Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.     

Analysis of a real time group consensus peer review process in radiation oncology: an evaluation of effectiveness and feasibility

Background

Peer review systems within radiation oncology are important to ensure quality radiation care. Several individualized methods for radiation oncology peer review have been described. However, despite the importance of peer review in radiation oncology barriers may exist to its effective implementation in practice. The purpose of this study was to quantify the rate of plan changes based on our group peer review process as well as the quantify amount of time and resources needed for this process.

Methods

Data on cases presented in our institutional group consensus peer review conference were prospectively collected. Cases were then retrospectively analyzed to determine the rate of major change (plan rejection) and any change in plans after presentation as well as the median time of presentation. Univariable logistic regression was used to determine factors associated with major change and any change.

Results

There were 73 cases reviewed over a period of 11?weeks. The rate of major change was 8.2% and the rate of any change was 23.3%. The majority of plans (53.4%) were presented in 6–10?min. Overall, the mean time of presentation was 8?min. On univariable logistic regression, volumetric modulated arc therapy plans were less likely to undergo a plan change but otherwise there were no factors significantly associated with major plan change or any type of change.

Conclusion

Group consensus peer review allows for a large amount of informative clinical and technical data to be presented per case prior to the initiation of radiation treatment in a thorough yet efficient manner to ensure plan quality and patient safety.

     

Less well known parameters of in vitro radiosensitivity

In addition to well known parameters used for measuring in vitro cellular radiosensitivity (mean lethal dose, extrapolation number, quasithreshold dose), there are other, less well known measures that may be more important. The authors recently surveyed the literature and found that mean activation dose (D) has been neglected in the analyses. Among 70 articles published in the radiation oncology and biology literature that used cell survival curves or parameters to measure radiosensitivity, only two used the values of D in their analysis. By recalculating D from published survival curves, different conclusions may be drawn. The authors see a definite need for more prospective application of D and surviving fraction at 2 Gy.     

Arterial inflammation in bronchial asthma

Background

Bronchial asthma is a chronic inflammatory condition associated with increased cardiovascular (CV) events. Here, we assess arterial inflammation, using 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging (FDG-PET/CT), in patients with bronchial asthma and low to intermediate Framingham risk scores (FRS).

Methods

A total of 102 patients underwent FDG-PET/CT imaging for clinical indications. Thirty-four patients (mean age 54.9 ± 16.1) with mild asthma and no known atherosclerotic disease were compared to 2 non-asthmatic groups. The first control group (n = 34) were matched by age, gender, and FRS. The second control group (n = 34) had clinical atherosclerosis and were matched by gender. Thereafter, arterial FDG uptake on PET images was determined, while blinded to patient identifiers.

Results

Target-to-background-ratio (TBR) in the aorta was higher in asthmatics vs non-asthmatic FRS-matched controls (1.96 ± 0.26 vs 1.76 ± 0.20; P < .001). The aortic TBR remained elevated in asthmatics vs non-asthmatic controls after adjusting traditional CV risk factors (P < .001). An inverse correlation was observed between FDG uptake and lung function, FEV₁ (P = .02) and peak flow (P = .03).

Conclusions

Bronchial asthma is associated with increased arterial inflammation beyond that estimated by current risk stratification tools. Further studies are required to evaluate whether attenuation of systemic inflammation will decrease CV events.     

Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression

Background  

p53 is the most studied tumor suppressor and its overexpression may or may not cause cell death depending upon the genetic background of the cells. p53 is degraded by human papillomavirus (HPV) E6 protein in cervical carcinoma. Several stress activated kinases are known to phosphorylate p53 and, among them cyclin dependent kinase 5 (Cdk5) is one of the kinase studied in neuronal cell system. Recently, the involvement of Cdk5 in phosphorylating p53 has been shown in certain cancer types. Phosphorylation at specific serine residues in p53 is essential for it to cause cell growth inhibition. Activation of p53 under non stress conditions is poorly understood. Therefore, the activation of p53 and detection of upstream kinases that phosphorylate non-genotoxically overexpressed p53 will be of therapeutic importance for cancer treatment.     

Correlation of CD4+ T-Cell Counts Estimated by an Immunocapture Technique (Capcellia) with Viral Loads in Human Immunodeficiency Virus-Seropositive Individuals

As antiretroviral therapy becomes more affordable, valid, reliable, and inexpensive laboratory tests are also needed to monitor the progression of disease in people with human immunodeficiency virus (HIV) infection. The CD4⁺ T-cell counts estimated by Capcellia, an immunocapture method, and flow cytometry were compared and were correlated with HIV type 1 (HIV-1) load. There was a significant negative correlation between the HIV-1 load and CD4⁺ T-cell counts estimated by flow cytometry (r = −0.63, P = <0.001) as well as between the HIV-1 load and CD4⁺ T-cell counts estimated by Capcellia (r = −0.61, P = <0.001). Capcellia is a cost-effective, user-friendly assay that correlated well with HIV-1 load determinations for individuals both with and without treatment.     

Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques

Rapid progression to AIDS is a significant problem, especially in developing countries, where the majority of HIV-infected individuals reside. As rapid disease progression is also frequently observed in SIV-infected macaques, they represent a valuable tool to investigate the pathogenesis of this condition in humans. Here, we have shown that pathogenic SIV infection in rhesus macaques resulted in a rapid depletion (as early as week 2) of activated memory B (CD21-CD27+; mBAct) cells that was strongly associated with rapid disease progression. This depletion was progressive and sustained in rapid progressors, but less severe and transient in typical progressors. Because of the rapid and sustained depletion of mBAct cells, rapid progressors failed to develop SIV-specific Ab responses, showed a decline in non-SIV-specific Ab titers, and succumbed faster to intestinal bacterial infections. Depletion of mBAct cells was strongly associated with preferential depletion of mBAct cells expressing programmed death-1 (PD-1), and in vitro blockade of PD-1 improved their survival. Furthermore, in vivo PD-1 blockade in SIV-infected macaques enhanced Ab responses to non-SIV as well as SIV Ags. Our results identify depletion of mBAct cells as a very early predictor of rapid disease progression in pathogenic SIV infection and suggest an important role for the PD-1 pathway in depletion of mBAct cells and impaired humoral immune responses in SIV-infected macaques.