Posterior laryngitis: a disease with different aetiologies affecting health-related quality of life: a prospective case-control study.

BACKGROUND: Laryngo-pharyngeal reflux (LPR) is assumed to be the most common cause of posterior laryngitis (PL). Since LPR is found in healthy subjects, and PL patients are not improved by acid-reducing therapy, other aetiologies to PL must be considered. The aims of this study in PL were to investigate the prevalence of acid reflux in the proximal oesophagus and functional gastrointestinal symptoms, to analyse motilin levels in plasma, and to assess health-related quality of life (HRQOL) before and after treatment. METHODS: Forty-six patients (26 women), with verified PL, median age 55 (IQR 41-68) years, were referred to oesophago-gastro-duodenoscopy and 24-h pH monitoring. Plasma motilin was analysed. The 36-item Short-Form questionnaire was completed at inclusion and at follow-up after 43±14 months, when also the Visual Analogue Scale for Irritable Bowel Syndrome was completed. Values were compared to controls. Treatment and relief of symptoms were noted from medical records. RESULTS: Thirty-four percent had proximal acid reflux and 40% showed signs of distal reflux. Ninety-four percent received acid-reducing treatment, with total relief of symptoms in 17%. Patients with reflux symptoms had lower plasma motilin levels compared to patients without reflux symptoms (p = 0.021). The HRQOL was impaired at inclusion, but improved over time. Patients, especially men, had more functional gastrointestinal symptoms than controls. CONCLUSIONS: This study indicates that a minority of patients with PL has LPR and is cured by acid-reducing therapy. Disturbed plasma motilin levels and presence of functional gastrointestinal symptoms are found in PL. The impaired HRQOL improves over time.

Dorsal agenesis of the pancreas - a rare cause of abdominal pain and insulin-dependent diabetes.

Dorsal agenesis of the pancreas is a rare congenital disorder. We report a case of a 65-year-old man with mild abdominal pain and insulin-dependent diabetes mellitus. Computed tomography (CT) of the abdomen showed a short pancreas with no pancreatic tissue ventral to the splenic vein. Magnetic resonance cholangiopancreatography (MRCP) visualized the absence of a dorsal duct system and confirmed the suspicion of complete agenesis of the dorsal pancreas. Endoscopic ultrasound (EUS) was also performed to rule out pancreatic malignancy.

Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis.

BACKGROUND & AIMS: Corticosteroids alone or in conjunction with azathioprine (AZA) is the standard treatment in autoimmune hepatitis (AiH). Individual variations in thiopurine (TP) metabolism may affect both drug efficacy and toxicity. Our aim was to investigate the utility of thiopurine methyltransferase (TPMT) as well as thioguanine nucleotide (TGN) and methylthioinosine monophosphate (meTIMP) metabolite measurements with regard to clinical outcome. METHODS: Two hundred thirty-eight patients with AiH were included in this cross-sectional study. TPMT status was assessed in all patients, while TGN and meTIMP were measured in patients with ongoing TP medication. Clinical outcome was evaluated by liver tests and the ability to withdraw steroids. RESULTS: TPMT genotyping (n=229) revealed 207 (90.4%) wild-type and 22 heterozygous patients. One hundred forty-three patients had ongoing TP therapy with AZA (n=134) or mercaptopurine (MP; n=9); response was judged as complete response (CR) in 113 patients and partial response (PR) in 30 patients. Both TP dose (1.64 vs 1.19 mg/kg; p=0.012) and TPMT activity (14.3 vs 13.5; p=0.05) were higher in PR, resulting in similar TGN levels (PR: 121 pmol/8 x 10(8) red blood cells [RBC]; CR: 113 pmol/8 x 10(8) RBC; p=0.33) but higher meTIMP levels in PR (1350 vs 400 pmol/8 x 10(8) RBC; p=0.004). Patients able to withdraw steroids or who were using 5 mg prednisolone daily were treated with lower TP doses than patients on higher steroid doses (1.15 vs 1.18 vs 1.82 mg/kg; p<0.001). CONCLUSIONS: TP metabolite measurements are of clinical value in AiH patients who do not respond to standard TP treatment and for the identification of a shifted metabolism, which may demand an alternative treatment strategy.

The natural history of small-duct primary sclerosing cholangitis.

BACKGROUND & AIMS: The long-term prognosis of patients with small-duct primary sclerosing cholangitis (PSC) remains incompletely characterized. We aimed at determining the natural history and long-term outcomes of a large number of patients with small-duct PSC. METHODS: Data from 83 patients with well-characterized small-duct PSC from several medical institutions in Europe and the United States were combined. Each patient with small-duct PSC was randomly matched to 2 patients with large-duct PSC by age, gender, calendar year of diagnosis, and institution. RESULTS: The median age at diagnosis in both groups was 38 years (61% males). Nineteen (22.9%) of the 83 patients with small-duct PSC progressed to large-duct PSC in a median of 7.4 (interquartile range [IQR], 5.1-14) years. One patient with small-duct PSC who progressed to large-duct PSC was diagnosed with cholangiocarcinoma but after progression to large-duct PSC; 20 patients with large-duct PSC developed cholangiocarcinoma. Patients with small-duct PSC had a significantly longer transplantation-free survival compared with large-duct PSC patients (13 years [IQR, 10-17] vs 10 years [IQR, 6-14], respectively; hazard ratio, 3.04; 95% confidence interval: 1.82-5.06; P < .0001). Two patients with small-duct PSC who underwent liver transplantation had recurrence of small-duct PSC in the graft 9 and 13 years, respectively, after transplantation. CONCLUSIONS: Small-duct PSC is a disease of progressive potential but associated with a better long-term prognosis as compared with large-duct PSC. Small-duct PSC may recur after liver transplantation. Cholangiocarcinoma does not seem to occur in patients with small-duct PSC, unless the disease has progressed to large-duct PSC.

Liver cirrhosis in Iceland and Sweden: incidence, aetiology and outcomes.

OBJECTIVE: The objectives of this study were to investigate the incidence, aetiology and mortality of liver cirrhosis in Iceland and in Gothenburg in Sweden. Further objectives were prognosis in relation to different aetiologies and to evaluate the relationship between alcohol consumption in these countries and the incidence of alcoholic cirrhosis in recent decades. The incidence and mortality of liver cirrhosis in Iceland has been reported to be the lowest in the Western world. There are very few data on aetiology, incidence and prognosis among cirrhotics in Sweden. MATERIAL AND METHODS: All patients diagnosed with liver cirrhosis in Gothenburg (600,000 inhabitants) and Iceland (300,000 inhabitants) during the period 1994-2003 were included. RESULTS: A total of 918 patients in Gothenburg and 98 in Iceland were identified. The annual incidence in Gothenburg was 15.3+/-2.4/100,000 compared to 3.3+/-1.2/100,000 in Iceland (p<0.0001). In Gothenburg, 69% were male and in Iceland 52% (p<0.001). In Gothenburg, 50% of the patients had alcoholic cirrhosis compared to 29% in Iceland (p<0.0001). In Gothenburg, the patients had a higher Child-Pugh score (9.0) (SD 2.5) compared to Iceland (7.3) (SD 2.7) (p<0.0001). There was no difference in survival between patients with alcoholic liver disease and those with other aetiologies. CONCLUSIONS: The incidence of liver cirrhosis is low in Iceland, i.e. 24% of the incidence in Gothenburg, due to the lower incidence of alcoholic and hepatitis C cirrhosis in Iceland. No increasing trends in the incidence of cirrhosis in these two countries were observed during the study period.

Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. METHODS: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. RESULTS: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohn's disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9). CONCLUSIONS: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.

Influence of harvest time on fuel characteristics of five potential energy crops in northern China.

Five potential energy crops in northern China were examined for fuel characteristics over different harvest times to test whether or not a delayed harvest improves fuel quality in a semiarid area in China as is the case in northern Europe and North America. The five crops include indigo bush (Amorpha fruticosa), sand willow (Salix cheilophila), switch grass (Panicum virgatum), reed canary grass (Phalaris arundinacea), and sainfoin (Onobrychis viciifolia). These crops are considered as fuels for thermal conversion. From September 2002 to April 2003, biomass was sampled monthly, and the effects of harvest time on the fuel characteristics of the five crops were studied. With respect to ash and some undesired element contents in biomass, a delayed harvest in spring resulted in a better fuel quality than a traditional harvest in autumn. Of the five species, indigo bush and sand willow had the lowest ash contents when harvested in spring. Switch grass is a promising herbaceous energy crop in semiarid areas in terms of its yield, fuel characteristics, and low water use. Chlorine had the most significant correlation with harvest time and ash content in the biomass. In a comparison with the biofuel crops in Europe and North America, a much higher proportion of chlorine was found in all examined plants. The results from this study indicate that an energy crop with delayed harvest may extend fuel resources and conserve soil in semiarid regions in northern China, practices that will help maintain and improve economical and ecological sustainability.

Abdominal tenderness in ascites patients indicates spontaneous bacterial peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP), which has been reported to be present in 10-30% of patients with cirrhotic ascites, may easily be overlooked. An important aim of our study was to determine whether there are any clinical signs which, in clinical practice, may predict or exclude SBP. METHODS: We studied 133 patients with cirrhotic ascites from medical units at nine Swedish university hospitals where there had been at least one diagnostic ascites tap with analysis of polymorphonuclear leukocytes in the ascites fluid. The patients had initially been questioned about background factors and physically examined according to a standardized case record form. Samples of blood, urine, and ascites were then drawn for analysis according to a structured schedule. RESULTS: SBP could be excluded in 80% of all the cases and was confirmed in 8% of the 133 patients in the final analysis. Abdominal pain and abdominal tenderness were more common in patients with SBP (p<0.01), but no other physical sign or laboratory test could separate SBP cases from the others. CONCLUSIONS: SBP was present in about one-tenth of the hospitalized patients with cirrhotic ascites in this cohort. Performing repeated physical examinations and paying particular attention to abdominal tenderness may be the best way to become aware of the possible development of this complication.

The Pharyngoesophageal Segment After Total Laryngectomy.

OBJECTIVE: The aim of the present study was to characterize the pharyngoesophageal segment in laryngectomees who rated themselves as functional tracheoesophageal speakers. METHODS: Voice perceptual assessment, high-resolution videomanometry of swallowing and phonation, and high-speed camera recording during phonation provided information about the anatomy and function of the pharyngoesophageal segment. RESULTS: Fourteen patients were included in the study. The voice assessments presented high intra/inter-listener reliability. We found a significant correlation between roughness and poor voice quality, hyperfunction and poor intelligibility, and poor voice quality, long time since the operation, and old age. High-resolution videomanometry during phonation revealed decreasing mean pressures from the distal esophagus to the pharynx and confirmed low resting pressures at the pharyngoesophageal segment and low esophageal peristaltic contraction pressures after laryngectomy in comparison to normal subjects. The neoglottis shape was mainly circular and presented a strong mucosal wave in most of the patients on the high-speed camera recording. CONCLUSIONS: Perceptual voice assessment and high-speed camera recordings provided baseline information about voice characteristics and vibration regularity of the neoglottis. Additionally, the quantitative measures obtained with high-resolution videomanometry may have clinical applicability as reference data in voice rehabilitation after total laryngectomy.

Perinatal events and the risk of developing primary sclerosing cholangitis.

AIM: To investigate whether perinatal events, intrauterine or postpartum, are associated with the development of primary sclerosing cholangitis (PSC) later in life. METHODS: Birth records from 97 patients with adult PSC in Sweden were reviewed. Information on perinatal events including medications and complications during pregnancy, gestation length, birth weight and length were collected. Two control children of the same sex were selected for each subject. Conditional multiple logistic regression was used to assess associations of the perinatal measures with development of PSC. RESULTS: No significant associations were found between gestational age, birth length, breastfeeding, and the majority of medical complications including infections or medication during pregnancy for the mothers or postpartum for the children. Vaginal bleeding and peripheral oedema showed associations with PSC, with matched odds ratios of 5.70 (95% CI, 1.13-28.83) and 2.28 (95% CI, 1.04-5.03), respectively. CONCLUSION: The associations of vaginal bleeding and oedema with subsequent PSC cannot readily be explained, so our findings do not strongly support the hypothesis of a significant role of perinatal events as a risk for the development of PSC later in life.

Hepatic findings in long-term clinical trials of ximelagatran.

OBJECTIVE: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. PATIENTS AND METHODS: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). RESULTS: An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. CONCLUSION: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.

Fatigue is not a specific symptom in patients with primary biliary cirrhosis.

BACKGROUND: Fatigue has been reported to be common in patients with primary biliary cirrhosis (PBC). Limited data exist on comparison with fatigue in the general population and comparison with patients with other chronic gastrointestinal disorders are lacking. METHOD: We enrolled 96 patients with PBC (87 females); mean age 63 (range 34-65) who completed the Fatigue Impact Scale (FIS). In comparison we included matched controls from the general population, patients with organic (OGD) and functional GI disorders (FGD). Liver function test and the latest liver biopsy were analysed and correlated with fatigue scores. RESULTS: The mean duration of PBC was 7.4 years, the mean bilirubin 13 micromol/l. Twelve per cent of patients had cirrhosis, 29% were in stage I on Ludwig's histology score and 30% and 29% were in stages II and III, respectively. The PBC patients had a median FIS total score of 29 in comparison with 38 in GP controls (P<0.05). Patients with OGD and FGD had more severe fatigue (FIS total score 67 and 59 (P<0.01 compared with PBC)). Fatigue in the PBC patients did not correlate with liver tests and histology stage. CONCLUSION: PBC patients had less severe fatigue measured with the FIS than controls from the GP and patients with OGD and FGD. This study also confirms results of other studies showing no correlation with fatigue in PBC and liver disease parameters. These results argues strongly against fatigue as a specific symptom in PBC.

Treatment of cricopharyngeal dysfunction: a comparative pilot study.

BACKGROUND: Cricopharyngeal dysfunction is a narrowing at the level of the upper oesophageal sphincter caused by failed or incomplete sphincter opening as a result of lack of pharyngoesophageal coordination or reduction in the muscular compliance of the upper oesophageal sphincter. Oropharyngeal dysphagia is a typical symptom. Videomanometry allows direct comparison of pressure readings with dynamic anatomy during swallowing. METHODS: This is a prospective randomized pilot study that compares the effect of balloon dilatation and laser myotomy in cricopharyngeal dysfunction. We used videomanometry as an objective measure and the Swedish version of Sydney Swallowing Questionnaire as patient's self-assessment at baseline and 1 and 6 months after treatment. RESULTS: The UES sagittal diameter increased from 5.6 mm pre-operatively to 8.4 mm 6 months post-operatively with no differences between treatment groups. Preoperative mean Sydney Swallowing Questionnaire score was 770 and 6 months post-operative score 559, with no difference between the treatments in our cohort. CONCLUSION: Cricopharyngeal dysfunction treatment by either laser myotomy or balloon dilatation improved upper oesophageal sphincter opening during at least 6 months. TRIAL REGISTRATION: ISRCTN84905610, date: 081214.

Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1.

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.

[Ursodeoxycholic acid in the treatment of chronic cholestatic liver disease. Documented delay in disease progress inspires hope]. / Ursodeoxicholsyra i behandlingen av kronisk kolestatisk leversjukdom. Visad fördröjd sjukdomsprogress inger förhoppning.

The effect of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) has been investigated in a large number of randomized controlled studies. Meta-analyses of these studies have not proved a beneficial effect on survival. However, these analyses have also comprised patients with end-stage PBC as well as patients with very early PBC. A prolonged survival in such groups of patients is not expected to be demonstrated in short-term studies. Modified meta-analyses are underway. A number of beneficial effects on the disease process and complications still make an optimistic view of the drug in PBC justifiable. Limited experience suggests a beneficial effect of UDCA also in other cholestatic diseases.

High-precision, room temperature screening assay for inhibitors of microsomal prostaglandin E synthase-1.

UNLABELLED: Microsomal prostaglandin E synthase-1 (mPGES-1) is the major enzyme catalyzing the isomerization of prostaglandin (PG) H(2) to PGE(2). Here we report the development of a robust and practical automated assay in a 384-well format for room temperature screening of mPGES-1 inhibitors with high precision and low reagent consumption. The assay should enable precise structure-activity relationship development. It uses acetonitrile as solvent for PGH(2), FeCl(2)/citrate as stop reagent, and a short reaction time. Combined with high-precision liquid transfer and extensive mixing after addition of reactants, these properties let the assay reach Z' > 0.7 and high reproducibility of inhibitor IC(50) values. Thorough investigation of the quality of mixing in all liquid transfer steps proved crucial for reaching high-precision performance. ABBREVIATIONS: mPGES-1 (microsomal prostaglandin E synthase-1); FRET (fluorescence resonance energy transfer); HTRF (homogeneous time-resolved fluorescence); PGH2 (prostaglandin H2); PGE2 (prostaglandin E2); SAR (structure-activity relationship); COX-2 (cyclooxygenase-2); GSH (glutathione); ALP (automated labware positioner).

Esophageal dysmotility is more common than gastroparesis in diabetes mellitus and is associated with retinopathy.

OBJECTIVES: Gastroparesis is a well-known complication of diabetes mellitus, both in symptomatic and asymptomatic patients. Esophageal dysmotility has also been described, but is not as well-characterized. The etiology and effect of these complications need to be clarified. The aim of the present study was to evaluate esophageal and gastric motility, complications, gastrointestinal symptoms, and plasma biomarkers in a cross-sectional study comprising patients with diabetes mellitus. METHODS: Patients with diabetes were consecutively asked to participate, and eventually 84 volunteers were included in the study. Esophageal manometry and the gastric emptying test were performed in all patients. Type of diabetes, symptoms, diabetic complications, body mass index (BMI), and biomarkers were recorded. Patients were interviewed about gastrointestinal symptoms. RESULTS: Esophageal dysmotility was present in 63% of patients and gastroparesis in 13% of patients. There was no difference in dysmotility between patients with type 1 and type 2 diabetes or between genders. Gastrointestinal symptoms did not correlate to objective findings. Age correlated negatively with gastric emptying rate (p = 0.004). Patients with esophageal dysmotility had longer duration of diabetes compared to those without dysmotility (p = 0.043). In logistic regression analysis, retinopathy was strongly associated with esophageal dysmotility, independent of duration (p = 0.003). CONCLUSIONS: Esophageal dysmotility is more common than gastroparesis in diabetes mellitus independent of gender, symptoms, and type of diabetes. There is a strong association between retinopathy and esophageal dysmotility.

Motilin concentrations in relation to gastro intestinal dysmotility in diabetes mellitus.

AIM: Dysmotility in the upper gastro intestinal (GI) tract are common problems in diabetics. Many peptides are involved in the regulation of the motility. The aim of this study was to examine whether plasma levels of motilin were related to dysfunction in the oesophagus and stomach in a well-defined diabetic patient group. METHODS: Nineteen patients with symptoms from the GI tract who had been examined with oesophageal manometry, gastric emptying scintigraphy and deep-breathing test were included. They received a fat-rich meal, after which blood samples were collected and analysed for motilin concentrations. RESULTS: Symptoms of abdominal fullness and gastro oesophageal reflux significantly associated with delayed gastric emptying, whereas no symptom correlated to oesophageal dysmotility. Plasma levels of motilin were increased after the fat-rich meal (p=0.000), with no difference between the groups. Abnormal manometry was characterized by aperistalsis and/or simultaneous contractions. The percentage of simultaneous contractions correlated to basic and peak motilin values (r(s)=0.898, p=0.006 and r(s)=0.842, p=0.017, respectively). Gastric emptying did not influence motilin concentrations. CONCLUSION: Plasma motilin concentrations vary with abnormalities of oesophageal motility in diabetics, but not with abnormalities of gastric emptying.