-making.

Study design: A longitudinal postal survey. Objectives: To evaluate the prevalence and characteristics of abdominal pain in long-term spinal cord injury (SCI). Setting: Members of the Danish SCI Association. Methods: In 2006, a questionnaire on chronic abdominal pain and discomfort was sent to the 284 members of the Danish SCI association who had been members for at least 10 years; 203 of them responded. An almost identical questionnaire including questions on intensity and interference of pain within the past 7 days, as well as descriptors and treatment, was sent to the 178 surviving members in 2015. Results: Of 130 (73%) responders, 125 answered the question on chronic abdominal pain. The mean time since injury was 30.5 (9.8) years. Chronic abdominal pain or discomfort was reported by 32.8% (41/125), and 23% (29/125) of responders had been at least moderately bothered by this in the past week. Abdominal pain or discomfort was more common in women and in those with self-reported constipation. The median intensity (numeric rating scale) was 6.0 (range 3–10) and it was often associated with autonomic symptoms. Nine (8%) of the 115 individuals who responded in both 2006 and 2015 had developed new abdominal pain or discomfort, 30 (26%) no longer reported it, and 28 (24%) reported it at both time points with a similar intensity. Conclusions: Chronic abdominal pain or discomfort is common and bothersome in long-term SCI. It has a late onset, but the prevalence and severity do not seem to further increase between 20 and 30 years following SCI.