Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI)

MEMRI offers the exciting possibility of tracing neuronal circuits in living animals by MRI. Here we use the power of mouse genetics and the simplicity of the visual system to test rigorously the parameters affecting Mn2+ uptake, transport and trans-synaptic tracing. By measuring electrical response to light before and after injection of Mn2+ into the eye, we determine the dose of Mn2+ with the least toxicity that can still be imaged by MR at 11.7 T. Using mice with genetic retinal blindness, we discover that electrical activity is not necessary for uptake and transport of Mn2+ in the optic nerve but is required for trans-synaptic transmission of this tracer to distal neurons in this pathway. Finally, using a kinesin light chain 1 knockout mouse, we find that conventional kinesin is a participant but not essential to neuronal transport of Mn2+ in the optic tract. This work provides a molecular and physiological framework for interpreting data acquired by MEMRI of circuitry in the brain.     

Renal tight junction proteins are decreased in cisplatin-induced nephrotoxicity in rats

Cisplatin (CP) is an antineoplastic agent that induces nephrotoxicity and oxidative stress. It is unknown whether renal tight junction (TJ) proteins expression and localization are modified in CP-induced nephrotoxicity.

Objective: To study if the expression of the TJ proteins occludin, claudin-2, claudin-5 and zonula occludens-1 (ZO-1) is modified in rats with CP-induced nephrotoxicity.

Materials and methods: Male Wistar rats (n?=?5/group) were injected with saline solution (V group), and the other group (CP group) was injected with a single dose of saline solution and CP (7.5?mg/kg i.p.). Rats were sacrificed 72?h after CP injection and blood, and 24-h urine samples were collected. Several plasma and urinary injury biomarkers as well as renal histopathology lesions, oxidative and nitrosative stress markers were evaluated, and protein levels of ocludin, claudin-2, claudin-5, ZO-1 were measured by Western blot. Statistically significant changes noted with different p?Results: Nephrotoxicity was evident by histological alterations, glycosuria, decrease in creatinine clearance, increase in fractional excretion of sodium, serum creatinine and kidney injury molecule-1. These changes were associated with oxidative/nitrosative stress (increased renal abundance of 3-nitrotyrosine and protein kinase Cβ2 and decreased renal expression of nuclear factor-erythroid-2-related factor 2) and decreased activity of antioxidant enzymes. Finally, it was found that CP-induced renal damage was associated with decreased renal expression of occludin and claudin-2.

Discussion and conclusion: CP altered the TJ proteins expression and localization in the proximal tubule that was associated with oxidative/nitrosative stress.     

Robotic Partial Nephrectomy with Superselective Versus Main Artery Clamping: A Retrospective Comparison

Background

Concerns have been raised regarding partial nephrectomy (PN) techniques that do not occlude the main renal artery.

Objective

Compare the perioperative outcomes of superselective versus main renal artery control during robotic PN.

Design, setting, and participants

A retrospective analysis of 121 consecutive patients undergoing robotic PN using superselective control (group 1, n = 58) or main artery clamping (group 2, n = 63).

Intervention

Group 1 underwent tumor-specific devascularization, maintaining ongoing arterial perfusion to the renal remnant at all times. Group 2 underwent main renal artery clamping, creating global renal ischemia.

Outcome measurements and statistical analysis

Perioperative and functional data were evaluated. The Pearson chi-square or Fisher exact and Wilcoxon rank sum tests were used.

Results and limitations

All robotic procedures were successful, all surgical margins were negative, and no kidneys were lost. Compared with group 2 tumors, group 1 tumors were larger (3.4 vs 2.6 cm, p = 0.004), more commonly hilar (24% vs 6%, p = 0.009), and more complex (PADUA 10 vs 8, p = 0.009). Group 1 patients had longer median operative time (p < 0.001) and transfusion rates (24% vs 6%, p < 0.01) but similar estimated blood loss (200 vs 150 ml), perioperative complications (15% vs 13%), and hospital stay. Group 1 patients had less decrease in estimated glomerular filtration rate at discharge (0% vs 11%, p = 0.01) and at last follow-up (11% vs 17%, p = 0.03). On computed tomography volumetrics, group 1 patients trended toward greater parenchymal preservation (95% vs 90%, p = 0.07) despite larger tumor size and volume (19 vs 8 ml, p = 0.002). Main limitations are the retrospective study design, small cohort, and short follow-up.

Conclusions

Robotic PN with superselective vascular control enables tumor excision without any global renal ischemia. Blood loss, complications, and positive margin rates were low and similar to main artery clamping. In this initial developmental phase, limitations included more perioperative transfusions and longer operative time. The advantage of superselective clamping for better renal function preservation requires validation by prospective randomized studies.

Patient summary

Preserving global blood flow to the kidney during robotic partial nephrectomy (PN) does not lead to a higher complication rate and may lead to better postoperative renal function compared with clamped PN techniques.     

Long-term Cancer-specific Outcomes of TaG1 Urothelial Carcinoma of the Bladder

Background

Few studies have investigated the natural history of TaG1 urothelial carcinoma of the bladder (UCB).

Objective

To assess the long-term outcomes of patients with TaG1 UCB and the impact of immediate postoperative instillation of chemotherapy (IPIC).

Design, setting, and participants

A retrospective analysis of 1447 patients with TaG1 UCB treated between 1996 and 2007 at eight centers. Median follow-up was 67.2 mo (interquartile range: 67.9). Patients were stratified into three European Association of Urology (EAU) guidelines risk categories; high-risk patients (n = 11) were excluded.

Intervention

Transurethral resection of the bladder with or without IPIC.

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression models addressed factors associated with disease recurrence, disease progression, death of disease, and any-cause death.

Results and limitations

Of the 1436 patients, 601 (41.9%) and 835 (58.1%) were assigned to low- and intermediate-risk categories, respectively. The actuarial estimate of 5-yr recurrence-free survival was 56% (standard error: ±1). Advancing age (p = 0.04), tumor >3 cm (p = 0.001), multiple tumors (p < 0.001), and recurrent tumors (p < 0.001) were independently associated with increased risk of disease recurrence, whereas IPIC was associated with decreased risk (p = 0.001). The actuarial estimate of 5-yr progression-free survival was 95% ± 1. Advancing age (p < 0.001) and multiple tumors (p = 0.01) were independent risk factors for disease progression. Five-year cancer-specific survival was 98% ± 1. Advancing age (p = 0.001) and previous recurrence (p = 0.04) were associated with increased risk, whereas female gender (p = 0.02) was associated with decreased risk of cancer-specific mortality. Compared with low-risk patients, intermediate-risk patients were at significantly higher risk of disease recurrence, disease progression, and cancer-specific mortality (all p < 0.01). Limitations include the retrospective design of the study and the lack of a central pathology review.

Conclusions

TaG1 UCB patients experience heterogeneous risks of disease recurrence. We validated the EAU guidelines risk stratification in TaG1 UCB patients. IPIC was associated with a reduced risk of disease recurrence in patients with low- and intermediate-risk TaG1 UCB.     

Management of Early-stage Esophageal Neoplasia (MESEN) Consensus

Background

Treatment of esophageal adenocarcinoma often involves surgical resection. Newer technologies in interventional endoscopy have led to a substantial paradigm shift in the management of early-stage neoplasia in Barrett’s esophagus comprising high-grade dysplasia (HGD), intramucosal carcinoma, and, in some cases, submucosal carcinoma. However, there has been no consensus regarding the indications for esophageal preservation in these cases. In this work, consensus guidelines were established for the management of early-stage esophageal neoplasia considering clinically relevant aspects (age, comorbidities, and social environment) in each scenario.

Methods

Seventeen experts were invited to participate based on their background and clinical expertise at high-volume centers. A questionnaire was created that included four clinical scenarios covering a wide range of situations within HGD and/or early esophageal neoplasia, particularly where controversies are likely to exist. Each of the clinical scenarios was open to discussion subdivided by patient age (20, 50, and 80 s). For each clinical scenario an expert was chosen to defend that position. Each defense triggered a subsequent discussion during a consensus meeting. Conclusions of that discussion together with an accompanying literature analysis allowed experts to confirm or change their original choices and served as the basis for the recommendations stated in this article.

Results

There was 100 % consensus supporting esophageal preservation in patients with HGD, independent of patient age or Barrett’s length. In patients with T1a adenocarcinoma, consensus for preservation was not reached (65 %) for young and middle-aged individuals but was supported for elderly patients (100 %). For T1b adenocarcinoma, consensus was reached for surgical resection (90 %), leaving organ preservation for patients with very low risk of nodal invasion or poor surgical candidates.

Conclusion

Advances in endoscopic imaging and therapy allow for organ preservation in most settings of early-stage neoplasia of the esophagus, provided that the patient understands the implications of this decision.     

Redo-urethroplasty: comparison of early functional results and quality of life in penile and bulbar strictures

Purpose

To assess bothersome results of surgery and changes in quality of life (QoL) in patients with redo-urethroplasty, comparing the functional results of penile and bulbar cases. As after previous urethroplasty scar tissue formation is likely to occur, less favorable functional results than at primary repair could be expected. Yet data on these items for techniques currently used are limited.

Methods

Retrospective analysis with standardized questionnaire including 33 consecutive patients treated with redo-urethroplasty for bulbar or penile strictures. Previous surgeries, recurrence rate, complications, incontinence, erectile function, satisfaction with the surgery and QoL were assessed.

Results

Overall success rate was 78.8 %, number of previous open urethroplasty once in 24 patients (72.7 %), and more than once in 9 (27.3 %). Urinary stress incontinence Grade I occurred in 5 patients (15.2 %) and Grade II in 2 patients (6.1 %). In 24 patients (72.7 %), no penile shortening occurred and in 28 (84.8 %), no deviation was observed. Eight patients (24.2 %) reported their glans sensitivity to be altered, in 3 (9.1 %) a disturbing alteration occurred. Overall satisfaction with the surgery was high (70 %), and an improvement in QoL was seen in 72.7 % (24 patients).

Conclusions

Urethroplasty after failed open repair gives good functional results and shows a high patient satisfaction rate. However, results are not quite as good as for primary repair, emphasizing the importance of a successful primary repair.     

The hypothalamic–pituitary–gonadal axis and prostate cancer: implications for androgen deprivation therapy

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) may play important roles in prostate cancer (PCa) progression. Specifically, LH expression in PCa tissues has been associated with metastatic disease with a poor prognosis, while FSH has been shown to stimulate prostate cell growth in hormone-refractory PCa cell lines. Gonadotropin-realizing hormone (GnRH) analogues are common agents used for achieving androgen deprivation in the treatment for PCa. GnRH analogues include LH-releasing hormone (LHRH) agonists and GnRH antagonists, both of which exhibit distinct mechanisms of action that may be crucial in terms of their overall clinical efficacy. LHRH agonists are typically used as the primary therapy for most patients and function via a negative-feedback mechanism. This mechanism involves an initial surge in testosterone levels, which may worsen clinical symptoms of PCa. GnRH antagonists provide rapid and consistent hormonal suppression without the initial surge in testosterone levels associated with LHRH agonists, thus representing an important therapeutic alternative for patients with PCa. The concentrations of testosterone and dihydrotestosterone are significantly reduced after treatment with both LHRH agonists and GnRH antagonists. This reduction in testosterone concentrations to castrate levels results in significant, rapid, and consistent reductions in prostatic-specific antigen, a key biomarker for PCa. Evidence suggests that careful maintenance of testosterone levels during androgen deprivation therapy provides a clinical benefit to patients with PCa, emphasizing the need for constant monitoring of testosterone concentrations throughout the course of therapy.