Barrett's Esophagus: New insights in the genetic patchwork of transdifferentiation and malignant transformation

De behandeling en vooruitzichten voor patiënten met een slokdarm carcinoom zijn weinig hoopgevend. Vroegtijdige detectie en preventie zijn noodzakelijk, en daarom richt veel onderzoek zich op de premaligne Barrett slokdarm, waarin gezond slokdarm epitheel vervangen is door darmachtig epitheel. De precieze ontstaanswijze en progressie van een Barrett slokdarm is onduidelijk. Daarom heeft dit proefschrift zich gericht op genen die van belang kunnen zijn hierin. Allereerst vonden wij dat de nucleaire receptor Pregnane X Receptor (PXR) niet aanwezig is in gezond slokdarm epitheel, maar wel in het darmachtige epitheel van Barrett slokdarm en adenocarcinomen. In adenocarcinomen werd PXR na blootstelling aan galzuren, in de celkernen gevonden waar het actief andere genen reguleert. Wij concluderen dat PXR mogelijk een voorspeller is van progressie in Barrett slokdarm. In een histologische studie hebben wij deze hypothese verder onderzocht en hierin aangetoond dat de combinatie van de eerder bestudeerde galzuur receptor Farnesoid X Receptor (FXR) en PXR, klinische waarde hebben voor de diagnostiek van dysplasie. Verder vonden wij dat bepaalde DNA mutaties in het regulerende deel van het Vitamine D receptor (VDR) gen geassocieerd zijn met een verminderd expressie van het VDR gen in Barrett slokdarm middels de binding van transcriptie factor GATA1. Het haplotype dat deze mutaties omvat is bovendien geassocieerd met een twee maal lager risico op het manifesteren van een Barrett slokdarm (OR 0.44; 95%CI 0.23-0.85) of adenocarcinoom in de slokdarm (OR 0.50; 95%CI 0.27-0.96). Het identificeren van dragers van dit haplotype is een eerste stap in het ontwikkelen van persoonspecifieke behandelingen voor slokdarmkanker. Ten slotte zochten we genen die verantwoordelijk kunnen zijn voor Barrett’s slokdarm. Een proces vergelijkbaar met Barrett’s metaplasie vindt plaats tijdens de embryonale ontwikkeling van het maag-darmkanaal, waarin Homeobox (HOX) genen een cruciale rol spelen. Wij toonden het belang van HOXA genen aan voor het epitheel van het volwassen maag-darmkanaal en identificeerden HOXA7 en A11 als belangrijke galgereguleerde spelers in Barrett metaplasie. Aanvullende studies zijn nodig om de regulerende rol van HOX genen te bestuderen in het ontstaan van Barrett slokdarm

Options for dust reduction from poultry houses

Large poultry houses emit high amounts of fine dust (PM10) and in many cases they exceed the ambient air quality standard set by the EU. Technologies for PM10 reduction need to be developed on short term to minimize PM10 emissions from poultry houses. Studied options for dust reduction were: application of an oil film on the litter and application of an ionization system. Rapeseed oil was sprayed daily in a quantity of 8 to 24 ml/m2 in broiler houses and 20 ml/m2 in layer houses. The ionization system was applied in a broiler house and had a voltage difference of -30kV, with a current of approximately 0.7 mA. Daily emissions of PM10 particles were determined at regular intervals by measuring concentrations at the ventilation inlet and outlet and by measuring the airflow rate. For the oil system PM10 emission reductions were in the ranges of 55 – 85% in broilers and 25 – 40% in layers. The ionization system, applied in broilers, reduced PM10 emission on average by 36%

Intussusception of the Small Intestine Caused by a Primary Melanoma?

Although the gastrointestinal tract is a fairly frequent site of melanoma metastases, reports of small bowel intussusception caused by melanoma are very rare. We report the case of a 77-year-old man who was admitted to our hospital with epigastric pain, melena and anaemia. After clinical examination, laboratory evaluation and radiological work-up the diagnosis of a jejunal intussusception was made. Exploratory laparoscopy revealed a large tumour arising from the jejunum, approximately 20 cm distal to the angle of Treitz. Small bowel resection with an end-to-end anastomosis was performed. Histological examination showed an intestinal melanoma. There are different theories concerning the origin of malignant melanoma in the small bowel. Although the small and large intestines normally contain no melanocytes, these cells have occasionally been found in the alimentary and respiratory tracts and even in lymph nodes, which supports the theory of a primary origin of melanoma at these sites. Since this was a solitary intestinal lesion and there was no history of cutaneous melanoma, we conclude that this could be an example of a very rare primary melanoma of the small intestine

Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study

BACKGROUND: Patients with schizophrenia are at high risk of developing metabolic abnormalities. METHOD: A prospective study focusing on metabolic disturbances in patients with schizophrenia, including an oral glucose tolerance test, is currently ongoing at our University Hospital and affiliate services. The prevalence of metabolic abnormalities at baseline was assessed in a cohort of 415 patients with schizophrenia. The sample was divided into 4 groups according to duration of illness: first-episode patients (<1.5 years), recent-onset patients (between 1.5 and 10 years), subchronic patients (between 10 and 20 years) and chronic patients (>20 years). RESULTS: Metabolic abnormalities were already present in first-episode patients, and considerably increased with increasing duration of illness. When compared to the general population matched for age and gender, much higher rates of the metabolic syndrome (MetS) and diabetes were observed for patients with schizophrenia. For MetS, the increase over time was similar to that of the general population. In contrast, the difference in the prevalence of diabetes in patients with schizophrenia and the general population dramatically and linearly increased from 1.6% in the 15–25 age-band to 19.2% in the 55–65 age-band. CONCLUSION: Thus, the current data suggest that on the one hand metabolic abnormalities are an inherent part of schizophrenic illness, as they are already present in first-episode patients. On the other hand, however, our results suggest a direct effect of the illness and/or antipsychotic medication on their occurence. The data underscore the need for screening for metabolic abnormalities in patients diagnosed with schizophrenia, already starting from the onset of the illness

A morphological algorithm for improving radio-frequency interference detection

A technique is described that is used to improve the detection of radio-frequency interference in astronomical radio observatories. It is applied on a two-dimensional interference mask after regular detection in the time-frequency domain with existing techniques. The scale-invariant rank (SIR) operator is defined, which is a one-dimensional mathematical morphology technique that can be used to find adjacent intervals in the time or frequency domain that are likely to be affected by RFI. The technique might also be applicable in other areas in which morphological scale-invariant behaviour is desired, such as source detection. A new algorithm is described, that is shown to perform quite well, has linear time complexity and is fast enough to be applied in modern high resolution observatories. It is used in the default pipeline of the LOFAR observatory.Comment: Accepted for publication in A&

CpG-A and B oligodeoxynucleotides enhance the efficacy of antibody therapy by activating different effector cell populations

Immunostimulatory CpG oligodeoxynucleotides (ODNs) can enhance the therapeutic effect of monoclonal antibodies (mAbs) by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). Distinct classes of CpG ODNs have been found recently to stimulate different effector cell populations. We used murine cancer models to explore the role of various effector cell populations in the antitumor activity seen with mAbs combined with CpG ODNs of the A and B classes. In the 38C13 syngeneic murine lymphoma model, both CpG A and CpG B enhanced the efficacy of murine antilymphoma mAb. Depletion of natural killer (NK) cells alone markedly decreased the efficacy of therapy with mAbs plus CpG A. In contrast, depletion of both NK cells and granulocytes was required to decrease the efficacy of mAb plus CpG B. A human (h) Fc gamma receptor I (FcgammaRI)-expressing transgenic (Tg) mouse model was used to explore the role of FcgammaRI in therapy with mAb and CpG ODN. CpG B induced up-regulation of FcgammaRI in hFcgammaRI Tg mice, whereas CpG A did not. In vitro CpG B also enhanced ADCC of HER-2/neu-expressing tumor cells by the FcgammaRI-directed bispecific antibody MDX-H210 using hFcgammaRI-positive effector cells. In a solid tumor model, tumor growth was inhibited in Tg mice treated with a combination of MDX-H210 and CpG B. These data suggest that CpG A enhance ADCC largely by activating NK cells. In contrast, other effector cell populations, including granulocytes, contribute to the antitumor activity of CpG B and mAbs. FcgammaRI plays an important role in this activity

Crucial role of antibodies to pertactin in Bordetella pertussis immunity

Pertussis, a serious infectious disease of the respiratory tract caused by Bordetella pertussis, is reemerging in vaccinated populations. Efforts to curtail this disease are hampered by limited insight into the basis of protective immunity. Opsonophagocytosis was recently found to play a central role in cellular bactericidal activity against B. pertussis. In the present study, we studied the specificity of opsonic antibodies. Anti-pertactin antibodies, but not anti-pertussis toxin, anti-fimbriae, or anti-filamentous hemagglutinin antibodies, were found to be crucial for B. pertussis phagocytosis. These data are consistent with field studies showing that levels of antibodies to pertactin correlate with protection.Centro de Investigación y Desarrollo en Fermentaciones Industriale

Which clinical and biochemical predictors should be used to screen for diabetes in patients with serious mental illness receiving antipsychotic medication? A large observational study

© 2019 Mitchell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective We aimed to investigate which clinical and metabolic tests offer optimal accuracy and acceptability to help diagnose diabetes among a large sample of people with serious mental illness in receipt of antipsychotic medication. Methods A prospective observational study design of biochemical and clinical factors was used. Biochemical measures were fasting glucose, insulin and lipids, oral glucose tolerance testing (OGTT), hemoglobin A1c, and insulin resistance assessed with the homeostatic model (HOMA-IR) were determined in a consecutive cohort of 798 adult psychiatric inpatients receiving antipsychotics. Clinical variables were gender, age, global assessment of functioning (GAF), mental health clinicians\u27 global impression (CGI), duration of severe mental illness, height, weight, BMI and waist/hip ratio. In addition, we calculated the risk using combined clinical predictors using the Leicester Practice Risk Score (LPRS) and the Topics Diabetes Risk Score (TDRS). Diabetes was defined by older criteria (impaired fasting glucose (IFG) or OGTT) as well as2010 criteria (IFG or OGTT or Glycated haemoglobin (HBA1c)) at conventional cut-offs. Results Using the older criteria, 7.8% had diabetes (men: 6.3%; women: 10.3%). Using the new criteria, 10.2% had diabetes (men: 8.2%, women: 13.2%), representing a 30.7% increase (p = 0.02) in the prevalence of diabetes. Regarding biochemical predictors, conventional OGTT, IFG, and HbA1c thresholds used to identify newly defined diabetes missed 25%, 50% and 75% of people with diabetes, respectively. The conventional HBA1c cut-point of ≥6.5% (48 mmol/mol) missed 7 of 10 newly defined cases of diabetes while a cut-point of ≥5.7% improved sensitivity from 44.4% to up to 85%. Specific algorithm approaches offered reasonable accuracy. Unfortunately no single clinical factor was able to accurately rule-in a diagnosis of diabetes. Three clinical factors were able to rule-out diabetes with good accuracy namely: BMI, waist/hip ratio and height. A BMI \u3c 30 had a 92% negative predictive value in ruling-out diabetes. Of those not diabetic, 20% had a BMI ≥ 30. However, for complete diagnosis a specific biochemical protocol is still necessary. Conclusions Patients with SMI maintained on antipsychotic medication cannot be reliably screened for diabetes using clinical variables alone. Accurate assessment requires a two-step algorithm consisting of HBA1c ≥5.7% followed by both FG and OGTT which does not require all patients to have OGTT and FG

Crucial role of antibodies to pertactin in Bordetella pertussis immunity

Pertussis, a serious infectious disease of the respiratory tract caused by Bordetella pertussis, is reemerging in vaccinated populations. Efforts to curtail this disease are hampered by limited insight into the basis of protective immunity. Opsonophagocytosis was recently found to play a central role in cellular bactericidal activity against B. pertussis. In the present study, we studied the specificity of opsonic antibodies. Anti-pertactin antibodies, but not anti-pertussis toxin, anti-fimbriae, or anti-filamentous hemagglutinin antibodies, were found to be crucial for B. pertussis phagocytosis. These data are consistent with field studies showing that levels of antibodies to pertactin correlate with protection.Centro de Investigación y Desarrollo en Fermentaciones Industriale