Vishal K. Sinha

Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury

Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms – diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.

Interaction of HIF-1α and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells

Expression of carbonic anhydrase 9 (CA9) is associated with poor prognosis and increased tumor aggressiveness and does not always correlate with HIF-1α expression. Presently, we analyzed the regulation of CA9 expression during hypoxia by HIF-1α, Notch3, and the von Hippel-Lindau (VHL) in breast carcinoma cells. Both HIF-1α and Notch3 were absolutely required for the expression of CA9 mRNA, protein, and reporter. Reciprocal co-immunoprecipitation of HIF-1α, Notch3 intracellular domain (NICD3), and pVHL demonstrated their association. The presence of common consensus prolyl hydroxylation and pVHL binding motifs (L(XY)LAP);LLPLAP(2191) suggested an oxygen-dependent regulation for NICD3. However, unlike the HIF-1α protein, NICD3 protein levels were not modulated with hypoxia or hypoxia-mimetic agents. Surprisingly, mutations of the common prolyl hydroxylation and pVHL binding domain lead to the loss of CA9 mRNA, protein, and reporter activity. Chromatin immunoprecipitation assay demonstrated the association of NICD3, HIF-1α, and pVHL at the CA9 promoter. Further, the NICD3 mutant defective in prolyl hydroxylation and subsequent pVHL binding caused a reduction in cell proliferation of breast carcinoma cells. We show here for the first time that the interaction of HIF-1α with NICD3 is important for the regulation of CA9 expression. These findings suggest that although CA9 is a hypoxia-responsive gene, its expression is modulated by the interaction of HIF-1α, Notch3, and VHL proteins. Targeting the expression of CA9 by targeting upstream regulators could be useful in cancer/stem cell therapy.

Role of Coil Embolization during Prostatic Artery Embolization: Incidence, Indications, and Safety Profile☆

PURPOSE To determine if coil embolization is a safe adjunctive measure to prevent nontarget embolization during prostatic artery embolization (PAE). MATERIALS AND METHODS A retrospective analysis of patients who underwent PAE with coil embolization (cPAE) or without coil embolization (nPAE) between January 2014 and June 2016 was conducted. Adverse events, identified in accordance with SIR guidelines, and procedural variables were compared between the 2 cohorts. RESULTS Of 122 patients, 32 (26.2%) underwent coil embolization in 39 arteries, with coils placed to prevent nontarget embolization (n = 36), treat prostatic artery extravasation (n = 2), and occlude an intraprostatic arteriovenous fistula (n = 1). Compared with nPAE, cPAE had a nonsignificant increase in dose area product (64,516 μGy·m2 vs 52,100 μGy·m2, P = .053) but significantly longer procedure (160.1 min vs 137.1 min, P = .022) and fluoroscopy (62.9 min vs 46.1 min, P = .023) times. One major complication (urosepsis) occurred in each group (cPAE, 1/32 [3.1%]; nPAE, 1/80 [1.3%]). Both cases resolved after 2 weeks of intravenous antibiotics. A minor ischemic complication (1/32 [3.1%]) occurred in a patient with coil embolization, which manifested as white discoloration of the glans penis and resolved with topical therapy. There were no statistically significant differences in major and minor complications between cohorts at 1-month and 3-month follow-up visits. CONCLUSIONS Although coil embolization leads to increases in procedure and fluoroscopy times, it is a safe adjunctive technique to occlude communications between the prostatic artery and pelvic vasculature to potentially prevent nontarget embolization.

Rare Prostatic Artery Origins and the Importance of Collateral Circulation in Prostate Artery Embolization: A Pictorial Essay

The variability of pelvic arterial anatomy has led to anatomic descriptions based on cadaveric specimens, computed tomography (CT) angiography, and digital subtraction angiography (DSA) [1e3]. This has been especially relevant in prostate artery embolization (PAE), an emerging therapy for lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) [4e8]. In certain patients, PAE has served as a minimally invasive alternative to more standard surgical options, such as transurethral resection of prostate (TURP) and open prostatectomy. PAE offers a more preferable safety profile with minimal adverse effects, such as a decreased risk of sexual dysfunction when compared to TURP [4]. Although the indications for PAE have not been uniformly standardized, it has been offered for patients with medication-refractory severe LUTS [4e6], with prostates 80 g in which surgery carries perioperative risk [7], with chronic urinary retention [8], or with refractory hematuria of prostatic origin [9]. Contraindications to PAE vary among institutions, but include neurogenic bladder disease and active urinary tract infection [10]. The procedure is performed via transfemoral or transradial access to cannulate the PA and perform bland embolization. Thus, familiarity with variable PA anatomy is

Prostate Artery Embolization in Patients with Prostate Volumes of 80 mL or More: A Single-Institution Retrospective Experience of 93 Patients

PURPOSE To evaluate the safety and efficacy of prostate artery embolization (PAE) for the treatment of benign prostatic hyperplasia for prostates ≥ 80 mL. PATIENTS AND METHODS A retrospective review was conducted of 93 patients with prostate volumes (PVs) ≥ 80 mL treated with PAE from April 2014 through October 2017. Mean patient age was 68.5 years (range 52-88) and mean age-adjusted Charlson comorbidity index was 3.2 (range 1-8). Exclusion criteria included history of biopsy-proven prostate cancer or catheter dependency. Clinical and urodynamic outcomes were reviewed at 1, 3, 6, and 12 months. Adverse events were graded according to the Clavien-Dindo classification. RESULTS Mean PV decreased significantly from 141.7 mL to 98.1 mL at 3 months (P < .01) and 82.2 mL at 12 months (P < .01). Significant improvements were seen in 3- and 12-month mean International Prostate Symptom Scores (IPSS) (22.3 vs 7.1 and 7.3, respectively; P < .01 for both), quality of life (QOL) (4.4 vs 1.2 and 1.3; P < .01 for both), and postvoid residual volume (196.7mL vs 92.1 and 61.2 mL; P < .01 and P < .01, respectively). Significant improvement was also seen in 3-month mean maximum urinary flow: 7.7 mL/s vs 12.8 mL/s (P < .01). One grade II complication of stroke occurred; all other complications were self-limited and grade I. CONCLUSIONS PAE achieved a clinically and statistically significant improvement in symptom burden and secondary outcome measures in patients with PVs ≥ 80 mL. PAE may be an alternate treatment for patients for whom conventional surgical options are limited or associated with significant morbidity.

Efficacy of Prostatic Artery Embolization for Catheter-Dependent Patients with Large Prostate Sizes and High Comorbidity Scores

PURPOSE To evaluate efficacy and safety of prostate artery embolization (PAE) in urinary catheter-dependent patients with large prostate volumes and high comorbidity scores. MATERIALS AND METHODS A retrospective single-center review was conducted of 30 patients with urinary retention at time of PAE from November 2014 through February 2017. Mean (range) age was 73.1 years (48-94 y), age-adjusted Charlson comorbidity index was 4.5 (0-10), duration of urinary retention was 63.4 days (2-224 d), International Prostate Symptom Score quality-of-life (IPSS-QOL) was 5.3 (3-6), and prostate volume was 167.3 cm3 (55-557 cm3). These parameters were collected at 3, 6, and 12 months after PAE. Trials of voiding were performed approximately 2 weeks after PAE and, if failed, every 2 weeks thereafter. Adverse events were graded using the Clavien-Dindo classification. RESULTS At a mean (range) of 18.2 days (1-72 d), 26 (86.7%) patients were no longer reliant on catheters. Follow-up was obtained in all patients eligible at 3 and 6 months and 17 of 20 (85.0%) patients eligible at 1 year. Mean (range) IPSS-QOL improved significantly to 1.2 (0-5), 0.7 (0-4), and 0.6 (0-4) at 3, 6, and 12 months (all P < .001). Mean (range) prostate volume decreased significantly to 115.9 cm3 (27-248 cm3) at 3 months (P < .001). Two patients experienced grade II urosepsis complications, which were successfully treated with intravenous antibiotics. All other complications were self-limited grade I complications. CONCLUSIONS PAE represents a safe and effective option for management of patients with urinary retention, especially patients with large prostates who are not ideal surgical candidates.