Corticosteroids, such as prednisone and dexamethasone, are commonly prescribed medications that suppress the immune system and decrease inflammation. Common side effects of long-term treatment with ...corticosteroids include weight gain, osteoporosis, and diabetes mellitus. This paper reviews the literature on psychiatric and cognitive changes during corticosteroid therapy and potential treatment options. Hypomania and mania are the most common mood changes during acute corticosteroid therapy, although depression has also been reported. However, depression is reported to be more common than mania during long-term treatment with corticosteroids. A decline in declarative and working memory is also reported during corticosteroid therapy. Corticosteroids are associated with changes in the temporal lobe, detected by structural, functional, and spectroscopic imaging. The mood and cognitive symptoms are dose dependent and frequently occur during the first few weeks of therapy. Other risk factors are not well characterized. Controlled trials suggest that lithium and phenytoin can prevent mood symptoms associated with corticosteroids. Lamotrigine and memantine also have been shown to reverse, at least partially, the declarative memory effects of corticosteroids. Uncontrolled trials suggest that antipsychotics, anti-seizure medications, and perhaps some antidepressants can also be useful for normalizing mood changes associated with corticosteroids. Thus, both the symptoms and treatment response are similar to those of bipolar disorder. Moreover, corticosteroid-induced mood and cognitive alterations have been shown to be reversible with dose reduction or discontinuation of treatment.
Epigenomic profiling by chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) is a prevailing methodology used to investigate chromatin-based regulation in ...biological systems such as human disease, but the lack of an empirical methodology to enable normalization among experiments has limited the precision and usefulness of this technique. Here, we describe a method called ChIP with reference exogenous genome (ChIP-Rx) that allows one to perform genome-wide quantitative comparisons of histone modification status across cell populations using defined quantities of a reference epigenome. ChIP-Rx enables the discovery and quantification of dynamic epigenomic profiles across mammalian cells that would otherwise remain hidden using traditional normalization methods. We demonstrate the utility of this method for measuring epigenomic changes following chemical perturbations and show how reference normalization of ChIP-seq experiments enables the discovery of disease-relevant changes in histone modification occupancy.
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•ChIP-seq is a prevailing methodology to investigate and compare epigenomic states•Lack of an empirical normalization strategy has limited the usefulness of ChIP-seq•ChIP-Rx allows genome-wide quantitative comparisons of histone modification status•ChIP-Rx identifies graded epigenomic changes following chemical perturbations
The lack of an empirical methodology to enable normalization among chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) experiments has limited the precision and comparative utility of this technique. Orlando et al. describe a method, called ChIP with reference exogenous genome (ChIP-Rx), that allows one to perform genome-wide quantitative comparisons of histone modification status across cell populations using defined quantities of a reference epigenome. They use the method to detect disease-relevant epigenomic changes following drug treatment.
Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we ...use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.
Oral microbiota contribute to health and disease, and their disruption may influence the course of oral diseases. Here, we used pyrosequencing to characterize the oral bacteriome and mycobiome of 12 ...HIV-infected patients and matched 12 uninfected controls. The number of bacterial and fungal genera in individuals ranged between 8-14 and 1-9, among uninfected and HIV-infected participants, respectively. The core oral bacteriome (COB) comprised 14 genera, of which 13 were common between the two groups. In contrast, the core oral mycobiome (COM) differed between HIV-infected and uninfected individuals, with Candida being the predominant fungus in both groups. Among Candida species, C. albicans was the most common (58% in uninfected and 83% in HIV-infected participants). Furthermore, 15 and 12 bacteria-fungi pairs were correlated significantly within uninfected and HIV-infected groups, respectively. Increase in Candida colonization was associated with a concomitant decrease in the abundance of Pichia, suggesting antagonism. We found that Pichia spent medium (PSM) inhibited growth of Candida, Aspergillus and Fusarium. Moreover, Pichia cells and PSM inhibited Candida biofilms (P = .002 and .02, respectively, compared to untreated controls). The mechanism by which Pichia inhibited Candida involved nutrient limitation, and modulation of growth and virulence factors. Finally, in an experimental murine model of oral candidiasis, we demonstrated that mice treated with PSM exhibited significantly lower infection score (P = .011) and fungal burden (P = .04) compared to untreated mice. Moreover, tongues of PSM-treated mice had few hyphae and intact epithelium, while vehicle- and nystatin-treated mice exhibited extensive fungal invasion of tissue with epithelial disruption. These results showed that PSM was efficacious against oral candidiasis in vitro and in vivo. The inhibitory activity of PSM was associated with secretory protein/s. Our findings provide the first evidence of interaction among members of the oral mycobiota, and identifies a potential novel antifungal.
How deeply cells feel: methods for thin gels Buxboim, Amnon; Rajagopal, Karthikan; Brown, Andre' E X ...
Journal of physics. Condensed matter,
05/2010, Volume:
22, Issue:
19
Journal Article
Peer reviewed
Open access
Tissue cells lack the ability to see or hear but have evolved mechanisms to feel into their surroundings and sense a collective stiffness. A cell can even sense the effective stiffness of rigid ...objects that are not in direct cellular contact - like the proverbial princess who feels a pea placed beneath soft mattresses. How deeply a cell feels into a matrix can be measured by assessing cell responses on a controlled series of thin and elastic gels that are affixed to a rigid substrate. Gel elasticity E is readily varied with polymer concentrations of now-standard polyacrylamide hydrogels, but to eliminate wrinkling and detachment of thin gels from an underlying glass coverslip, vinyl groups are bonded to the glass before polymerization. Gel thickness is nominally specified using micron-scale beads that act as spacers, but gels swell after polymerization as measured by z-section, confocal microscopy of fluorescent gels. Atomic force microscopy (AFM) is used to measure E at gel surfaces, employing stresses and strains that are typically generated by cells and yielding values for E that span a broad range of tissue microenvironments. To illustrate cell sensitivities to a series of thin-to-thick gels, the adhesive spreading of mesenchymal stem cells was measured on gel mimics of a very soft tissue (eg. brain, E ~ 1 kPa). Initial results show that cells increasingly respond to the rigidity of an underlying 'hidden' surface starting at about 10-20 microm gel thickness with a characteristic tactile length of less than about 5 microm.
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of ...three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies.
Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts.
Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab).
In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.
We conducted a two-night photometric survey of small Kuiper Belt objects (KBOs) near opposition using the wide-field Hyper Suprime-Cam instrument on the 8.2 m Subaru Telescope. The survey covered ...about 90 deg super(2) of sky, with each field imaged in the g and i bands. We detected 356 KBOs, ranging in absolute magnitude from 6.5 to 10.4. Filtering for high-inclination objects within the hot KBO population, we show that the g- i color distribution is strongly bimodal, indicative of two color classes-the red and very red subpopulations. After categorizing objects into the two subpopulations by color, we present the first dedicated analysis of the magnitude distributions of the individual color subpopulations and demonstrate that the two distributions are roughly identical in shape throughout the entire size range covered by our survey. Comparing the color distribution of small hot KBOs with that of Centaurs, we find that they have similar bimodal shapes, thereby providing strong confirmation of previous explanations for the attested bimodality of Centaurs. We also show that the magnitude distributions of the two KBO color subpopulations and the two color subpopulations observed in the Jupiter Trojans are statistically indistinguishable. Finally, we discuss a hypothesis describing the origin of the KBO color bimodality based on our survey results.
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