HHV-8-negative multicentric Castleman disease presenting as a crescentic immune complexes membranoproliferative glomerulonephritis.

Multicentric Castleman disease is a rare polyclonal lymphoproliferative disorder mainly associated with two renal manifestations: thrombotic microangiopathy and amyloidosis. Nevertheless, we report here a case of human herpes virus-8 negative multicentric Castleman disease with membranous proliferative glomerulonephritis and extracapillary proliferation. A patient was successfully treated with corticosteroids, anti-CD20 and cyclophosphamide therapy

Stem cells and the stem cell niche in the breast: an integrated hormonal and developmental perspective

The mammary gland is a unique organ in that it undergoes most of its development after birth under the control of systemic hormones. Whereas in most other organs stem cells divide in response to local stimuli, to replace lost cells, in the mammary gland large numbers of cells need to be generated at specific times during puberty, estrous cycles and pregnancy to generate new tissue structures. This puts special demands on the mammary stem cells and requires coordination of local events with systemic needs. Our aim is to understand how the female reproductive hormones control mammary gland development and influence tumorigenesis. We have shown that steroid hormones act in a paracrine fashion in the mammary gland delegating different functions to locally produced factors. These in turn, affect cell-cell interactions that result in changes of cell behavior required for morphogenesis and differentiation. Here, we discuss how these hormonally regulated paracrine interactions may impinge on stem cells and the stem cell niche and how this integration of signals adds extra levels of complexity to current mammary stem cell models. We propose a model whereby the stem cell niches change depending on the developmental stages and the hormonal milieu. According to this model, repeated hormone stimulation of stem cells and their niches in the course of menstrual cycles may be an important early event in breast carcinogenesis and may explain the conundrum why breast cancer risk increases with the number of menstrual cycles experienced prior to a first pregnancy

Prevalence and management of chronic insomnia in Swiss primary care: Cross-sectional data from the “Sentinella” practice-based research network

We investigated the prevalence and treatment of patients with chronic insomnia presenting to Swiss primary care physicians (PCPs) part of “Sentinella”, a nationwide practice-based research network. Each PCP consecutively asked 40 patients if they had sleep complaints, documented frequency, duration, comorbidities, and reported ongoing treatment. We analysed data of 63% (83/132) of the PCPs invited. The PCPs asked 76% (2,432/3,216) of included patients about their sleep (51% female); 31% (761/2,432) of these had had insomnia symptoms; 36% (875/2,432) had current insomnia symptoms; 11% (269/2,432) met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for chronic insomnia (61% female). In all, 75% (201/269) of patients with chronic insomnia had comorbidities, with 49% (99/201) reporting depression. Chronic insomnia was treated in 78% (209/269); 70% (188/268) took medication, 38% (102/268) benzodiazepines or benzodiazepine receptor agonists, 32% (86/268) took antidepressants. Only 1% (three of 268) had been treated with cognitive behavioural therapy for insomnia (CBT-I). A third of patients presenting for a non-urgent visit in Swiss primary care reported insomnia symptoms and 11% met the DSM-5 criteria for chronic insomnia. Hypnotics were the most common treatment, but almost no patients received first-line CBT-I. Reducing the burden of insomnia depends on disseminating knowledge about and access to CBT-I, and encouraging PCPs to discuss it with and offer it as a first-line treatment to patients with chronic insomnia

Treating insomnia in Swiss primary care practices: A survey study based on case vignettes

Guidelines recommend cognitive behavioural therapy for insomnia (CBT-I) as first-line treatment for chronic insomnia, but it is not clear how many primary care physicians (PCPs) in Switzerland prescribe this treatment. We created a survey that asked PCPs how they would treat chronic insomnia and how much they knew about CBT-I. The survey included two case vignettes that described patients with chronic insomnia, one with and one without comorbid depression. PCPs also answered general questions about treating chronic insomnia and about CBT-I and CBT-I providers. Of the 820 Swiss PCPs we invited, 395 (48%) completed the survey (mean age 54 years; 70% male); 87% of PCPs prescribed sleep hygiene and 65% phytopharmaceuticals for the patient who had only chronic insomnia; 95% prescribed antidepressants for the patient who had comorbid depression. In each case, 20% of PCPs prescribed benzodiazepines or benzodiazepine receptor agonists, 8% prescribed CBT-I, 68% said they knew little about CBT-I, and 78% did not know a CBT-I provider. In the clinical case vignettes, most PCPs treated chronic insomnia with phytopharmaceuticals and sleep hygiene despite their lack of efficacy, but PCPs rarely prescribed CBT-I, felt they knew little about it, and usually knew no CBT-I providers. PCPs need more information about the benefits of CBT-I and local CBT-I providers and dedicated initiatives to implement CBT-I in order to reduce the number of patients who are prescribed ineffective or potentially harmful medications

RsmW, Pseudomonas aeruginosa small non-coding RsmA-binding RNA upregulated in biofilm versus planktonic growth conditions

BACKGROUND: Biofilm development, specifically the fundamentally adaptive switch from acute to chronic infection phenotypes, requires global regulators and small non-coding regulatory RNAs (sRNAs). This work utilized RNA-sequencing (RNA-seq) to detect sRNAs differentially expressed in Pseudomonas aeruginosa biofilm versus planktonic state. RESULTS: A computational algorithm was devised to detect and categorize sRNAs into 5 types: intergenic, intragenic, 5′-UTR, 3′-UTR, and antisense. Here we report a novel RsmY/RsmZ-type sRNA, termed RsmW, in P. aeruginosa up-transcribed in biofilm versus planktonic growth. RNA-Seq, 5’-RACE and Mfold predictions suggest RsmW has a secondary structure with 3 of 7 GGA motifs located on outer stem loops. Northern blot revealed two RsmW binding bands of 400 and 120 bases, suggesting RsmW is derived from the 3’-UTR of the upstream hypothetical gene, PA4570. RsmW expression is elevated in late stationary versus logarithmic growth phase in PB minimal media, at higher temperatures (37°C versus 28°C), and in both gacA and rhlR transposon mutants versus wild-type. RsmW specifically binds to RsmA protein in vitro and restores biofilm production and reduces swarming in an rsmY/rsmZ double mutant. PA4570 weakly resembles an RsmA/RsmN homolog having 49% and 51% similarity, and 16% and 17% identity to RsmA and RsmN amino acid sequences, respectively. PA4570 was unable to restore biofilm and swarming phenotypes in ΔrsmA deficient strains. CONCLUSION: Collectively, our study reveals an interesting theme regarding another sRNA regulator of the Rsm system and further unravels the complexities regulating adaptive responses for Pseudomonas species

EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer

Introduction PolycombGroup (PcG) proteins maintain gene repression through histone modifications and have been implicated in stem cell regulation and cancer. EZH2 is part of Polycomb Repressive Complex 2 (PRC2) and trimethylates H3K27. This histone mark recruits the BMI1-containing PRC1 that silences the genes marked by PRC2. Based on their role in stem cells, EZH2 and BMI1 have been predicted to contribute to a poor outcome for cancer patients. Methods We have analysed the expression of EZH2 and BMI1 in a well-characterised dataset of 295 human breast cancer samples. Results Interestingly, although EZH2 overexpression correlates with a poor prognosis in breast cancer, BMI1 overexpression correlates with a good outcome. Although this may reflect transformation of different cell types, we also observed a functional difference. The PcG-target genes INK4A and ARF are not expressed in tumours with high BMI1, but they are expressed in tumours with EZH2 overexpression. ARF expression results in tumour protein P53 (TP53) activation, and we found a significantly higher proportion of TP53 mutations in tumours with high EZH2. This may explain why tumours with high EZH2 respond poorly to therapy, in contrast to tumours with high BMI1. Conclusions Overall, our data highlight that whereas EZH2 and BMI1 may function in a 'linear' pathway in normal development, their overexpression has different functional consequences for breast tumourigenesi

An oestrogen-dependent model of breast cancer created by transformation of normal human mammary epithelial cells

INTRODUCTION: About 70% of breast cancers express oestrogen receptor alpha (ESR1/ERalpha) and are oestrogen-dependent for growth. In contrast with the highly proliferative nature of ERalpha-positive tumour cells, ERalpha-positive cells in normal breast tissue rarely proliferate. Because ERalpha expression is rapidly lost when normal human mammary epithelial cells (HMECs) are grown in vitro, breast cancer models derived from HMECs are ERalpha-negative. Currently only tumour cell lines are available to model ERalpha-positive disease. To create an ERalpha-positive breast cancer model, we have forced normal HMECs derived from reduction mammoplasty tissue to express ERalpha in combination with other relevant breast cancer genes. METHODS: Candidate genes were selected based on breast cancer microarray data and cloned into lentiviral vectors. Primary HMECs prepared from reduction mammoplasty tissue were infected with lentiviral particles. Infected HMECs were characterised by Western blotting, immunofluorescence microscopy, microarray analysis, growth curves, karyotyping and SNP chip analysis. The tumorigenicity of the modified HMECs was tested after orthotopic injection into the inguinal mammary glands of NOD/SCID mice. Cells were marked with a fluorescent protein to allow visualisation in the fat pad. The growth of the graft was analysed by fluorescence microscopy of the mammary glands and pathological analysis of stained tissue sections. Oestrogen dependence of tumour growth was assessed by treatment with the oestrogen antagonist fulvestrant. RESULTS: Microarray analysis of ERalpha-positive tumours reveals that they commonly overexpress the Polycomb-group gene BMI1. Lentiviral transduction with ERalpha, BMI1, TERT and MYC allows primary HMECs to be expanded in vitro in an oestrogen-dependent manner. Orthotopic xenografting of these cells into the mammary glands of NOD/SCID mice results in the formation of ERalpha-positive tumours that metastasise to multiple organs. The cells remain wild type for TP53, diploid and genetically stable. In vivo tumour growth and in vitro proliferation of cells explanted from tumours are dependent on oestrogen. CONCLUSION: We have created a genetically defined model of ERalpha-positive human breast cancer based on normal HMECs that has the potential to model human oestrogen-dependent breast cancer in a mouse and enables the study of mechanisms involved in tumorigenesis and metastasi