Nox1/4 inhibition exacerbates age dependent perivascular inflammation and fibrosis in a model of spontaneous hypertension.

Hypertension is associated with oxidative stress and perivascular inflammation, critical contributors to perivascular fibrosis and accelerated vascular ageing. Oxidative stress can promote vascular inflammation, creating options for potential use of NADPH oxidase inhibitors in pharmacological targeting of perivascular inflammation and its consequences. Accordingly, we characterized age-related changes in oxidative stress and immune cell infiltration in normotensive (WKY) and spontaneously hypertensive rats (SHRs). Subsequently, we used pharmacological inhibitors of Nox1 (ML171) and Nox1/Nox4 (GKT137831; 60 mg/kg), to modulate NADPH oxidase activity at the early stage of spontaneous hypertension and investigated their effects on perivascular inflammation and fibrosis. RESULTS: Ageing was associated with a progressive increase of blood pressure as well as an elevation of the total number of leukocytes, macrophages and NK cells infiltrating perivascular adipose tissue (PVAT) in SHRs but not in WKY. At 1 month of age, when blood pressure was not yet different, only perivascular NK cells were significantly higher in SHR. Spontaneous hypertension was also accompanied by the higher perivascular T cell accumulation, although this increase was age independent. Aortic Nox1 and Nox2 mRNA expression increased with age only in SHR but not in WKY, while age-related increase of Nox4 mRNA in the vessels has been observed in both groups, it was more pronounced in SHRs. At early stage of hypertension (3-months) the most pronounced differences were observed in Nox1 and Nox4. Surprisingly, GKT137831, dual inhibitor of Nox1/4, therapy increased both blood pressure and perivascular macrophage infiltration. Mechanistically, this was linked to increased expression of proinflammatory chemokines expression (CCL2 and CCL5) in PVAT. This inflammatory response translated to increased perivascular fibrosis. This effect was likely Nox4 dependent as the Nox1 inhibitor ML171 did not affect the development of spontaneous hypertension, perivascular macrophage accumulation, chemokine expression nor adventitial collagen deposition. In summary, spontaneous hypertension promotes ageing-associated perivascular inflammation which is exacerbated by Nox4 but not Nox1 pharmacological inhibition.

Validation of PRIMO Monte Carlo Model of Clinac®iX 6MV Photon Beam.

PURPOSE: This study aims to model 6MV photon of Clinac®iX linear accelerator using PRIMO Monte Carlo (MC) code and to assess PRIMO as an independent MC-based dose verification and quality assurance tool. MATERIALS AND METHODS: The modeling of Clinac®iX linear accelerator has been carried out by using PRIMO simulation software (Version 0.3.1.1681). The simulated beam parameters were compared against the measured beam data of the Clinac®iX machine. The PRIMO simulation model of Clinac®iX was also validated against Eclipse® Acuros XB dose calculations in the case of both homogenous and inhomogeneous mediums. The gamma analysis method with the acceptance criteria of 2%, 2 mm was used for the comparison of dose distributions. RESULTS: Gamma analysis shows a minimum pass percentage of 99% for depth dose curves and 95.4% for beam profiles. The beam quality index and output factors and absolute point dose show good agreement with measurements. The validation of PRIMO dose calculations, in both homogeneous and inhomogeneous medium, against Acuros® XB shows a minimum gamma analysis pass rate of 99%. CONCLUSIONS: This study shows that the research software PRIMO can be used as a treatment planning system-independent quality assurance and dose verification tool in daily clinical practice. Further validation will be performed with different energies, complex multileaf collimators fields, and with dynamic treatment fields.

Interobserver variation in rectal and bladder doses in orthogonal film-based treatment planning of cancer of the uterine cervix.

Orthogonal film-based treatment planning is the most commonly adopted standard practice of treatment planning for cancer of the uterine cervix using high dose rate brachytherapy (HDR). This study aims at examining the variation in rectal and bladder doses when the same set of orthogonal films was given to different observers. Five physicists were given 35 pairs of orthogonal films obtained from patients who had undergone HDR brachytherapy. They were given the same instructions and asked to plan the case assuming the tumor was centrally placed, using the treatment-planning system, PLATO BPS V13.2. A statistically significant difference was observed in the average rectal (F = 3.407, P = 0.01) and bladder (F = 3.284, P = 0.013) doses and the volumes enclosed by the 100% isodose curve (P < 0.01) obtained by each observer. These variations may be attributed to the differences in the reconstruction of applicators, the selection of source positions in ovoids and the intrauterine (IU) tube, and the differences in the selection of points especially for the rectum, from lateral radiographs. These variations in planning seen within a department can be avoided if a particular source pattern is followed in the intrauterine tube, unless a specific situation demands a change. Variations in the selection of rectal points can be ruled out if the posterior vaginal surface is clearly seen.