Early intervention with ColdZyme mouth spray after self-diagnosis of common cold: A randomized, double-blind, placebo-controlled study.

BACKGROUND: Previous clinical and in vitro investigations have supported the efficacy of a glycerol throat spray containing cold-adapted cod trypsin (ColdZyme) against respiratory viruses causing the common cold bycreating a protective mucosal barrier shown to deactivate common cold virus in vitro and decrease pharyngeal rhinovirus load. METHODS AND FINDINGS: This was a double-blind, randomized, parallel-group, placebo-controlled study conducted at 10 German sites to evaluate the efficacy of the medical device ColdZyme, a glycerol mouth spray containing cold-adapted cod trypsin for a naturally occurring common cold versus placebo spray. Adults experiencing a minimum of three common colds during the previous year, but otherwise healthy, were enrolled to begin treatment with the mouth spray or placebo six times daily at first sign of a common cold. Jackson's symptom scale and the 9-item Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) quality of life (QoL) domain and a sore throat scale were recorded daily by subjects, as well as any use of allowed rescue treatment. Between January and April 2019, 701 subjects were enrolled and randomly assigned to the ColdZyme group (n = 351) or the placebo group (n = 350). Of the 701 subjects, 438 (62.5%) subjects developed symptoms typical of common cold, and all 438 started study treatment (n = 220 in the ColdZyme group and n = 218 in the placebo group). The demographic profile of the treatment groups were comparable with 68.1% female and almost all subjects being Caucasian (98.4%). The age ranged between 18 and 70 years with a mean age of 41.3 (±14.4) years. There were no differences between the groups in primary and major secondary endpoints, however, the assessment using the WURSS-21 QoL domain and Jackson score suggests a slightly faster recovery with ColdZyme as symptoms and complaints affecting the quality of life were shortened by about 1 day. The beneficial effect of ColdZyme was particularly noticeable on the fifth day of the common cold. A positive difference between treatment groups was also seen for the subjects' assessments of global efficacy of the investigational product A robust safety profile for ColdZyme was demonstrated throughout the study. CONCLUSION: The safety and tolerability of ColdZyme have been confirmed in a large study population and further establishes evidence of a faster recovery from common cold symptoms. Early self-diagnosis and early use of ColdZyme mouth spray is a safe alternative for treatment of naturally occurring colds.

Safety, Efficacy, and Dose Protocol of Metoprolol for Heart Rate Reduction in Pediatric Outpatients Undergoing Cardiac CT Angiography. / Segurança, Eficácia e Protocolo de Dose de Metoprolol para Redução de Frequência Cardíaca em Pacientes Pediátricos Externos que Passaram por Angiografia Cardíaca por TC.

BACKGROUND: Image quality and radiation dose are optimized with a slow, steady heart rate (HR) when imaging the coronary arteries during cardiac computed tomography angiography (CCTA). The safety, efficacy, and protocol for HR reduction with beta blocker medication is not well described in a pediatric patient population. OBJECTIVE: Provide a safe and efficient metoprolol dose protocol to be used in pediatric outpatients undergoing CCTA. METHODS: We conducted a retrospective review of all pediatric outpatients who received metoprolol during CCTA. Demographic and clinical characteristics were summarized and the average reduction in HR was estimated using a multivariate linear regression model. Images were evaluated on a 1-4 scale (1= optimal). RESULTS: Seventy-eight pediatric outpatients underwent a CCTA scan with the use of metoprolol. The median age was 13 years, median weight of 46 kg, and 36 (46%) were male. The median doses of metoprolol were 1.5 (IQR 1.1, 1.8) mg/kg and 0.4 (IQR 0.2, 0.7) mg/kg for oral and intravenous administrations, respectively. Procedural dose-length product was 57 (IQR 30, 119) mGy*cm. The average reduction in HR was 19 (IQR 12, 26) beats per minute, or 23%. No complications or adverse events were reported. CONCLUSION: Use of metoprolol in a pediatric outpatient setting for HR reduction prior to CCTA is safe and effective. A metoprolol dose protocol can be reproduced when a slower HR is needed, ensuring faster acquisition times, clear images, and associated reduction in radiation exposure in this population. (Arq Bras Cardiol. 2021; 116(1):100-105).

FUNDAMENTO: Qualidade de imagem e dose de radiação são otimizadas com uma frequência cardíaca (FC) lenta e estável na realização de imagens de artérias coronárias durante a angiografia cardíaca por tomografia computadorizada (CCTA, do inglês cardiac computed tomography angiography) A segurança, a eficácia e o protocolo para a redução da FC com medicamento betabloqueador ainda não foi bem descrita em uma população de pacientes pediátricos. OBJETIVO: Oferecer um protocolo de dose de metoprolol eficiente a ser usado em pacientes pediátricos externos durante a CCTA. MÉTODOS: Realizamos uma revisão retrospectiva de todos os pacientes pediátricos externos que receberam o metoprolol durante a CCTA. As características demográficas e clínicas foram resumidas e a redução média em FC foi estimada utilizando-se um modelo de regressão linear multivariada. As imagens foram avaliadas em uma escala de 1 a 4 (1= ideal). RESULTADOS: Um total de 78 pacientes externos passaram a uma CCTA com o uso de metoprolol. A média de idade foi de 13 anos, a média de peso foi de 46 kg, e 36 pacientes (46%) eram do sexo masculino. As doses médias de metoprolol foram 1,5 (IQR 1,1; 1,8) mg/kg, e 0,4 (IQR 0,2; 0,7) mg/kg para administrações orais e intravenosas, respectivamente. O produto dose-comprimento por exame foi de 57 (IQR 30, 119) mGy*cm. A redução média da FC foi 19 (IQR 12, 26) batimentos por minuto, ou 23%. Não foram relatadas complicações ou eventos adversos. CONCLUSÃO: O uso de metoprolol num cenário de pacientes pediátricos externos para redução da FC antes de uma CCTA é seguro e eficiente. Pode-se reproduzir um protocolo de dose de metoprolol quando for necessário atingir uma FC mais lenta, garantindo tempos de aquisição mais rápidos, imagens mais claras e redução na exposição à radiação nessa população. (Arq Bras Cardiol. 2021; 116(1):100-105).

Segurança, Eficácia e Protocolo de Dose de Metoprolol para Redução de Frequência Cardíaca em Pacientes Pediátricos Externos que Passaram por Angiografia Cardíaca por TC / Safety, Efficacy, and Dose Protocol of Metoprolol for Heart Rate Reduction in Pediatric Outpatients Undergoing Cardiac CT Angiography

Resumo Fundamento Qualidade de imagem e dose de radiação são otimizadas com uma frequência cardíaca (FC) lenta e estável na realização de imagens de artérias coronárias durante a angiografia cardíaca por tomografia computadorizada (CCTA, do inglês cardiac computed tomography angiography) A segurança, a eficácia e o protocolo para a redução da FC com medicamento betabloqueador ainda não foi bem descrita em uma população de pacientes pediátricos. Objetivo Oferecer um protocolo de dose de metoprolol eficiente a ser usado em pacientes pediátricos externos durante a CCTA. Métodos Realizamos uma revisão retrospectiva de todos os pacientes pediátricos externos que receberam o metoprolol durante a CCTA. As características demográficas e clínicas foram resumidas e a redução média em FC foi estimada utilizando-se um modelo de regressão linear multivariada. As imagens foram avaliadas em uma escala de 1 a 4 (1= ideal). Resultados Um total de 78 pacientes externos passaram a uma CCTA com o uso de metoprolol. A média de idade foi de 13 anos, a média de peso foi de 46 kg, e 36 pacientes (46%) eram do sexo masculino. As doses médias de metoprolol foram 1,5 (IQR 1,1; 1,8) mg/kg, e 0,4 (IQR 0,2; 0,7) mg/kg para administrações orais e intravenosas, respectivamente. O produto dose-comprimento por exame foi de 57 (IQR 30, 119) mGy*cm. A redução média da FC foi 19 (IQR 12, 26) batimentos por minuto, ou 23%. Não foram relatadas complicações ou eventos adversos. Conclusão O uso de metoprolol num cenário de pacientes pediátricos externos para redução da FC antes de uma CCTA é seguro e eficiente. Pode-se reproduzir um protocolo de dose de metoprolol quando for necessário atingir uma FC mais lenta, garantindo tempos de aquisição mais rápidos, imagens mais claras e redução na exposição à radiação nessa população. (Arq Bras Cardiol. 2021; 116(1):100-105)

Abstract Background Image quality and radiation dose are optimized with a slow, steady heart rate (HR) when imaging the coronary arteries during cardiac computed tomography angiography (CCTA). The safety, efficacy, and protocol for HR reduction with beta blocker medication is not well described in a pediatric patient population. Objective Provide a safe and efficient metoprolol dose protocol to be used in pediatric outpatients undergoing CCTA. Methods We conducted a retrospective review of all pediatric outpatients who received metoprolol during CCTA. Demographic and clinical characteristics were summarized and the average reduction in HR was estimated using a multivariate linear regression model. Images were evaluated on a 1-4 scale (1= optimal). Results Seventy-eight pediatric outpatients underwent a CCTA scan with the use of metoprolol. The median age was 13 years, median weight of 46 kg, and 36 (46%) were male. The median doses of metoprolol were 1.5 (IQR 1.1, 1.8) mg/kg and 0.4 (IQR 0.2, 0.7) mg/kg for oral and intravenous administrations, respectively. Procedural dose-length product was 57 (IQR 30, 119) mGy*cm. The average reduction in HR was 19 (IQR 12, 26) beats per minute, or 23%. No complications or adverse events were reported. Conclusion Use of metoprolol in a pediatric outpatient setting for HR reduction prior to CCTA is safe and effective. A metoprolol dose protocol can be reproduced when a slower HR is needed, ensuring faster acquisition times, clear images, and associated reduction in radiation exposure in this population. (Arq Bras Cardiol. 2021; 116(1):100-105)

Reduced display of conformational epitopes in the N-terminal truncated GAD65 isoform: relevance for people with stiff person syndrome or DQ8/8-positive Type 1 diabetes mellitus.

AIMS: To investigate whether the N-terminal truncated glutamic acid decarboxylase 65 (GAD65) isoform is as well recognized by people with stiff person syndrome as it is by people with Type 1 diabetes, and whether conformational GAD65 antibody epitopes are displayed properly by the isoform. METHODS: GAD65 antibody-positive healthy individuals (n=13), people with stiff-person syndrome (n=15) and children with new-onset Type 1 diabetes (n=654) were analysed to determine binding to full-length GAD65 and the N-terminal truncated GAD65 isoform in each of these settings. GAD65 autoantibody epitope specificity was correlated with binding ratios of full-length GAD65/N-terminal truncated GAD65. RESULTS: The N-terminal truncated GAD65 isoform was significantly less recognized in GAD65Ab-positive people with stiff-person syndrome (P=0.002) and in healthy individuals (P=0.0001) than in people with Type 1 diabetes. Moreover, at least two specific conformational GAD65Ab epitopes were not, or were only partially, presented by the N-terminal truncated GAD65 isoform compared to full-length GAD65. Finally, an N-terminal conformational GAD65Ab epitope was significantly less recognized in DQ8/8 positive individuals with Type 1 diabetes (P=0.02). CONCLUSIONS: In people with stiff person syndrome preferred binding to the full-length GAD65 isoform over the N-terminal truncated molecule was observed. This binding characteristic is probably attributable to reduced presentation of two conformational epitopes by the N-terminal truncated molecule. These findings support the notion of disease-specific GAD65Ab epitope specificities and emphasize the need to evaluate the applicability of novel assays for different medical conditions.

Clinical diagnosis of Larsen syndrome, Stickler syndrome and Loeys-Dietz syndrome in a 19-year old male: a case report.

BACKGROUND: Larsen syndrome is a hereditary disorder characterized by osteochondrodysplasia, congenital large-joint dislocations, and craniofacial abnormalities. The autosomal dominant type is caused by mutations in the gene that encodes the connective tissue protein, filamin B (FLNB). Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by arterial aneurysms, dissections and tortuosity, and skeletal, including craniofacial, manifestations. Mutations in five genes involved in the transforming growth factor beta (TGF-ß) signaling pathway cause five types of LDS. Stickler syndrome is a genetically heterogeneous arthro-ophthalmopathy caused by defects in collagen, exhibiting a wide specter of manifestations in connective tissue. A rare case is reported that was diagnosed with all these three hereditary connective tissue disorders. CASE PRESENTATION: A 19 year-old, Norwegian male with a clinical diagnosis of Larsen syndrome and with healthy, non-consanguineous parents attended a reference center for rare connective tissue disorders. Findings at birth were hypotonia, joint hypermobility, hyperextended knees, adductovarus of the feet, cervical kyphosis, craniofacial abnormalities, and an umbilical hernia. From toddlerhood, he required a hearing aid due to combined conductive and sensorineural hearing loss. Eye examination revealed hyperopia, astigmatism, and exotropia. At 10 years of age, he underwent emergency surgery for rupture of an ascending aortic aneurysm. At 19 years of age, a diagnostic re-evaluation was prompted by the findings of more distal aortic dilation, tortuosity of precerebral arteries, and skeletal findings. High throughput sequencing of 34 genes for hereditary connective tissue disorders did not identify any mutation in FLNB, but did identify a de novo missense mutation in TGFBR2 and a nonsense mutation in COL2A1 that was also present in his unaffected father. The diagnosis was revised to LDS Type 2. The patient also fulfills the proposed criteria for Stickler syndrome with bifid uvula, hearing loss, and a known mutation in COL2A1. CONCLUSION: LDS should be considered in patients with a clinical diagnosis of Larsen syndrome, in particular in the presence of arterial aneurysms or tortuosity. Due to genetic heterogeneity and extensive overlap of clinical manifestations, genetic high throughput sequencing analysis is particularly useful for the differential diagnosis of hereditary connective tissue disorders.

Results after sacral nerve stimulation for chronic constipation.

BACKGROUND: Sacral nerve stimulation is an established treatment for fecal incontinence and initial reports describe successful results also in subjects with chronic constipation. METHODS: Consecutive patients with slow transit or outlet obstruction type constipation were offered external stimulation through a test electrode inserted in a sacral foramen during a 3-week period. The symptomatic evaluation was based on the number of bowel movements and a validated obstructed defecation score (ODS). A permanent implant was performed provided an overall 50% decrease in symptoms was observed. KEY RESULTS: In total, 44 patients with chronic constipation were treated with a 3-week test stimulation. Fifteen experienced a 50% reduction of symptoms and received a permanent implant. Four of the 15 with permanent implants were explanted during the course of the study. Five subjects (11% of original group) reported sustained symptom relief at final follow-up after a mean of 24 months (range 4-81). Mean ODS score did not change during the treatment. Patients with predominantly slow transit constipation or outlet obstruction did not differ concerning success rate. CONCLUSIONS & INFERENCES: Sacral nerve stimulation has limited efficacy in unselected patients with chronic constipation and cannot be recommended for treatment on routine basis.

Towards a global system of vigilance and surveillance in unrelated donors of haematopoietic progenitor cells for transplantation.

Safety of living donors is critical to the success of blood, tissue and organ transplantation. Structured and robust vigilance and surveillance systems exist as part of some national entities, but historically no global systems are in place to ensure conformity, harmonisation and the recognition of rare adverse events (AEs). The World Health Assembly has recently resolved to require AE/reaction (AE/R) reporting both nationally and globally. The World Marrow Donor Association (WMDA) is an international organisation promoting the safety of unrelated donors and progenitor cell products for use in haematopoietic progenitor cell (HPC) transplantation. To address this issue, we established a system for collecting, collating, analysing, distributing and reacting to serious adverse events and reactions (SAE/R) in unrelated HPC donors. The WMDA successfully instituted this reporting system with 203 SAE/R reported in 2011. The committee generated two rapid reports, reacting to specific SAE/R, resulting in practice changing policies. The system has a robust governance structure, formal feedback to the WMDA membership and transparent information flows to other agencies, specialist physicians and transplant programs and the general public.

Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids.

BACKGROUND: A recent case-controlled study reported an increased risk of diabetes mellitus in patients treated with inhaled corticosteroids for asthma or COPD, versus age-matched controls. OBJECTIVE: The purpose of the current study was to evaluate whether there was an increased risk of new onset diabetes mellitus or hyperglycaemia among patients with asthma or COPD treated with inhaled corticosteroids. METHODS: A retrospective analysis evaluated all double-blind, placebo-controlled, trials in patients ≥4 years of age involving budesonide or budesonide/formoterol in asthma (26 trials; budesonide: n = 9067; placebo: n = 5926), and in COPD (8 trials; budesonide: n = 4616; non-ICS: n = 3643). A secondary dataset evaluated all double-blind, controlled trials in asthma involving the use of inhaled corticosteroids (60 trials; budesonide: n = 33,496; fluticasone: n = 2773). RESULTS: In the primary asthma dataset, the occurrence of diabetes mellitus/hyperglycaemia adverse events (AEs) was 0.13% for budesonide and 0.13% for placebo (HR 0.98 [95% CI: 0.38-2.50], p = 0.96) and serious adverse events (SAEs) was 0% for budesonide and 0.05% for placebo. In the secondary dataset, the occurrence of diabetes/hyperglycaemia as AE and SAE was 0.19% and 0.03%, respectively. In the COPD dataset, the occurrence of diabetes mellitus/hyperglycaemia AEs was 1.3% for budesonide and 1.2% for non-ICS (HR 0.99 [95% CI: 0.67-1.46], p = 0.96) and SAEs was 0.1% for budesonide and 0.03% for non-ICS. CONCLUSION AND CLINICAL RELEVANCE: Treatment with inhaled corticosteroids in patients with asthma or COPD was not associated with increased risk of new onset diabetes mellitus or hyperglycaemia.

Growth performance, digestibility and faecal coliform bacteria in weaned piglets fed a cereal-based diet including either chicory (Cichorium intybus L) or ribwort (Plantago lanceolata L) forage.

Twenty-five weaned 35-day-old piglets were used in a 35-day growth experiment to evaluate the effect of inclusion of chicory and ribwort forage in a cereal-based diet on growth performance, feed intake, digestibility and shedding of faecal coliform bacteria. A total of seven experimental diets were formulated, a cereal-based basal diet (B), and six diets with inclusion of 40, 80 and 160 g/kg chicory (C40, C80 and C160) or ribwort (R40, R80 and R160). Piglets had ad libitum access to feed and water throughout the experiment. Three and five weeks post-weaning faeces samples for determination of digestibility were collected once a day for five subsequent days. Additional faeces samples for determination of coliform counts were collected at days 1, 16 and 35 post-weaning. Piglets fed diet R160 had the lowest average daily feed intake (DFI) and daily weight gain (DWG), and differed (P < 0.05) from piglets fed diets B, R40 and R80. There were no differences in DFI and DWG between the chicory diets and diet B. Inclusion of chicory or ribwort had a minor negative impact on the coefficient of total tract apparent digestibility (CTTAD) of dry matter, organic matter and crude protein, whereas inclusion of both chicory and ribwort resulted in higher CTTAD of non-starch polysaccharides and neutral detergent fibre (NDF). The CTTAD of arabinose were higher for diets C160 and R160 than for diet B (P < 0.05), and the CTTAD of uronic acid was higher for diets C40, C80, C160, R80 and R160 than for diet B (P < 0.05). Age affected the CTTAD for all parameters (P < 0.05) except for NDF, with higher values at 5 than at 3 weeks post-weaning. The coliform counts decreased with increasing age (P < 0.05), but was not affected by treatment. The results indicate that inclusion of up to 160 g/kg of chicory do not negatively affect performance, whereas high inclusion of ribwort have a negative impact on feed consumption and consequently on growth rate. Both herbs have a higher digestibility of fibre compared to cereal fibre. Chicory and ribwort are both promising as feedstuffs to weaned piglets, but the low palatability of ribwort limits the inclusion level.

Safety of formoterol in children and adolescents: experience from asthma clinical trials.

BACKGROUND: The safety of long-acting ß(2) agonist (LABA) therapy in asthma remains controversial but no large scale analyses have been published of LABA safety in children. METHODS: The frequency of asthma-related deaths and hospitalisations following formoterol use in children (4-11 years) and adolescents (12-17 years), compared with non-LABA treatment, was assessed in all AstraZeneca-sponsored, randomised, controlled, parallel-group trials (≥3 months) where formoterol was used as maintenance and/or as reliever therapy. RESULTS: 11,849 children and adolescents under the age of 18 years from 41 trials were identified, 82% of whom used an inhaled corticosteroid (ICS) as concomitant medication. The number of asthma-related deaths (one 13-year-old boy among 7796 formoterol-treated patients, and none among 4053 non-LABA-treated patients) was too low to allow any between-group comparison. The frequency of patients with asthma-related hospitalisations was not different in formoterol-treated versus non-LABA-treated patients, either in children (1.16% (38/3263) vs 1.11% (24/2165)) or in adolescents (0.51% (23/4533) vs 0.85% (16/1888)). Asthma-related hospitalisations based on daily dose of formoterol were: (A) 4.5 or 9 µg: 1.9% (18/980); (B) 18 µg: 0.5% (14/2870); (C) 36 µg: 0% (0/67); and (D) variable dosing: 0.75% (29/3879). There was no difference between formoterol-treated and non-LABA-treated patients as regards ethnicity. CONCLUSIONS: Formoterol use in children and adolescents (4-17 years) with asthma in this large study where the majority are prescribed concomitant ICS is not associated with any increased risk of asthma-related hospitalisations. The results are not influenced by dose or ethnicity.

Standards, regulations and accreditation for registries involved in the worldwide exchange of hematopoietic stem cell donors and products.

The World Marrow Donor Association (WMDA) is working closely with other international organizations working in cellular therapy such as the Worldwide Network for Blood and Marrow Transplantation (WBMT) to develop and maintain global recommendations and requirements for a standardized practice. WMDA launched its registry accreditation program in September 2003. Since then, 17 of the 71 hematopoietic stem cell donor registries worldwide have been accredited. These accredited registries list over 80% of the hematopoietic stem cell donors and umbilical cord blood units listed in the database of BM Donors Worldwide. The goal of the WMDA Standards and Accreditation process is to protect donors while serving the needs of patients who are urgently seeking histocompatible donors in worldwide searches. These activities address the increasing governmental regulations regarding the quality and safety of stem cells collected internationally for national patients.

Biodiversity effects on yield and unsown species invasion in a temperate forage ecosystem.

BACKGROUND AND AIMS: Current agricultural practices are based on growing monocultures or binary mixtures over large areas, with a resultant impoverishing effect on biodiversity at several trophic levels. The effects of increasing the biodiversity of a sward mixture on dry matter yield and unsown species invasion were studied. METHODS: A field experiment involving four grassland species [two grasses--perennial ryegrass (Lolium perenne) and cocksfoot (Dactylis glomerata)--and two legumes--red clover (Trifolium pratense) and white clover (Trifolium repens)], grown in monocultures and mixtures in accordance with a simplex design, was carried out. The legumes were included either as single varieties or as one of two broad genetic-base composites. The experiment was harvested three times a year over three years; dry matter yield and yield of unsown species were determined at each harvest. Yields of individual species and interactions between all species present were estimated through a statistical modelling approach. KEY RESULTS: Species diversity produced a strong positive yield effect that resulted in transgressive over-yielding in the second and third years. Using broad genetic-base composites of the legumes had a small impact on yield and species interactions. Invasion by unsown species was strongly reduced by species diversity, but species identity was also important. Cocksfoot and white clover (with the exception of one broad genetic-base composite) reduced invasion, while red clover was the most invaded species. CONCLUSIONS: The results show that it is possible to increase, and stabilize, the yield of a grassland crop and reduce invasion by unsown species by increasing its species diversity.

Detection of cholangiocarcinoma with magnetic resonance spectroscopy of bile in patients with and without primary sclerosing cholangitis.

BACKGROUND: Early detection of cholangiocarcinoma (CC) is very difficult, especially in patients with primary sclerosing cholangitis (PSC) who are at increased risk of developing CC. PURPOSE: To evaluate 1H magnetic resonance spectroscopy ((1)H-MRS) of bile as a diagnostic marker for CC in patients with and without PSC. MATERIAL AND METHODS: The institutional review board approved the study, and all patients gave informed consent. Bile from 49 patients was sampled and investigated using 1H-MRS. MR spectra of bile samples from 45 patients (18 female; age range 22-87 years, mean age 57 years) were analyzed both conventionally and using computerized multivariate analysis. Sixteen of the patients had CC, 18 had PSC, and 11 had other benign findings. RESULTS: The spectra of bile from CC patients differed from the benign group in the levels of phosphatidylcholine, bile acids, lipid, and cholesterol. It was possible to distinguish CC from benign conditions in all patients with malignancy. Two benign non-PSC patients were misclassified as malignant. The sensitivity, specificity, and accuracy were 88.9%, 87.1%, and 87.8%, respectively. CONCLUSION: With 1H-MRS of bile, cholangiocarcinoma could be discriminated from benign biliary conditions with or without PSC.

Epitope analysis of GAD65 binding in both cord blood and at the time of clinical diagnosis of childhood type 1 diabetes.

The GAD65 epitope immunoglobulin binding pattern in cord blood of children (n=37), who later developed type 1 diabetes at 3.2-14.9 years of age, was analyzed. First, the binding at diagnosis was compared with that in the cord blood serum. The next comparison was between the cord blood serum and the mothers' serum taken at delivery. Basal GAD65 binding levels were determined in Protein A Sepharose-based radiobinding assays with (35)S-labeled human and rat GAD65, rat GAD67 and GAD65/67 fusion proteins representing N-terminal (N), middle (M) and C-terminal (C) epitopes. In the first comparison, 28/37 children had GAD65 binding above 2.44 relative units (RU) (upper three quartiles), representing a marked increase from birth in the binding to human GAD65 (p<0.0001), rat GAD65 (p<0.0001), N- (p=0.04), M- (p<0.0001), C- (p=0.001), and M + C-epitopes (p<0.0001), but not to rat GAD67. At birth, 9/37 had GAD65 binding above 1.56 RU (upper quartile) demonstrating that their binding of human (35)S-GAD65 was higher in cord blood than in the mother (p=0.008). Higher cord blood binding was also observed for the N- (p=0.02) terminal epitope but not for rat GAD65, rat GAD67, and the remaining epitopes. These data suggest that differences in the epitope GAD65 binding between mother and child at birth are limited. In contrast, the epitope pattern at diagnosis differed from that at birth, supporting the view that disease-associated epitopes develop between birth and diagnosis.

Diagnostic and prognostic implications of DNA ploidy and S-phase evaluation in the assessment of malignancy in biliary strictures.

BACKGROUND AND STUDY AIMS: Brush cytology of biliary strictures has a low sensitivity for diagnosing malignancy, and additional diagnostic tools are needed. The aim of the present study was to assess the diagnostic and prognostic importance of DNA measurements as an adjunct to brush cytology in patients with biliary strictures. PATIENTS AND METHODS: All patients (n = 225) with bile duct strictures who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 1997 and October 2003 at the Department of Radiology at Karolinska University Hospital, Huddinge, Sweden, were included in the study. While 66 patients had an unclear final diagnosis and were therefore excluded, the remaining 159 patients were assessed with brush cytology and DNA flow cytometry. RESULTS: Sensitivity and specificity of DNA aneuploidy for tumor detection were 43 % and 96 %. Using DNA analysis in addition to brush cytology, the sensitivity was 62 % compared with 57 % for brush cytology alone (not significant). Patients with diploid DNA tumors had a significantly better survival than patients with aneuploid DNA tumors ( P = 0.02). The mean survival was 10 months for diploid cancers and 6 months for aneuploid cancers. CONCLUSION: DNA ploidy measurement may be a diagnostic method that could supplement brush cytology in the identification of malignancy in biliary strictures. DNA aneuploidy is a marker of poor prognosis in patients with malignant biliary strictures.

Effects of three months of low molecular weight heparin (dalteparin) treatment after bypass surgery for lower limb ischemia--a randomised placebo-controlled double blind multicentre trial.

OBJECTIVES: To test the hypothesis that long-term postoperative dalteparin (Fragmin), Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment. DESIGN: Prospective randomised double blind multicenter study. MATERIALS AND METHODS: Using a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000 IU dalteparin or placebo injections once daily for 3 months. All patients received 75 mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months. RESULTS: At 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups. CONCLUSIONS: In patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia.

Intraoperative endoscopic retrograde cholangiopancreatography (ERCP) to remove common bile duct stones during routine laparoscopic cholecystectomy does not prolong hospitalization: a 2-year experience.

BACKGROUND: There is still some controversy regarding the optimal timing and best method for the removal of common bile duct stones (CBDS). Intraoperative endoscopic retrograde cholangiopancreaticography (IO-ERCP) is an alternative method that should be considered for this procedure. The aim of our study was to investigate the clinical outcome of a single-step procedure (IO-ERCP) to remove CBDS, thereby combining two existing high-volume clinical modalities-i.e., laparoscopic cholecystectomy (LC) and ERCP. METHODS: Between January 2000 and December 2001, 674 patients, 192 male and 482 female, underwent cholecystectomy at our hospital. There were 612 LC (90.8%), 37 converted procedures (5.5%), and 25 open operations (3.7%). In 592 of the patients, (87.8%) intraoperative cholangiography (IOC) was performed. In 34 (5.7%) of those who had and IOC, an IO-ERCP was performed. While the surgeon waited for the endoscopist, care was taken to introduce a thin guidewire through the lOC catheter and pass it through the sphincter of Oddi, out into the duodenum. This complementary procedure greatly facilitated the subsequent cannulation of the bile ducts. RESULTS: The cannulation frequency of the CBD was 100%. Common bile duct stones were successfully extracted in 93.5%. Endoscopic sphincterotomy (EST), followed by the insertion of a plastic endoprosthesis, was performed in two patients with remaining stones. The CBD of these two patients was cleared by postoperative ERCP. None of the patients developed postoperative pancreatitis. The operating time was prolonged as compared with the time for LC (192 vs 110 mins; p < 0.05). The length of hospitalization for IO-ERCP patients did not differ from that for patients undergoing cholecystectomy alone (2.6 vs 2.1. days; NS). CONCLUSIONS: The study suggests that elective IO-ERCP is a safe and efficient method for removing CBDS that has a low risk of inducing postoperative pancreatitis and does not prolong postoperative hospitalization. This technique enables perioperative extraction of CBDS without open or laparoscopic surgical exploration of the CBD and can be used safely in a routine clinical setting.

Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: Strictures of the bile ducts due to malignant changes are difficult to distinguish from benign changes, particularly in patients with primary sclerosing cholangitis (PSC). The aim of this study was to evaluate diagnostic methods for malignancy in biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography (ERCP). PATIENTS AND METHODS: Bile duct strictures were identified during ERCP in 57 patients, who were thus included in the present study. Brush samples from the strictures were taken for cytology and for evaluation of DNA content by flow cytometry. The tumor markers CA 19-9 and CEA were determined both in serum and bile fluid. Two independent radiologists evaluated all cholangiograms. The diagnostic sensitivity, specificity, and accuracy of each diagnostic method were evaluated separately and in combination. RESULTS: 32 patients were found to have malignant strictures and when the four methods: brush cytology, DNA analysis, serum CA 19-9 and serum CEA were combined, a diagnostic sensitivity of 88 % and specificity of 80 % were reached. Seven of the 20 patients with PSC were found also to suffer from cholangiocarcinoma, yielding a sensitivity and specificity of 100 % and 85 %, respectively. Analyses of CA 19-9 and CEA in bile fluid had no diagnostic significance. CONCLUSION: An ERCP procedure with brush cytology, a DNA analysis, combined with serum analysis of CA 19-9 and CEA, can increase the possibility of distinguishing between malignant and benign biliary strictures, especially in PSC patients.

E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo.

The C/EBPalpha transcription factor is required for differentiation of adipocytes and neutrophil granulocytes, and controls cellular proliferation in vivo. To address the molecular mechanisms of C/EBPalpha action, we have identified C/EBPalpha mutants defective in repression of E2F-dependent transcription and found them to be impaired in their ability to suppress cellular proliferation, and to induce adipocyte differentiation in vitro. Using targeted mutagenesis of the mouse germline, we show that E2F repression-deficient C/EBPalpha alleles failed to support adipocyte and granulocyte differentiation in vivo. These results indicate that E2F repression by C/EBPalpha is critical for its ability to induce terminal differentiation, and thus provide genetic evidence that direct cell cycle control by a mammalian lineage-instructive transcription factor couples cellular growth arrest and differentiation.