No abstract

Mitochondrial dysfunction plays a pivotal role in the progression of Alzheimer's disease (AD), and yet the mechanisms underlying the impairment of mitochondrial function in AD remain elusive. Recent evidence suggested a role for Presenilins (PS1 or PS2) in mitochondrial function. Mutations of PSs, the catalytic subunits of the γ-secretase complex, are responsible for the majority of inherited AD cases (FAD). PSs were shown to be present in mitochondria and particularly enriched in mitochondria-associated membranes (MAM), where PS2 is involved in the calcium shuttling between mitochondria and the endoplasmic reticulum (ER). We investigated the precise contribution of PS1 and PS2 to the bioenergetics of the cell and to mitochondrial morphology in cell lines derived from wild type (PS+/+), PS1/2 double knock-out (PSdKO), PS2KO and PS1KO embryos. Our results showed a significant impairment in the respiratory capacity of PSdKO and PS2KO cells with reduction of basal oxygen consumption, oxygen utilization dedicated to ATP production and spare respiratory capacity. In line with these functional defects, we found a decrease in the expression of subunits responsible for mitochondrial oxidative phosphorylation (OXPHOS) associated with an altered morphology of the mitochondrial cristae. This OXPHOS disruption was accompanied by a reduction of the NAD+/NADH ratio. Still, neither ADP/ATP ratio nor mitochondrial membrane potential (ΔΨ) were affected, suggesting the existence of a compensatory mechanism for energetic balance. We observed indeed an increase in glycolytic flux in PSdKO and PS2KO cells. All these effects were truly dependent on PS2 since its stable re-expression in a PS2KO background led to a complete restoration of the parameters impaired in the absence of PS2. Our data clearly demonstrate here the crucial role of PS2 in mitochondrial function and cellular bioenergetics, pointing toward its peculiar role in the formation and integrity of the electron transport chain.

We studied the influence of vessels crossing the ureteropelvic junction and of the grade of hydronephrosis in 86 patients who underwent endoureteropyelotomy. With a follow-up ranging from 1 to 12 years, the presence of crossing vessels had a significant negative influence on the outcome and recurrence rate of the procedure. The success rate was 82% when no vessels were present but only 33% when crossing vessels were documented. In 13 of 15 failures (87%), a crossing vessel was found at open pyeloplasty. The degree of hydronephrosis was a less potent detrimental factor, with an 81% success rate in low-grade and 54% in high-grade hydronephrosis. The best results (90% success) were obtained in patients with no crossing vessels and low-grade hydronephrosis and the worst (30% success) in those with high-grade hydronephrosis in the presence of crossing vessels. Selection of patients according to those prognostic factors is recommended. Conventional intravenous urographic imaging techniques proved insufficient, and only angiography provided diagnostic accuracy; less-invasive methods are desirable.

In this prospective randomized study 60 Gy. external radiation therapy administered between 3 and 4 months after radical prostatectomy for pathologically locally advanced prostate cancer had no significant influence on urinary continence.