Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea.

BACKGROUND: Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency. AIM: The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD. METHODS: Patients with seven-day 75selenium-homocholic acid taurine (SeHCAT) scan retention <10% were randomised in a double-blind protocol to two weeks treatment with twice-daily A3384 250 mg (n = 6), 1 g (n = 7) or placebo (n = 6). Thirteen patients were taking conventional sequestrants at the start of the study. Symptoms were recorded and serum FGF19 and 7α-hydroxy-4-cholesten-3-one (C4) measured. RESULTS: Median serum FGF19 on conventional sequestrant treatment was 28% lower than baseline values in BAD (p < 0.05). C4 on conventional sequestrant treatment was 58% higher in BAD (p < 0.001). No changes were seen on starting or withdrawing A3384. A3384 improved diarrhoeal symptoms, with a median reduction of 2.2 points on a 0-10 Likert scale compared to placebo, p < 0.05. CONCLUSIONS: Serum FGF19 was suppressed and bile acid production up-regulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.

[Retinal Vein Occlusion - Which Treatment When?] / Retinaler Venenverschluss ­ wann, womit und wie therapieren?

According to the latest findings, macular oedema due to retinal vein occlusion is best treated safely and effectively with near-term intravitreal anti-VEGF therapy (aflibercept, bevacizumab [off label], ranibizumab). After an initial upload of 3 monthly injections of anti-VEGF, the decision on re-injection should be based on OCT (rather than on visual acuity). After initial monthly injections, the "pro-re-nata" (PRN) and the "treat-and-extend" regimens have been predominantly used in the further course of therapy. Taking into account the side effect spectrum (in particular cataract progression, increased intraocular pressure), intravitreal therapy with a dexamethasone implant may be a reasonable alternative. The prognosis for visual acuity and the decline in macular oedema depend on starting treatment early and continuing it consistently. Before starting treatment, as well as during treatment, fluorescein angiography is necessary to detect ischemic retinal areas. There is evidence that early targeted laser coagulation of ischemic retina may reduce the frequency of necessary injections and improve the response of the oedema to therapy. Significant retinal ischemia may lead to proliferations, rubeosis iridis and secondary glaucoma and therefore requires laser treatment.

[Orbital complication of acute sinusitis : Orbital cellulitis in a 10-year-old child]. / Orbitale Komplikation einer akuten Sinusitis : Orbitaphlegmone bei einem 10-jährigen Kind.

Bacterial orbital cellulitis is a life-threatening infection of the postseptal orbital tissue. It can occur in the context of sinusitis, particularly in children and adolescents. Ocular complications include exposure keratopathy, increased intraocular pressure, occlusion of the central retinal artery or vein and optic neuropathy. Rarely, a subperiosteal abscess can occur, and osteomyelitis can lead to spread of the infection to the cerebrum. A rapid diagnosis and targeted therapy are essential for saving the eye as well as the life of the patient.

Fecal incontinence in irritable bowel syndrome: Prevalence and associated factors in Swedish and American patients.

BACKGROUND: Fecal incontinence (FI) is a prevalent but poorly recognized problem in the general population with profound negative effects on daily life. The prevalence of FI in irritable bowel syndrome (IBS) and its association with clinical, demographic, and pathophysiological factors remain largely unknown. METHODS: One US (n=304) and one Swedish (n=168) patient cohort fulfilling Rome III criteria for IBS completed Rome III diagnostic questions on FI and IBS symptoms, and questionnaires on IBS symptom severity, quality of life, anxiety and depression, and work productivity impairment. The patients also underwent assessments of colorectal sensitivity and motility. KEY RESULTS: Fecal incontinence ≥ one day per month was reported by 19.7% (USA) and 13.7% (Sweden) of IBS patients. These proportions rose to 43.4% and 29.8% if patients with less frequent FI were included. Fecal incontinence prevalence was higher in older age groups, with a clear increase above age 40. Irritable bowel syndrome patients with FI reported greater overall IBS symptom severity, more frequent and loose stools, and greater urgency. Negative effects of FI on quality of life, psychological distress, and work productivity were demonstrated. No associations were found between colorectal physiology and FI. CONCLUSIONS & INFERENCES: Fecal incontinence is common in IBS patients, and similar to previous general population reports, the major risk factors for FI in IBS are older age, rectal urgency, and loose, frequent stools. When IBS patients have comorbid FI, the impact on quality of life, psychological symptoms, and work impairment appears greater.

Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients.

BACKGROUND: Real-life long-term data on infliximab treatment in ulcerative colitis are limited. AIM: To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined. METHODS: A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age ≥18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant. RESULTS: Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy. CONCLUSIONS: Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.

Review article: bile acid diarrhoea - pathogenesis, diagnosis and management.

BACKGROUND: Bile acid diarrhoea results from imbalances in the homoeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease/dysfunction, associated with other GI pathology or can be idiopathic. AIMS: To summarise the different types of bile acid diarrhoea and discuss the currently available diagnostic methods and treatments. RESULTS: Bile acid diarrhoea is found in up to 40% of patients diagnosed as having functional diarrhoea/IBS-D, and in up to 80% of patients who have undergone ileal resection. It is likely under-diagnosed and under-treated. In idiopathic disease, errors in regulation feedback of fibroblast growth factor 19 contribute to the development of the condition. Clinical therapeutic trials for bile acid diarrhoea have been used to diagnose it, but the 75 SeHCAT test is the primary current method. It is sensitive, specific and widely available, though not in the USA. Other diagnostic methods (such as serum measurement of the bile acid intermediate 7α-hydroxy-4-cholesten-3-one, or C4) have less widespread availability and documentation, and some (such as faecal measurement of bile acids) are significantly more complex and costly. First-line treatment of bile acid diarrhoea is with the bile acid sequestrant cholestyramine, which can be difficult to administer and dose due to gastrointestinal side effects. These side effects are less prominent in newer agents such as colesevelam, which may provide higher efficacy, tolerability and compliance. CONCLUSION: Bile acid diarrhoea is common, and likely under-diagnosed. Bile acid diarrhoea should be considered relatively early in the differential diagnosis of chronic diarrhoea.

[Quantum of luck with a self-induced penetrating orbital injury]. / Quäntchen Glück bei einer selbst induzierten penetrierenden Orbitaverletzung.

Presentation of a patient with two foreign bodies each 21 cm long in left nasal orbit and penetrating as far as the sinciput. The patient had been knitting at the time of the accident and had probably autonomously thrust the two knitting needles into the left orbit, as assessed by questioning of other parties. The patient had a known history of paranoid schizophrenia and dementia. Central imaging revealed the position of the knitting needles with respect to the intracranial vessels to be threatening. The surgical removal of the knitting needles was carried out without any serious complications, such as intracranial hemorrhage.

Cultured blood T-cell responses predict anti-TNF therapy response in patients with ulcerative colitis.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy is used for treatment of ulcerative colitis (UC). As approximately 30% of patients with UC do not benefit from the treatment, it is of clinical interest to identify biomarkers of response before therapy is initiated. AIM: To identify prognostic biomarkers of anti-TNF therapy response in anti-TNF therapy-naïve patients with UC. METHODS: Peripheral blood cells were obtained from 56 patients with UC before therapy started. Thirty-four patients were included in an exploratory cohort and 22 patients in a validation cohort. Blood cells were stimulated in vitro with influenza vaccine with and without anti-TNF. T-cell surface receptor expression and cytokine release were determined (in total 17 variables). Treatment response was evaluated using the Mayo score 12-14 weeks after the first infusion. RESULTS: In the exploratory cohort, blood cells from the patients showed stronger anti-TNF-dependent suppression of T-cell surface receptor expression and cytokine secretion among therapy responders than nonresponders. In particular, anti-TNF suppressed the expression of CD25 on T cells and secretion of interleukin 5, to a higher degree in responders than in nonresponders. These variables were used to a create model to predict therapy outcome, which was confirmed in the validation cohort. Correct classification of future therapy response was achieved in 91% of the cases in the validation cohort. CONCLUSION: The effects of anti-TNF on cultured blood T cells, obtained before therapy started, predict treatment outcome in patients with UC.

Modulatory role of calreticulin as chaperokine for dendritic cell-based immunotherapy.

Heat shock proteins (HSPs) play a regulatory role for maturation of antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages. Whereas HSP70 has been shown to enhance the maturation of human DCs via a nuclear factor kappa-B (NF-κB)-dependent pathway, the regulatory role of calreticulin (CRT), which is a HSP with similar functions to HSP70, is not well studied. To investigate the role of CRT as adjuvant in cell activation and co-stimulatory responses we determined the effects of CRT on human APC maturation in comparison to that of HSP70. To facilitate eukaryotic endotoxin-free CRT protein expression, three different methods were compared. We demonstrate that CRT induces the maturation of human DCs and increases the production of proinflammatory cytokines via the NF-κB pathway. CRT-mediated maturation was qualitatively similar to that induced by HSP70. Interestingly, priming of monocytes with HSPs showed an even more prominent effect on maturation than exposure of immature DCs to these compounds. A higher expression of CD86, CD83 and CCR7 on mature DCs were found in response to CRT. Our data provide novel insights into the role of extracellular HSPs as chaperokines in the processes of APC generation and may thus be useful to improve adoptive immunotherapy.

Randomised clinical trial: The ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation--a double-blind study.

BACKGROUND: One half of patients with constipation are not satisfied with available therapies, hence there is a need for more effective and well-tolerated drugs. AIM: To evaluate the effects of a specific inhibitor of the Ileal Bile Acid Transporter (IBAT; syn apical sodium-dependent bile acid transporter; ASBT) in patients with chronic idiopathic constipation (CIC) with focus on safety, colonic transit and efficacy signals. METHODS: This was a single-centre, prospective, randomised, double-blind, placebo-controlled study with a dose-escalating design in patients with CIC. In addition to evaluation of conventional safety and tolerability parameters, (i) colonic transit time (CTT) was measured using radio-opaque markers, (ii) metabolic parameters [lipid profile, C4 (7α-hydroxy-4-cholesten-3-one) and FGF19 (Fibroblast Growth Factor 19)] were evaluated, and (iii) constipation parameters, such as changes in stool frequency and consistency, were analysed. RESULTS: Thirty patients were randomised into five dose-levels (range: 0.1-10 mg/day) or to placebo. All patients completed a 14-day treatment period, and the safety/tolerability analysis was favourable. A3309, present in picomolar concentrations in plasma, induced up to a three-fold increase in bile acid synthesis (C4) and a reduction of plasma FGF19, as well as reduction in total and LDL cholesterol. CTT was reduced in the highest dose groups; the main acceleration was identified in the left colon. Efficacy parameters showed trends for increased number of spontaneous bowel movements and improved stool consistency. CONCLUSIONS: Ileal Bile Acid Transporter inhibition is a novel mechanism for treatment of patients with chronic idiopathic constipation and has additional benefits of improving metabolic parameters (EudraCT 2008-003255-72).

Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain.

BACKGROUND: Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor 'transient receptor potential vanilloid 1'(TRPV1) are a potential drug class for GERD treatment. AIM: To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. METHODS: Twenty-two healthy men (20-31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. DATA ANALYSIS: intention-to-treat. RESULTS: A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10-38%] and 28%, respectively (CI: 14-43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1-3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0-5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported 'feeling cold' and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4±0.3 °C and 0.7±0.3 °C, respectively, P<0.05). CONCLUSIONS: AZD1386 increased oesophageal and skin heat pain thresholds and had a safe adverse-event profile. This drug class may have a potential for treatment of GERD.

Indirect evidence for increased mechanosensitivity of jejunal secretomotor neurones in patients with idiopathic bile acid malabsorption.

AIM: The interdigestive motor rhythm, the migrating motor complex (MMC), is accompanied by active secretion of chloride during periods of distally propagating maximal motor activity (MMC phase III). We studied the behaviour of this system in bile acid malabsorption (BAM), a relative common cause of chronic diarrhoea. We measured motor activity and transmucosal potential difference (PD, reflecting active chloride secretion), in the proximal jejunum in healthy controls (n = 18) and in a group of patients with BAM (n = 11). The phase III-generated voltage was related to the degree of BAM quantified by the (75)SeHCAT test. METHODS: We used a multi-channel intestinal infusion system to simultaneously measure jejunal pressure and PD. Saline passing calomel half-cells was infused into the jejunum and subcutaneously. Pressure and PD were recorded in the fasting state and after a test meal. RESULTS: In the absence of motor activity, jejunal PD was not significantly different from zero in either group. During MMC phase III, PD reached significantly higher mean and peak levels in BAM patients. The product of MMC phase III length multiplied by voltage, over 3 h, was also significantly higher in BAM patients (controls: median 307 mV x cm, range 70-398; BAM: median 511, range 274-2271, P < 0.01). This value was also significantly correlated with the degree of BAM as reflected by the (75)SeHCAT test (P < 0.05). CONCLUSION: Phase III induced jejunal secretion may be upregulated in BAM patients, resulting in overload of colonic reabsorption capacity.

Budesonide treatment is associated with increased bile acid absorption in collagenous colitis.

BACKGROUND: Bile acid malabsorption is frequent in collagenous colitis and harmful bile acids may play a pathophysiological role. Glucocorticoids increase ileal bile acid transport. Budesonide have its main effect in the terminal ileum. AIMS: To evaluate whether the symptomatic effect of budesonide is linked to increased uptake of bile acids. METHODS: Patients with collagenous colitis were treated with budesonide 9 mg daily for 12 weeks. Prior to and after 8 weeks of treatment, the (75)SeHCAT test, an indirect test for the active uptake of bile acid-s, measurements of serum 7alpha-hydroxy-4-cholesten-3-one, an indicator of hepatic bile acid synthesis, and registration of symptoms were performed. RESULTS: The median (75)SeHCAT retention increased from 18% to 35% (P < 0.001, n = 25) approaching the values of healthy controls (38%). The 7alpha-hydroxy-4-cholesten-3-one values decreased significantly among those with initially high synthesis (from 36 to 23 ng/mL, P = 0.04, n = 9); however, for the whole group the values were not altered (19 ng/mL vs. 13 ng/mL, P = 0.23, N.S., n = 19). CONCLUSION: The normalization of the (75)SeHCAT test and the reduction of bile acid synthesis in patients with initially high synthetic rate, suggests that the effect of budesonide in collagenous colitis may be in part due to decreased bile acid load on the colon.

Overuse of acid suppressive therapy in hospitalised patients with pulmonary diseases.

OBJECTIVES: Overuse of acid suppressive therapy (AST) has been reported in hospitalised patients, but the use in specific patient categories is unexplored. We assessed the use of and indication for AST and upper endoscopic investigations in hospitalised patients on a pulmonary ward compared with patients on other wards. METHODS: 301 patients were enrolled in the study. 162 were hospitalised on a pulmonary ward with a control group consisting of 139 from both a surgical and general internal medicine ward. Adequate indications for AST were those strongly supported by medical literature. RESULTS: Among the 301 patients enrolled, 132 (44%) used AST. 78 (59%) had no adequate indication for AST. On the pulmonary ward 79 (49%) patients used AST, compared to only 10 (20%) on the internal medicine ward (P < 0.05). On the pulmonary ward 68% of the patients had no adequate indication for AST, which was more common than inappropriate use of ASTon the control wards (P < 0.05). The most common inadequate indication for AST was peptic ulcer prophylaxis during corticoidsteroid therapy. CONCLUSION: In hospitalised patients a significant overuse of AST was observed, particularly among pulmonary patients. More adequate use of AST can contribute to substantial savings for the health-care system.