Short, frequent, light-intensity walking activity improves postprandial vascular-inflammatory biomarkers in people with type 1 diabetes: The SIT-LESS randomized controlled trial.

AIM: To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. RESULTS: Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1ß, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1ß, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1ß (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. CONCLUSIONS: Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. TRIAL REGISTRATION: The trial was prospectively registered (ISRCTN13641847).

End of Life Care for Unplanned Vascular Admissions.

BACKGROUND: Unplanned vascular admissions have a high mortality. Previous studies have indicated that end of life care (EoLC) among this group of patients is low but there exist limited data on EoLC in the United Kingdom. The aim of this study was to evaluate the quality and predictors of EoLC for unplanned vascular admissions to a tertiary center in the United Kingdom. METHODS: This was a retrospective single-center cohort study of unplanned vascular surgery admissions from August 1, 2019 to January 22, 2020. Data on patient demographics, markers of quality of palliative care, mortality, and cause of death of unplanned admission to the vascular surgery department were collected from hospital and general practitioner records and evaluated against EoLC to evaluate predictors and efficacy of EoLC. Quality of palliative care markers included documentation of preferred place of death and care priorities, time spent in hospital and the intensive care unit toward the end of life, and realization of documented care objectives. EoLC input was defined as a dedicated palliative care consultation (PCC) by a palliative care professional, medical doctor, surgeon, or advanced care practitioner. We also conducted a subgroup analysis of patients within this group with chronic limb-threatening ischemia (CLTI), diabetic foot, and ruptured aortic aneurysms, as all patients in this group should be offered EoLC according to international guidelines. RESULTS: One-hundred and fifty patients were included. Median age at presentation was 70.5 years, and the cohort consisted of mostly men (72%). CLTI (31%) was the most common reason for admission. Surgical intervention was carried out in 60% of patients. Two-year mortality was 36%, and pneumonia (22%) was the most common cause of death. Seven percent of patients received PCC, which occurred a median of 10 days before death. Only a minority of patients had preferred place of care/death (14%), care priorities (37%), and family involvement during advance care planning (17%) documented in their notes; 29% of patients had Recommended Summary Plan for Emergency Care and Treatment forms in place. A diagnosis of left ventricular systolic dysfunction, chronic kidney disease, and increasing age predicted Recommended Summary Plan for Emergency Care and Treatment form completion. Patients with PCC were more likely to have advance care planning, but this did not translate into improvements in the other markers of quality of palliative and, consequently, EoLC. CONCLUSIONS: EoLC was insufficient and of low quality despite a high mortality in this group. Clinical guidelines and pathways are needed to ensure these patients are considered for EoLC and those with CLTI, diabetic foot sepsis or ruptured abdominal aortic aneurysms are offered it by default. Further research is needed to help identify vascular patients who would benefit from EoLC earlier to improve quality at end of life.

Outcomes following cardiac resynchronisation therapy in older people.

INTRODUCTION: Older patients may be less likely to receive cardiac resynchronisation therapy (CRT) for the management of heart failure. We aimed to describe the differences in clinical response, complications, and subsequent outcomes following CRT implantation compared to younger patients. METHODS: We conducted a retrospective cohort study of unselected, consecutive patients implanted with CRT devices between March 2008 and July 2017. We recorded complications, symptomatic and echocardiographic response, hospitalisation for heart failure, and all-cause mortality comparing patients aged <70, 70-79 and ≥ 80 years. RESULTS: Five hundred and seventy-four patients (median age 76 years [interquartile range 68-81], 73.3% male) received CRT. At baseline, patients aged ≥80 years had worse symptoms, were more likely to have co-morbidities, and less likely to be receiving comprehensive medical therapy, although left ventricular function was similar. Older patients were less likely to receive CRT-defibrillators compared to CRT-pacemakers. Complications were infrequent and not more common in older patients. Age was not a predictor of symptomatic or echocardiographic response to CRT (67.2%, 71.2% and 62.6% responders in patients aged <70, 70-79 and ≥ 80 years, respectively; P = 0.43), and time to first heart failure hospitalisation was similar across age groups (P = 0.28). Ten-year survival was lower for older patients (49.9%, 23.9% and 6.8% in patients aged <70, 70-79 and ≥ 80 years, respectively; P < 0.001). CONCLUSIONS: The benefits of CRT on symptoms and left ventricular function were not different in older patients despite a greater burden of co-morbidities and less optimal medical therapy. These findings support the use of CRT in an ageing population.

The Cellular and Protein Arms of Coagulation in Diabetes: Established and Potential Targets for the Reduction of Thrombotic Risk.

Diabetes is a metabolic condition with a rising global prevalence and is characterised by abnormally high blood glucose levels. Cardiovascular disease (CVD) accounts for the majority of deaths in diabetes and, despite improvements in therapy, mortality and hospitalisations in this cohort remain disproportionally higher compared to individuals with normal glucose metabolism. One mechanism for increased CVD risk is enhanced thrombosis potential, due to altered function of the cellular and acellular arms of coagulation. Different mechanisms have been identified that mediate disordered blood clot formation and breakdown in diabetes, including dysglycaemia, insulin resistance, and metabolic co-morbidities. Collectively, these induce platelet/endothelial dysfunction and impair the fibrinolytic process, thus creating a prothrombotic milieu. Despite these abnormalities, current antithrombotic therapies are largely similar in diabetes compared to those without this condition, which explains the high proportion of patients experiencing treatment failure while also displaying an increased risk of bleeding events. In this narrative review, we aimed to summarise the physiological functioning of haemostasis followed by the pathological effects of diabetes mellitus on platelets and the fibrin network. Moreover, we carefully reviewed the literature to describe the current and future therapeutic targets to lower the thrombosis risk and improve vascular outcomes in diabetes.

Outcomes After Liver Transplantation With Incidental Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is currently a contraindication to liver transplantation (LT) in the United Kingdom (UK). Incidental CCA occurs rarely in some patients undergoing LT. We report on retrospective outcomes of patients with incidental CCA from six UK LT centres. Cases were identified from pathology records. Data regarding tumour characteristics and post-transplant survival were collected. CCA was classified by TNM staging and anatomical location. 95 patients who underwent LT between 1988-2020 were identified. Median follow-up after LT was 2.1 years (14 days-18.6 years). Most patients were male (68.4%), median age at LT was 53 (IQR 46-62), and the majority had underlying PSC (61%). Overall median survival after LT was 4.4 years. Survival differed by tumour site: 1-, 3-, and 5-year estimated survival was 82.1%, 68.7%, and 57.1%, respectively, in intrahepatic CCA (n = 40) and 58.5%, 42.6%, and 30.2% in perihilar CCA (n = 42; p = 0.06). 1-, 3-, and 5-year estimated survival was 95.8%, 86.5%, and 80.6%, respectively, in pT1 tumours (28.2% of cohort), and 65.8%, 44.7%, and 31.1%, respectively, in pT2-4 (p = 0.018). Survival after LT for recipients with incidental CCA is inferior compared to usual outcomes for LT in the United Kingdom. LT for earlier stage CCA has similar survival to LT for hepatocellular cancer, and intrahepatic CCAs have better survival compared to perihilar CCAs. These observations may support LT for CCA in selected cases.

Thirty-day mortality following surgical management of hip fractures during the COVID-19 pandemic: findings from a prospective multi-centre UK study.

PURPOSE: Thirty-day mortality of patients with hip fracture is well researched and predictive; validated scoring tools have been developed (Nottingham Hip Fracture Score, NHFS). COVID-19 has significantly greater mortality in the elderly and comorbid patients which includes hip fracture patients. Non-operative treatment is not appropriate due to significantly higher mortality, and therefore, these patients are often exposed to COVID-19 in the peri-operative period. What is unclear is the effect of concomitant COVID-19 infection in these patients. METHODS: A multicentre prospective study across ten sites in the United Kingdom (responsible for 7% of hip fracture patients per annum in the UK). Demographic and background information were collected by independent chart review. Data on surgical factors included American Society of Anesthesiologists (ASA) score, time to theatre, Nottingham Hip fracture score (NHFS) and classification of fracture were also collected between 1st March 2020 and 30th April 2020 with a matched cohort from the same period in 2019. RESULTS: Actual and expected 30-day mortality was found to be significantly higher than expected for 2020 COVID-19 positive patients (RR 3.00 95% CI 1.57-5.75, p < 0.001), with 30 observed deaths compared against the 10 expected from NHFS risk stratification. CONCLUSION: COVID-19 infection appears to be an independent risk factor for increased mortality in hip fracture patients. Whilst non-operative management of these fractures is not suggested due to the documented increased risks and mortality, this study provides evidence to the emerging literature of the severity of COVID-19 infection in surgical patients and the potential impact of COVID-19 on elective surgical patients in the peri-operative period.

Correction to: Thirty-day mortality following surgical management of hip fractures during the COVID-19 pandemic: findings from a prospective multi-centre UK study.

The published online version contains mistake, as the Fig. 1 legend should read "Kaplan-Meier survival curve for 30-day survival for 2020 cohort COVID-19 positive vs COVID-19 negative" whilst the Fig. 2 legend should read "Kaplan-Meier survival curve for 30-day survival 2020 COVID-19 negative group vs 2019 cohort".

Rhizosphere-associated Alcaligenes and Bacillus strains that induce resistance against blast and sheath blight diseases, enhance plant growth and improve mineral content in rice.

AIMS: To examine the biocontrol activities of five rhizobacterial strains (i.e. Alcaligenes faecalis strains Bk1 and P1, Bacillus amyloliquefaciens strain Bk7 and Brevibacillus laterosporus stains B4 and S5), to control the rice blast and sheath blight diseases in greenhouse and to study their possible modes of action. METHODS AND RESULTS: Five potential plant growth-promoting rhizobacterial (PGPR) strains isolated from rice rhizospheres were tested for in vitro antifungal activities against Magnaporthe oryzae, Rhizoctonia solani, Botrytis cinerea and Fusarium graminearum. In vitro trials showed that three strains, Bk1, P1 and Bk7, were able to unanimously suppress the mycelial growth of the target pathogens. In greenhouse, the application of these three PGPR strains significantly suppressed the incidences of rice blast and sheath blight diseases. At 2 weeks after pathogen inoculation, the highest percentages of disease suppression were noted for Alc. faecalis strain Bk1 (72%) for rice blast, Alc. faecalis strain P1 (71%) for sheath blight, followed by B. amyloliquefaciens strain Bk7. Moreover, these strains significantly improved the plant growth, enriched the content of mineral nutrients in seedlings and increased the expression of major defence-related rice genes. All three strains were marked positive for phosphate solubilization, the production of indoleacetic acid, ammonia and siderophores and catalase activity. In addition, these strains were able to form biofilms and carried multiple lipopeptide biosynthetic genes as revealed by multiplex PCR. CONCLUSION: This study reports new potential biocontrol agents for blast and sheath blight diseases of rice. SIGNIFICANCE AND IMPACT OF THE STUDY: This study contributes to better understanding of the mechanisms involved in interaction between beneficial rhizobacteria, fungal pathogens and host plants.

Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar.

Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease-causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease-causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1-bp deletion (c.915del) in NSUN2 in a male proband with Noonan-like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease-causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ˜25% of our cases.

Understanding the current acute aortic syndrome (AAS) pathways-The Collaborative Acute Aortic Syndrome Project (CAASP) protocol.

BACKGROUND: Acute aortic syndrome (AAS) is an emergency associated with high peri-hospital mortality rates. Variable clinical presentation makes timely diagnosis challenging and such delays in diagnosis directly impact patient outcomes. AIMS AND OBJECTIVES: The aims of the Collaborative Acute Aortic Syndrome Project (CAASP) are to characterise and evaluate the current AAS pathways of a cohort of hospitals in the UK, USA and New Zealand to determine if patient outcomes are influenced by the AAS pathway (time to hospital admission, diagnosis and management plan) and demographic, social, geographic and patient-specific factors (clinical presentation and comorbidities). The objectives are to describe different AAS pathways and time duration between hospital admission to diagnosis and management plan instigation, and to compare patient outcomes between pathways. METHODS: The study is a multicentre, retrospective service evaluation project of adult patients diagnosed on imaging with AAS. It will be coordinated by the UK National Interventional Radiology Trainee Research (UNITE) network and Vascular and Endovascular Research Network (VERN) in conjunction with The Aortic Dissection Charitable Trust (TADCT). All AAS cases diagnosed on imaging between 1st January 2018 to 1st June 2021 will be included and followed-up for 6 months. Eligibility criteria include aortic dissection (AD) Type A, Type B, non A/B, penetrating aortic ulcer, and intramural haematoma. Exclusion criteria are non-AAS pathology, acute on chronic AAS, and age<18. This project will evaluate patient demographics, timing of presentation, patient symptoms, risk factors for AD, physical examination findings, timing to imaging and treatment, hospital stay, and mortality. Univariate and multivariate analysis will be used to identify predictors associated with prolonged time to diagnosis or treatment and mortality at 30 days.

Molecular mechanism of antimicrobial co-resistance Colistin (mcr-1) and ESBLs genes among Escherichia coli isolates from commercial chickens in Pakistan.

Emergence of plasmid mediated colistin and extended spectrum ß-lactamases (ESBL) resistant genes has been impacted the efficacy of colistin and ß-lactams drugs like 3rd, 4th generation cephalosporin. Current study was aimed to investigate antimicrobial resistance genes (ARGs) among Escherichia coli isolates from meat producing commercial broilers in Pakistan. Two hundred (n=200) fecal samples were collected during January-2018 to August-2019. For isolation of E. coli, pink colonies on MacConkey agar were transferred to EMB agar. Metallic sheen color colonies were tested biochemically using API-20E kit. The molecular identification of E. coli (n=153) was targeted by amplification of uid gene through polymerase chain reaction (PCR) and different ARGs i.e. gentamicin, streptomycin, tetracycline, colistin, ß-lactams drugs, quinolone and ampicillin followed by sequence analysis. Genotypically, followed by phenotypically of resistant ARGs of isolated PCR-confirmed E. coli (153) shoed resistant against gentamicin (aac(3)-IV), streptomycin (aadA1), tetracycline (tetA), colistine (mcr-1), ampicillin (bla-TEM) and bla-CTX-M were 86%, 88%, 86%, 88%, 83% & 77% respectively. 33/38 (86%) of the isolate was positive for quinolone resistance. Colistine (mcr-1), ESBLs (bla-TEM) and (bla-CTX-M) resistance genes were 88%, 83% and 77% respectively. About 33 isolated E. coli harbored the both mcr-1 and ESBLs genes. All of E. coli isolates were found sensitive to ceftriaxone (CTX-30) and imipenem (IMP-10). The Isolated E. coli showed single or multi clade decadency. The E. coli and ARGs sequences showed single or multi clade decadency. This is first comprehensive study from Pakistan that described the molecular evidences of ARGs and their co-existence in single isolates originated from commercial poultry. Commercial chicken (Broilers) can act as melting pot of antibiotic resistance genes for human being. It is alarming situation for surveillance of antibiotic resistance program because of more regulated prescription of antimicrobial agents in Pakistan.

Prevalence and risk factors of Syphilis among blood donors of Punjab, Pakistan.

Syphilis is a sexually transmitted disease and its actual prevalence among Pakistani blood donors is currently unknown. A cross sectional study was conducted at different district healthcare hospitals of Punjab, Pakistan with an aim to evaluate the prevalence and risk factors associated with syphilis in blood donors using immunochromatographic test (ICT) and enzyme linked immunosorbent assay (ELISA). A total (n=1200) blood samples were collected from donors aged 18-65 years. All the information regarding personal data, demographic data and risk factors was collected via structured questionnaire. On the basis of ICT and ELISA, the overall prevalence of syphilis was 3.91% among blood donors. The demographic factors positively linked with syphilis were age (P= 0.000; Odds ratio, OR= 7.18; 95% confidence interval CI= 2.816-18.295) and education status (P= 0.000; Odds ratio, OR= 12.33; 95% confidence interval CI= 3.469-43.849) of donors. Similarly among the risk factors analyzed, marital status (P= 0.012; Odds ratio OR= 2.251; 95% confidence interval CI= 1.206- 4.202) and blood transfusion history (P= 0.030; Odds ratio OR= 1.981; 95% confidence interval CI= 1.083-3.623) were also strongly associated with syphilis. We emphasized the importance of promoting preventive measures for syphilis. The syphilis diagnosis should not be based on a single test. The present study indicates that higher prevalence is alarming for blood donors in Pakistan. Stringent donor screening is highly recommended to ensure maximum safe blood transfusion.

Sero-epidemiology and risk factor analysis of human brucellosis in Punjab, Pakistan: a cross sectional study.

Human brucellosis is a neglected zoonotic problem worldwide with a high degree of morbidity in humans and is mostly overlooked due to other febrile conditions. The aim of this study was to evaluate the sero-prevalence and risk factors of human brucellosis among subjects living in Punjab, Pakistan. In this cross-sectional study, human blood samples were collected from seven districts of Punjab, Pakistan. Information regarding personal data, demographic data and potential risk factors was collected through a structured questionnaire. Detection of anti-Brucella antibodies was done through Rose Bengal Plate Test (RBPT) and Enzyme Linked Immunosorbent Assay (ELISA). Descriptive analysis, Chi square test and Odds ratio was applied using STATA software version 12. The sero-prevalence of human brucellosis was 13.13% with significantly higher percentage in males 17.23% and age group 25-40 years 16.50% (P=< 0.001). The demographic factors positively associated with human brucellosis were lack of education (P = 0.003; OR = 1.85) and farming as an occupation (P =<0.001; OR = 2.50) Similarly, among the risk factors studied, keeping animals at home (P =<0.001; OR = 2.03), slaughtering of animals (P =<0.001; OR = 15.87) and consuming raw milk (P =<0.001; OR = 5.42) were the factors strongly connected with human brucellosis. A massive awareness should be given to livestock farmers and individuals directly linked to animals regarding risk factors and transmission of brucellosis. Consumption of unpasteurized milk and its products should be condemned to curtail this neglected disease.

The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.

The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty-two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world.

In situ distinction between steroid receptor binding and transactivation at a target gene.

We have developed a DNA interference assay in the yeast Saccharomyces cerevisiae that is designed to indicate the intracellular DNA-binding status of the estrogen receptor. The assay utilizes a promoter containing multiple copies of a GAL4-estrogen receptor binding sequence. This element is designed so that either an estrogen receptor or a GAL4 molecule, but not both, can occupy it simultaneously. The assay is extremely sensitive, and at concentrations of estrogen receptor below that required for maximal transcriptional activation of its target estrogen response element, a quantitative inhibition of GAL4-mediated transcription is seen. Inhibition occurs thought the disruption of complex cooperative interactions among the GAL4 molecules in this reporter. The data obtained from our experiments show that at low concentrations of receptor, hormone is required to promote DNA binding. Overexpression of receptor leads to occupation of the estrogen receptor element in the absence of ligand. In contrast, this latter receptor form will not activate transcription. Our results are consistent with a two-step process for receptor activation. Ligand first causes dissociation of receptor from an inhibitory complex within the cell and produces a DNA-binding form. Second, it converts receptor to a transcriptionally competent form. With use of this yeast model system, these two steps can be distinguished in situ.

The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.

In this study, we found that the E6-associated protein (E6-AP/UBE3A) directly interacts with and coactivates the transcriptional activity of the human progesterone receptor (PR) in a hormone-dependent manner. E6-AP also coactivates the hormone-dependent transcriptional activities of the other members of the nuclear hormone receptor superfamily. Previously, it was shown that E6-AP serves the role of a ubiquitin-protein ligase (E3) in the presence of the E6 protein from human papillomavirus types 16 and 18. Our data show that the ubiquitin-protein ligase function of E6-AP is dispensable for its ability to coactivate nuclear hormone receptors, showing that E6-AP possesses two separable independent functions, as both a coactivator and a ubiquitin-protein ligase. Disruption of the maternal copy of E6-AP is correlated with Angelman syndrome (AS), a genetic neurological disorder characterized by severe mental retardation, seizures, speech impairment, and other symptoms. However, the exact mechanism by which the defective E6-AP gene causes AS remains unknown. To correlate the E6-AP coactivator function and ubiquitin-protein ligase functions with the AS phenotype, we expressed mutant forms of E6-AP isolated from AS patients and assessed the ability of each of these mutant proteins to coactivate PR or provide ubiquitin-protein ligase activity. This analysis revealed that in the majority of the AS patients examined, the ubiquitin-protein ligase function of E6-AP was defective whereas the coactivator function was intact. This finding suggests that the AS phenotype results from a defect in the ubiquitin-proteosome protein degradation pathway.

Mucin expression profile in Barrett's, dysplasia, adenocarcinoma sequence in the esophagus.

BACKGROUND: The molecular events that accompany the progression to adenocarcinoma (ADC) of the esophagus are poorly understood. Aberrant mucin receptor expression can contribute to increased cell growth and metastatic ability. AIM: The aim of this study was to establish a pattern for mucin (MUC) gene expression in the esophageal mucosa under normal and pathological conditions. SETTING: University Hospital Cancer Center Laboratory. Archived tissue samples studied in a retrospective fashion. MATERIALS AND METHODS: Tissue samples were obtained from the archives of patients with histological evidence of Barrett's esophagus (BE) progressing to ADC. Immunohistochemical analysis was performed using mouse monoclonal antibodies for MUC1, MUC2, MUC5AC, MUC6. Semiquantitative scoring of histological staining was performed using a linear scoring system: 0-staining absent; 1-staining in 0-25%; 2-staining in 25-50%; and 3-staining in 50-75% of the epithelium. The Binomial test was used to explore trends and differences in frequency of mucin expression along the pathological sequence. RESULTS: Only mild superficial staining of MUC1 was seen in normal squamous epithelium. MUC1 and MUC2 were uniformly expressed in all samples (7/7) of BE and dysplasia (P=0.008). MUC1 expression was upregulated (7/7) in progression to adenocarcinoma (P=0.008). The secretory mucins, MUC5AC and MUC6 showed a decrease in expression with progression from BE to dysplasia to ADC (P< 0.05). CONCLUSIONS: Downregulation of MUC5AC and MUC6 decreases mucosal protection against gastric acid. Increasing MUC1 expression is associated with progression from dysplasia to ADC. Upregulation of MUC2 reflects intestinal metaplasia in BE.

The pure antiestrogen ICI 182,780 inhibits progestin-induced transcription.

The pure antiestrogen ICI 182,780 binds to the estrogen receptor with high affinity and is currently in clinical trials for the treatment of human breast cancer. We now show for the first time that ICI 182,780 also exhibits potent antiprogestin activity at doses frequently used in laboratory investigations. The antiprogestin activity of ICI 182,780 was detected in HeLa, HepG2, and CV1 cells transiently transfected with either the A or B forms of the human progesterone receptor and a luciferase construct driven by a progesterone-response element. ICI 182,780 inhibited progesterone-induced gene transcription in a dose-dependent fashion with maximum inhibition obtained at 10(-6) M and an IC50 of approximately 2 x 10(-7) M. The ICI compound produced the same degree of inhibition as that obtained with the antiprogestin RU-486. The antiestrogen tamoxifen did not display antiprogestin activity in this test system, and ICI 182,780 did not inhibit the activity of transfected androgen or glucocorticoid receptors. These results clearly establish that ICI 182,780 has significant antiprogestin activity in addition to its well-documented antiestrogenic activity and raises the possibility that both antihormonal properties of this compound are exhibited in laboratory studies and in the course of treatment of human breast tumors.