Interferon Gamma, but not Calcitriol Improves the Osteopetrotic Phenotypes in ADO2 Mice

ADO2 is a heritable osteosclerotic disorder that usually results from heterozygous missense dominant negative mutations in the chloride channel 7 gene (CLCN7). ADO2 is characterized by a wide range of features and severity, including multiple fractures, impaired vision due to secondary bony overgrowth and/or the lack of the optical canal enlargement with growth, and osteonecrosis/osteomyelitis. The disease is presently incurable, although anecdotal evidence suggests that calcitriol and interferon gamma-1b (IFN-G) may have some beneficial effects. To identify the role of these drugs for the treatment of ADO2, we utilized a knock-in (G213R mutation in Clcn7) ADO2 mouse model that resembles the human disease. Six-week-old ADO2 heterozygous mice were administered vehicle (PBS) or calcitriol or IFN-G 5 times per week for 8 weeks. We determined bone phenotypes using DXA and μCT, and analyzed serum biochemistry and bone resorption markers. ADO2 mice treated with all doses of IFN-G significantly (p<0.05) attenuated the increase of whole body aBMD and distal femur BV/TV gain in both male and female compared to the vehicle group. In contrast, mice treated with low and medium doses of calcitriol showed a trend of higher aBMD and BV/TV whereas high dose calcitriol significantly (p<0.05) increased bone mass compared to the vehicle group. The calcium and phosphorus levels did not differ between vehicle and IFN-G or calcitriol treated mice; however, we detected significantly (p<0.05) elevated levels of CTX/TRAP5b ratio in IFN-G treated mice. Our findings indicate that while IFN-G at all doses substantially improved the osteopetrotic phenotypes in ADO2 heterozygous mice, calcitriol treatment at any dose did not improve the phenotype and at high dose further increased bone mass. Thus, use of high dose calcitriol therapy in ADO2 patients merits serious reconsideration. Importantly, our data support the prospect of a clinical trial of IFN-G in ADO2 patients

Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice

Glucocorticoids (GC) are commonly used for the treatment of a wide variety of autoimmune, pulmonary, gastrointestinal, and malignancy conditions. One of the devastating side effects of GC use is osteoporotic fractures, particularly in the spine and hip. Bisphosphonates (BP) are the most commonly prescribed pharmacological agents for the prevention and treatment of GC-induced osteoporosis (GIO). However, GIO is marked by reduced bone formation and BP serves mainly to decrease bone resorption. The WNT signaling pathway plays a major role in bone and mineral homeostasis. Previously, we demonstrated that overexpression of WNT16 in mice led to higher bone mineral density and improved bone microarchitecture and strength. We hypothesized that WNT16 overexpression would prevent bone loss due to glucocorticoid treatment in mice. To test our hypothesis, we treated adult wild-type and WNT16-transgenic mice with vehicle and GC (prednisolone; 2.1 mg/kg body weight) via slow-release pellets for 28 days. We measured bone mass and microarchitecture by dual-energy X-ray absorptiometry (DXA) and micro-CT, and performed gene expression and serum biochemical analysis. We found that GC treatment compared with the vehicle significantly decreased femoral areal bone mineral density (aBMD), bone mineral content (BMC), and cortical bone area and thickness in both wild-type and transgenic female mice. In contrast, the trabecular bone parameters at distal femur were not significantly changed by GC treatment in male and female mice for both genotypes. Further, we observed significantly lower level of serum P1NP and a tendency of higher level of serum TRAP in wild-type and transgenic mice due to GC treatment in both sexes. Gene expression analysis showed lower mRNA levels of Wnt16, Opg, and Opg/Rankl ratio in GC-treated female mice for both genotypes compared with the sex-matched vehicle-treated mice. These data suggest that although WNT16 overexpression resulted in higher baseline bone mineral density and bone volume per trabecular volume (BV/TV) in the transgenic mice, this was insufficient to prevent bone loss in mice due to glucocorticoid treatment

Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes

Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1-hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions

Do I have something in my teeth? The trouble with genetic analyses of diet from archaeological dental calculus

Dental calculus and other preserved microbiome substrates are an attractive target for dietary reconstruction in past populations through a variety of physical, chemical, and molecular means. Recently, studies have attempted to reconstruct diet from archaeological dental calculus using archaeogenetic techniques. While dental calculus may provide a relatively stable environment for DNA preservation, the detection of plants and animals possibly consumed by an individual through DNA analysis is primarily hindered by microbial richness and incomplete reference databases. Moreover, high genomic similarity within eukaryotic groups - such as mammals - can obfuscate precise taxonomic identification. In the current study we demonstrate the challenges associated with accurate taxonomic identification and authentication of dietary taxa in ancient DNA data using both synthetic and ancient dental calculus datasets. We highlight common errors and sources of contamination across ancient DNA datasets, provide recommendations for dietary DNA validation, and call for caution in the interpretation of diet from dental calculus and other archaeological microbiome substrates.J.A.F.Y. was partially funded by the European Research Council (ERC) under the European Union's Horizon 2020 research innovation programme (ERC-2015-StG 678901-FoodTransforms to Philipp W. Stockhammer, Ludwig Maximilian University Munich, Germany). Z.F. was supported by the Werner Siemens Stiftung through Dr. Christina Warinner. This research was supported in part through computational resources provided by the Department of Archaeogenetics at the Max Planck Institute for the Science of Human History (J.A.F.Y).Ye

Antiseptics and disinfectants for the treatment of bacterial vaginosis: a systematic review

Background: The study objective was to assess the available data on efficacy and tolerability of antiseptics and disinfectants in treating bacterial vaginosis (BV). Methods: A systematic search was conducted by consulting PubMed (1966-2010), CINAHL (1982-2010), IPA (1970-2010), and the Cochrane CENTRAL databases. Clinical trials were searched for by the generic names of all antiseptics and disinfectants listed in the Anatomical Therapeutic Chemical (ATC) Classification System under the code D08A. Clinical trials were considered eligible if the efficacy of antiseptics and disinfectants in the treatment of BV was assessed in comparison to placebo or standard antibiotic treatment with metronidazole or clindamycin and if diagnosis of BV relied on standard criteria such as Amsel\u27s and Nugent\u27s criteria. Results: A total of 262 articles were found, of which 15 reports on clinical trials were assessed. Of these, four randomised controlled trials (RCTs) were withheld from analysis. Reasons for exclusion were primarily the lack of standard criteria to diagnose BV or to assess cure, and control treatment not involving placebo or standard antibiotic treatment. Risk of bias for the included studies was assessed with the Cochrane Collaboration\u27s tool for assessing risk of bias. Three studies showed non-inferiority of chlorhexidine and polyhexamethylene biguanide compared to metronidazole or clindamycin. One RCT found that a single vaginal douche with hydrogen peroxide was slightly, though significantly less effective than a single oral dose of metronidazole. Conclusion: The use of antiseptics and disinfectants for the treatment of BV has been poorly studied and most studies are somehow methodologically flawed. There is insufficient evidence at present to advocate the use of these agents, although some studies suggest that some antiseptics may have equal efficacy compared to clindamycin or metronidazole. Further study is warranted with special regard to the long-term efficacy and safety of antiseptics and disinfectants for vaginal use

Effectiveness of a psycho-educational program for improving quality of life of fibromyalgia patients

<p>Abstract</p> <p>Background</p> <p>Most fibromyalgia patients are seen in primary care (PC). However, the effectiveness of the treatments prescribed by general practitioners is usually minimal. The main objective of the present research is to assess the efficacy of structured psycho-educational intervention, combined with relaxation, developed to improve the quality of life of patients suffering fibromyalgia (FM). The second objective is to assess the cost-effectiveness of this multimodal intervention.</p> <p>Method/Design</p> <p><it>Design</it>. Randomized controlled trial with a 12-month follow-up involving two groups, one of which is the intervention group that includes patients receiving a psychoeducational program and the other the control group consisting of patients treated for FM in the usual way.</p> <p><it>Setting</it>. Three urban PC centers in the province of Barcelona (Spain).</p> <p><it>Sample</it>. The total sample comprises 218 patients (over 18 years of age) suffering FM, selected from a database (Rheumatology service-Viladecans Hospital) of patients with this illness. Only those patients introduced in the database between the years 2005 and 2007 were included in the selection. Selected patients will be asked for written informed consent to participate in the study.</p> <p><it>Intervention</it>. Multi-component program including information about the illness, counselling about physical exercise and training in autogenic relaxation. The intervention consists of nine 2-hour sessions delivered during a two-month period. The pharmacological treatment prescribed by the physician was maintained in both groups.</p> <p><it>Main variables</it>. Sociodemographic characteristics, quality of life, use and cost of healthcare and social services.</p> <p><it>Measures</it>. Quality of life is to be measured with the FIQ and the EuroQol-5D, and the use of healthcare services with an adapted version of the Client Service Receipt Inventory (CSRI). These variables will be measured before the beginning of the program (baseline) and 1, 2, 6 and 12 months later.</p> <p>Discussion</p> <p>This research project is an attempt to demonstrate that a psycho-educational program implemented in the context of PC can produce a significant increase in the quality of life for patients with FM, as well as a decrease in the use of healthcare and social services, compared with usual care.</p> <p>Trial registration</p> <p>NCT00550966</p

Epigenetic regulation during cancer transitions across 11 tumour types

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasi

Antibiotic susceptibility of Atopobium vaginae

BACKGROUND: Previous studies have indicated that a recently described anaerobic bacterium, Atopobium vaginae is associated with bacterial vaginosis (BV). Thus far the four isolates of this fastidious micro-organism were found to be highly resistant to metronidazole and susceptible for clindamycin, two antibiotics preferred for the treatment of BV. METHODS: Nine strains of Atopobium vaginae, four strains of Gardnerella vaginalis, two strains of Lactobacillus iners and one strain each of Bifidobacterium breve, B. longum, L. crispatus, L. gasseri and L. jensenii were tested against 15 antimicrobial agents using the Etest. RESULTS: All nine strains of A. vaginae were highly resistant to nalidixic acid and colistin while being inhibited by low concentrations of clindamycin (range: < 0.016 μg/ml), rifampicin (< 0.002 μg/ml), azithromycin (< 0.016 – 0.32 μg/ml), penicillin (0.008 – 0.25 μg/ml), ampicillin (< 0.016 – 0.94 μg/ml), ciprofloxacin (0.023 – 0.25 μg/ml) and linezolid (0.016 – 0.125 μg/ml). We found a variable susceptibility for metronidazole, ranging from 2 to more than 256 μg/ml. The four G. vaginalis strains were also susceptible for clindamycin (< 0.016 – 0.047 μg/ml) and three strains were susceptible to less than 1 μg/ml of metronidazole. All lactobacilli were resistant to metronidazole (> 256 μg/ml) but susceptible to clindamycin (0.023 – 0.125 μg/ml). CONCLUSION: Clindamycin has higher activity against G. vaginalis and A. vaginae than metronidazole, but not all A. vaginae isolates are metronidazole resistant, as seemed to be a straightforward conclusion from previous studies on a more limited number of strains

A global database of lake surface temperatures collected by in situ and satellite methods from 1985–2009

Global environmental change has influenced lake surface temperatures, a key driver of ecosystem structure and function. Recent studies have suggested significant warming of water temperatures in individual lakes across many different regions around the world. However, the spatial and temporal coherence associated with the magnitude of these trends remains unclear. Thus, a global data set of water temperature is required to understand and synthesize global, long-term trends in surface water temperatures of inland bodies of water. We assembled a database of summer lake surface temperatures for 291 lakes collected in situ and/or by satellites for the period 1985–2009. In addition, corresponding climatic drivers (air temperatures, solar radiation, and cloud cover) and geomorphometric characteristics (latitude, longitude, elevation, lake surface area, maximum depth, mean depth, and volume) that influence lake surface temperatures were compiled for each lake. This unique dataset offers an invaluable baseline perspective on global-scale lake thermal conditions as environmental change continues

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease