Analysis of anti-tumour necrosis factor-induced skin lesions reveals strong T helper 1 activation with some distinct immunological characteristics.

BACKGROUND: Psoriasiform and eczematous eruptions are the most common dermatological adverse reactions linked to anti-tumour necrosis factor (TNF)-α therapy. Yet, a detailed characterization of their immune phenotype is lacking. OBJECTIVES: To characterize anti-TNF-α-induced inflammatory skin lesions at a histopathological, cellular and molecular level, compared with psoriasis, eczema (atopic dermatitis) and healthy control skin. METHODS: Histopathological evaluation, gene expression (quantitative real-time polymerase chain reaction) and computer-assisted immunohistological studies (TissueFAXS) were performed on 19 skin biopsies from patients with inflammatory bowel disease (n = 17) and rheumatoid arthritis (n = 2) with new-onset inflammatory skin lesions during anti-TNF-α-therapy. RESULTS: Although most biopsies showed a psoriasiform and/or spongiotic (eczematous) histopathological architecture, these lesions were inconsistent with either psoriasis or eczema on a molecular level using an established chemokine (C-C motif) ligand 27/inducible nitric oxide synthase classifier. Despite some differences in immune skewing depending on the specific histopathological reaction pattern, all anti-TNF-α-induced lesions showed strong interferon (IFN)-γ activation, at higher levels than in psoriasis or eczema. IFN-γ was most likely produced by CD3/CD4/Tbet-positive T helper 1 lymphocytes. CONCLUSIONS: New-onset anti-TNF-α-induced eruptions previously classified as psoriasis or spongiotic dermatitis (eczema) exhibit a molecular profile that is different from either of these disorders.

Gut Microbiome Composition in Lynch Syndrome With and Without History of Colorectal Neoplasia and Non-Lynch Controls.

BACKGROUND: While Lynch syndrome (LS) is a highly penetrant colorectal cancer (CRC) syndrome, there is considerable variation in penetrance; few studies have investigated the association between microbiome and CRC risk in LS. We analyzed the microbiome composition among individuals with LS with and without personal history of colorectal neoplasia (CRN) and non-LS controls. METHODS: We sequenced the V4 region of the 16S rRNA gene from the stool of 46 individuals with LS and 53 individuals without LS. We characterized within community and in between community microbiome variation, compared taxon abundance, and built machine learning models to investigate the differences in microbiome. RESULTS: There was no difference within or between community variations among LS groups, but there was a statistically significant difference in both within and between community variation comparing LS to non-LS. Streptococcus and Actinomyces were differentially enriched in LS-CRC compared to LS-without CRN. There were numerous differences in taxa abundance comparing LS to non-LS; notably, Veillonella was enriched and Faecalibacterium and Romboutsia were depleted in LS. Finally, machine learning models classifying LS from non-LS controls and LS-CRC from LS-without CRN performed moderately well. CONCLUSIONS: Differences in microbiome composition between LS and non-LS may suggest a microbiome pattern unique to LS formed by underlying differences in epithelial biology and immunology. We found specific taxa differences among LS groups, which may be due to underlying anatomy. Larger prospective studies following for CRN diagnosis and microbiome composition changes are needed to determine if microbiome composition contributes to CRN development in patients with LS.

Lynch Syndrome/Hereditary Non-polyposis Colorectal Cancer (HNPCC).

Lynch Syndrome (LS), also known as Hereditary Non-polyposis Colorectal Cancer (HNPCC), is the most common hereditary colorectal cancer syndrome and is estimated to account for 3-5% of CRC cases. LS is caused by mutations in DNA mismatch repair (MMR) genes which are inherited in an autosomal dominant pattern and are associated with accelerated development of cancers. Families affected with Lynch Syndrome typically contain multiple individuals affected with CRC and/or endometrial cancer, with many of the cases diagnosed at younger ages. Lifetime risk for colorectal and endometrial cancers approaches 70-80% and 40-60% respectively, in the absence of medical intervention. Individuals with Lynch Syndrome also have an increased risk for developing other cancers and variations in clinical presentation can make diagnosis difficult. Clinical genetic testing has identified mutations in the MMR genes MLH1, MSH2, MSH6, and PMS2 in many families with Lynch Syndrome. Colonoscopy at frequent intervals has been shown to be effective in reducing morbidity and mortality from Lynch-associated colorectal cancer.

Surveillance for pancreatic cancer in high-risk individuals.

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high-risk individuals who had either low- or high-risk neoplastic precursor lesions compared with that in patients who developed PDAC.

Antecedentes: Se podrían obtener mejores resultados con el seguimiento de individuos de alto riesgo para adenocarcinoma ductal pancreático (pancreatic ductal adenocarcinoma, PDAC) y lesiones precursoras. El objetivo de este estudio fue determinar la prevalencia y los resultados del PDAC y de las lesiones precursoras de alto riesgo neoplásico en pacientes que participaron en programas de seguimiento. Métodos: Se llevó a cabo un estudio multicéntrico a través del registro internacional del consorcio CAPS (Common Automotive Platform Standard) para identificar a las personas de alto riesgo que se habían sometido a una resección pancreática o habían progresado a PDAC avanzado mientras estaban en seguimiento. Se definieron como lesiones neoplásicas precursoras de alto riesgo la neoplasia intraepitelial pancreática de tipo 3 (PanIN­3), la neoplasia papilar mucinosa intraductal (intraductal papillary mucinous neoplasia, IPMN) con displasia de alto grado y los tumores neuroendocrinos pancreáticos (pancreatic neuroendocrine tumours, PanNET) de ≥ 2 cm de diámetro. Resultados: De 76 individuos con lesiones de alto riesgo identificados en 11 programas de seguimiento, 71 fueron tratados quirúrgicamente y 5 fueron diagnosticados de un PDAC inoperable. De las 71 resecciones, 32 (45%) tenían PDAC o una lesión precursora de alto riesgo (19 PDAC, 4 IPMN de conducto principal, 4 IPMN de rama secundaria y 5 PanIN­3). Los otros 39 pacientes tenían lesiones que se consideraron asociadas con un menor riesgo de progresión neoplásica. La edad ≥ 65 años, el sexo femenino, el ser portador de una mutación genética y la localización de la lesión en la cabeza/proceso uncinado fueron factores asociados a las lesiones precursoras de alto riesgo o al PDAC. No hubo diferencias en la supervivencia de individuos de alto riesgo con lesiones neoplásicas de bajo riesgo frente a aquellos que presentaron lesiones precursoras de alto riesgo. La supervivencia fue peor en los pacientes con PDAC. No hubo mortalidad relacionada con la cirugía. Conclusión: Un elevado porcentaje de individuos de alto riesgo que se sometieron a resección quirúrgica tras la detección de lesiones pancreáticas en el seguimiento tenían una lesión precursora neoplásica de alto riesgo o un PDAC. La supervivencia fue mejor en individuos de alto riesgo que tenían lesiones precursoras neoplásicas de bajo o alto riesgo en comparación con aquellos pacientes que habían desarrollado un PDAC.

Effects of chronic morphine treatment on responding for intracranial stimulation in female versus male rats.

Morphine was administered to Sprague-Dawley rats twice daily at 0, 3, 10, and 20 mg/kg/ injection during Weeks 1, 2, 3, and 4, respectively; responding for medial forebrain bundle stimulation was assessed 1, 2, and 3 hr after morning injections in female versus male rats. There were no sex differences in responding under control conditions (Week 1). Morphine's effect on response rate depended on dose, time post-injection, stimulation frequency, and day of treatment. Significant sex differences in morphine's effects occurred at 10 mg/kg, which decreased responding more in males at 1 hr and increased responding more in females at 2 hr, at some frequencies and on some test days. Similar trends were observed at other frequencies, test days, and doses. Morphine's differential effect in males versus females in this procedure suggests that sex comparisons of opioid effects in many animal models may be influenced by sex differences in opioid effects on behavioral output.

Community-based domestic violence services.

Community-based domestic violence services have grown significantly since their emergence in the 1970s. Now more than 2,000 in number, domestic violence organizations have expanded their range of programs. In addition to crisis-oriented services, such as telephone hot lines and temporary shelter, many of these agencies provide legal, health, mental health, or vocational services or referrals, and assistance in finding housing, relocating, and planning for safety. Most recently, in response to increasing knowledge about the deleterious effects of exposure to domestic violence on children, community-based service providers have developed programs addressing children's mental health, health, educational, and safety needs. This article describes and analyzes trends in service delivery by these community-based organizations to children affected by domestic violence. It concludes that, although there has been significant growth in services, substantial segments of the target population still are not reached, and most organizations do not yet have a sufficient range of services to meet children's diverse needs. Challenges posed by inadequate funding, needs for specialized staffing, and a dearth of data on the efficacy of current intervention programs hamper domestic violence service providers' ability to meet children's needs. However, this article highlights promising new directions in service delivery. Community-based domestic violence organizations increasingly are using innovative strategies to address children's service needs. These agencies are expanding community outreach efforts and attempts to educate the public and professionals about domestic violence and children. In addition, these organizations are building important collaborative relationships with other agencies concerned with children's welfare, such as child protective services, law enforcement, schools, and health care facilities. These and related developments suggest cautious optimism that future years will see continuing progress in attempts by community-based organizations to address the needs of children whose well-being is jeopardized by their exposure to domestic violence.