Current-density functional theory of time-dependent linear response in quantal fluids: recent progress

Vignale and Kohn have recently formulated a local density approximation to the time-dependent linear response of an inhomogeneous electron system in terms of a vector potential for exchange and correlation. The vector potential depends on the induced current density through spectral kernels to be evaluated on the homogeneous electron-gas. After a brief review of their theory, the case of inhomogeneous Bose superfluids is considered, with main focus on dynamic Kohn-Sham equations for the condensate in the linear response regime and on quantal generalized hydrodynamic equations in the weak inhomogeneity limit. We also present the results of calculations of the exchange-correlation spectra in both electron and superfluid boson systems.Comment: 12 pages, 2 figures, Postscript fil

Patterns of cervical and masticatory impairment in subgroups of people with temporomandibular disorders–an explorative approach based on factor analysis

Objectives: To identify clinical patterns of impairment affecting the cervical spine and masticatory systems in different subcategories of temporomandibular disorder (TMD) by an explorative data-driven approach. Methods: For this observational study, 144 subjects were subdivided according to Research Diagnostic Criteria for TMDs into: Healthy controls, temporomandibular joint (TMJ) signs without symptoms, TMJ affected, temporomandibular muscles affected, or TMJ and muscles affected. Factor analysis and linear regression were applied to cervical spine and masticatory data to identify and characterize clinical patterns in subgroups. Results: Factor analysis identified five clinical dimensions, which explained 59% of all variance: Mechanosensitivity, cervical movement, cervical and masticatory dysfunction, jaw movement, and upper cervical movement. Regression analysis identified different clinical dimensions in each TMD subgroup. Conclusion: Distinct clinical patterns of cervical spine and masticatory function were found among subgroups of TMD, which has clinical implications for therapeutic management

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application

Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Background:Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro.Conclusions/Significance:These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Timing of glioblastoma surgery and patient outcomes: a multicenter cohort study.

BACKGROUND: The impact of time-to-surgery on clinical outcome for patients with glioblastoma has not been determined. Any delay in treatment is perceived as detrimental, but guidelines do not specify acceptable timings. In this study, we relate the time to glioblastoma surgery with the extent of resection and residual tumor volume, performance change, and survival, and we explore the identification of patients for urgent surgery. METHODS: Adults with first-time surgery in 2012–2013 treated by 12 neuro-oncological teams were included in this study. We defined time-to-surgery as the number of days between the diagnostic MR scan and surgery. The relation between time-to-surgery and patient and tumor characteristics was explored in time-to-event analysis and proportional hazard models. Outcome according to time-to-surgery was analyzed by volumetric measurements, changes in performance status, and survival analysis with patient and tumor characteristics as modifiers. RESULTS: Included were 1033 patients of whom 729 had a resection and 304 a biopsy. The overall median time-to-surgery was 13 days. Surgery was within 3 days for 235 (23%) patients, and within a month for 889 (86%). The median volumetric doubling time was 22 days. Lower performance status (hazard ratio [HR] 0.942, 95% confidence interval [CI] 0.893–0.994) and larger tumor volume (HR 1.012, 95% CI 1.010–1.014) were independently associated with a shorter time-to-surgery. Extent of resection, residual tumor volume, postoperative performance change, and overall survival were not associated with time-to-surgery. CONCLUSIONS: With current decision-making for urgent surgery in selected patients with glioblastoma and surgery typically within 1 month, we found equal extent of resection, residual tumor volume, performance status, and survival after longer times-to-surgery

Nicotine Overrides DNA Damage-Induced G1/S Restriction in Lung Cells

As an addictive substance, nicotine has been suggested to facilitate pro-survival activities (such as anchorage-independent growth or angiogenesis) and the establishment of drug resistance to anticancer therapy. Tobacco smoking consists of a variety of carcinogens [such as benzopyrene (BP) and nitrosamine derivatives] that are able to cause DNA double strand breaks. However, the effect of nicotine on DNA damage-induced checkpoint response induced by genotoxins remains unknown. In this study, we investigated the events occurred during G1 arrest induced by γ-radiation or BP in nicotine-treated murine or human lung epithelial cells. DNA synthesis was rapidly inhibited after exposure to γ-radiation or BP treatment, accompanied with the activation of DNA damage checkpoint. When these cells were co-treated with nicotine, the growth restriction was compromised, manifested by upregulation of cyclin D and A, and attenuation of Chk2 phosphorylation. Knockdown of cyclin D or Chk2 by the siRNAs blocked nicotine-mediated effect on DNA damage checkpoint activation. However, nicotine treatment appeared to play no role in nocodazole-induced mitotic checkpoint activation. Overall, our study presented a novel observation, in which nicotine is able to override DNA damage checkpoint activated by tobacco-related carcinogen BP or γ-irradiation. The results not only indicates the potentially important role of nicotine in facilitating the establishment of genetic instability to promote lung tumorigenesis, but also warrants a dismal prognosis for cancer patients who are smokers, heavily exposed second-hand smokers or nicotine users

Cervical spine signs and symptoms: perpetuating rather than predisposing factors for temporomandibular disorders in women

AIM: The purpose of this study was to assess in a sample of female community cases the relationship between the increase of percentage of cervical signs and symptoms and the severity of temporomandibular disorders (TMD) and vice-versa. MATERIAL AND METHODS: One hundred women (aged 18-26 years) clinically diagnosed with TMD signs and symptoms and cervical spine disorders were randomly selected from a sample of college students. RESULTS: 43% of the volunteers demonstrated the same severity for TMD and cervical spine disorders (CSD). The increase in TMD signs and symptoms was accompanied by increase in CSD severity, except for pain during palpation of posterior temporal muscle, more frequently observed in the severe CSD group. However, increase in pain during cervical extension, sounds during cervical lateral flexion, and tenderness to palpation of upper fibers of trapezius and suboccipital muscles were observed in association with the progression of TMD severity. CONCLUSION: The increase in cervical symptomatology seems to accompany TMD severity; nonetheless, the inverse was not verified. Such results suggest that cervical spine signs and symptoms could be better recognized as perpetuating rather than predisposing factors for TMD