Matthew Ferroni

eNOS transfection of adipose‐derived stem cells yields bioactive nitric oxide production and improved results in vascular tissue engineering

This study evaluates the durability of a novel tissue engineered blood vessel (TEBV) created by seeding a natural vascular tissue scaffold (decellularized human saphenous vein allograft) with autologous adipose‐derived stem cells (ASC) differentiated into endothelial‐like cells. Previous work with this model revealed the graft to be thrombogenic, likely due to inadequate endothelial differentiation as evidenced by minimal production of nitric oxide (NO). To evaluate the importance of NO expression by the seeded cells, we created TEBV using autologous ASC transfected with the endothelial nitric oxide synthase (eNOS) gene to produce NO. We found that transfected ASC produced NO at levels similar to endothelial cell (EC) controls in vitro which was capable of causing vasorelaxation of aortic specimens ex vivo. TEBV (n = 5) created with NO‐producing ASC and implanted as interposition grafts within the aorta of rabbits remained patent for two months and demonstrated a non‐thrombogenic surface compared to unseeded controls (n = 5). Despite the xenograft nature of the scaffold, the TEBV structure remained well preserved in seeded grafts. In sum, this study demonstrates that upregulation of NO expression within adult stem cells differentiated towards an endothelial‐like lineage imparts a non‐thrombogenic phenotype and highlights the importance of NO production by cells to be used as endothelial cell substitutes in vascular tissue engineering applications. Copyright

Role of the brain stem in tibial inhibition of the micturition reflex in cats.

This study examined the role of the brain stem in inhibition of bladder reflexes induced by tibial nerve stimulation (TNS) in α-chloralose-anesthetized decerebrate cats. Repeated cystometrograms (CMGs) were performed by infusing saline or 0.25% acetic acid (AA) to elicit normal or overactive bladder reflexes, respectively. TNS (5 or 30 Hz) at three times the threshold (3T) intensity for inducing toe movement was applied for 30 min between CMGs to induce post-TNS inhibition or applied during the CMGs to induce acute TNS inhibition. Inhibition was evident as an increase in bladder capacity without a change in amplitude of bladder contractions. TNS applied for 30 min between saline CMGs elicited prolonged (>2 h) poststimulation inhibition that significantly (P < 0.05) increased bladder capacity to 30-60% above control; however, TNS did not produce this effect during AA irritation. TNS applied during CMGs at 5 Hz but not 30 Hz significantly (P < 0.01) increased bladder capacity to 127.3 ± 6.1% of saline control or 187.6 ± 5.0% of AA control. During AA irritation, naloxone (an opioid receptor antagonist) administered intravenously (1 mg/kg) or directly to the surface of the rostral brain stem (300-900 μg) eliminated acute TNS inhibition and significantly (P < 0.05) reduced bladder capacity to 62.8 ± 22.6% (intravenously) or 47.6 ± 25.5% (brain stem application). Results of this and previous studies indicate 1) forebrain circuitry rostral to the pons is not essential for TNS inhibition; and 2) opioid receptors in the brain stem have a critical role in TNS inhibition of overactive bladder reflexes but are not involved in inhibition of normal bladder reflexes.

Role of µ, κ, and δ Opioid Receptors in Tibial Inhibition of Bladder Overactivity in Cats

In α-chloralose anesthetized cats, we examined the role of opioid receptor (OR) subtypes (µ, κ, and δ) in tibial nerve stimulation (TNS)-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.25% acetic acid (AA). The sensitivity of TNS inhibition to cumulative i.v. doses of selective OR antagonists (cyprodime for µ, nor-binaltorphimine for κ, or naltrindole for δ ORs) was tested. Naloxone (1 mg/kg, i.v., an antagonist for µ, κ, and δ ORs) was administered at the end of each experiment. AA caused bladder overactivity and significantly (P < 0.01) reduced bladder capacity to 21.1% ± 2.6% of the saline control. TNS at 2 or 4 times threshold (T) intensity for inducing toe movement significantly (P < 0.01) restored bladder capacity to 52.9% ± 3.6% or 57.4% ± 4.6% of control, respectively. Cyprodime (0.3–1.0 mg/kg) completely removed TNS inhibition without changing AA control capacity. Nor-binaltorphimine (3–10 mg/kg) also completely reversed TNS inhibition and significantly (P < 0.05) increased AA control capacity. Naltrindole (1–10 mg/kg) reduced (P < 0.05) TNS inhibition but significantly (P < 0.05) increased AA control capacity. Naloxone (1 mg/kg) had no effect in cyprodime pretreated cats, but it reversed the nor-binaltorphimine–induced increase in bladder capacity and eliminated the TNS inhibition remaining in naltrindole pretreated cats. These results indicate a major role of µ and κ ORs in TNS inhibition, whereas δ ORs play a minor role. Meanwhile, κ and δ ORs also have an excitatory role in irritation-induced bladder overactivity.

Androgen Suppression Strategies for Prostate Cancer: Is There an Ideal Approach?

Androgen suppression therapy (AST) was first described in 1941 as a treatment of prostate cancer (PCa) and remains the mainstay of therapy in patients with hormone-naïve metastatic disease. It also is used in locally advanced or recurrent disease and in combination with radiation therapy in patients with higher-risk features. Several approaches to AST have been developed as a result of increased understanding of the pathways controlling testosterone production. Increased recognition of the side effects has resulted in strategies to minimize complications associated with AST. Attempts to reduce AST adverse effects include intermittent hormonal therapy and methods to reduce amount of intracellular androgens without reducing the circulating testosterone levels.

Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats

This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.

Segmental testicular infarction due to minocycline-induced antineutrophil cytoplasmic antibody--positive vasculitis.

Segmental testicular infarction is an uncommon clinical entity marked by acute scrotal pain and swelling. Classically, these appear as wedge-shaped, avascular, hypoechoic lesions on a testicular ultrasound. We present a unique case of testicular infarct caused by an antineutrophil cytoplasmic antibody-positive vasculitis secondary to the use of the antibiotic minocycline. The patients symptoms resolved with cessation of minocycline. We suggest that patients who present with otherwise unexplained testicular infarction undergo a careful review of medications to uncover a potential cause.

Transcutaneous Electrical Nerve Stimulation of the Foot: Results of a Novel At-home, Noninvasive Treatment for Nocturnal Enuresis in Children

OBJECTIVE To evaluate the effect of a novel at-home approach to electrical foot stimulation of peripheral tibial nerve branches on the frequency of nocturnal enuresis episodes in children. MATERIALS AND METHODS Children aged 5 to 18 having 2 or more bedwetting episodes per week for at least 3 consecutive months were eligible. The study was a total of 6 weeks. Participants completed a baseline nighttime voiding diary during the first 2 weeks. This was followed by 2 weeks of foot stimulation for 60 minutes each night. During the stimulation period, and the following 2 weeks poststimulation, participants completed the nighttime voiding diary. RESULTS Twenty-two patients with a mean age of 11.4 years (range 7-16) completed the study. Overall, there was a significant reduction in mean total wet nights from 9.0 ± 4.0 to 6.8 ± 4.8 during the stimulation period (P < .01) and a sustained significant reduction to 7.2 ± 5.0 wet nights during the poststimulation period (P = .02). Sixteen patients (72.7%) showed improvement of at least 1 less wet night during stimulation, demonstrating a significant improvement from a mean of 7.9 ± 3.7 to 4.8 ± 3.5 wet nights during the 2-week stimulation (P < .01) and maintained an improved mean of 5.1 ± 4.0 wet nights during the poststimulation period (P < .01). There were no adverse events experienced by any child. CONCLUSION Transcutaneous foot stimulation is a well-tolerated, noninvasive, at-home treatment that may reduce the number of wet nights in children with nocturnal enuresis.

Short-term Outcomes of Intraoperative Cell Saver Transfusion During Open Partial Nephrectomy.

OBJECTIVE To determine whether transfusion using the Cell Saver system is associated with inferior outcomes in patients undergoing open partial nephrectomy. METHODS All patients who underwent open partial nephrectomy by a single surgeon (BJD) from August 2008 to April 2015 were retrospectively identified. Operations were grouped and compared according to whether they included a transfusion using the Cell Saver intraoperative cell salvage system. RESULTS Sixty-nine open partial nephrectomies in 67 patients were identified. Thirty-three procedures (48%) included a Cell Saver transfusion. Most tumors were clear cell renal cell carcinoma (62%) and stage T1a (68%). There were no significant differences between groups for any measured clinical or pathologic characteristics. Operations including a Cell Saver transfusion were longer (141 vs 108 minutes, P <.001), had significantly greater blood loss (600 vs 200 mL, P <.001), and had longer median renal ischemia times (15 vs 10 minutes, P = .03). There were no significant differences in postoperative complication rate (21% vs 17%, P = .83) or median length of hospital stay (3 vs 3 days, P = .09). At a median follow-up of 23 months (interquartile range: 8-42 months), 1 patient in the non-Cell Saver transfusion group had cancer recurrence. There was no metastatic progression or cancer-specific mortality in either group. CONCLUSION Cell Saver transfusion during open partial nephrectomy was not associated with inferior outcomes with short-term follow-up, and no patients developed metastatic disease.

Asymptomatic Bacteriuria in Noncatheterized Adults

Asymptomatic bacteriuria (ASB) is a common finding and frequently detected in premenopausal nonpregnant women, institutionalized patients, patients with diabetes mellitus, and the ambulatory elderly population. Despite clear recommendations regarding diagnosis and management of ASB in these populations from the Infectious Diseases Society of America (IDSA), there remains an alarming rate of antimicrobial overuse. This article reviews definitions of ASB, epidemiology of ASB, literature surrounding ASB in diabetic patients, risk factors of ASB, microbiologic data regarding bacterial virulence, use of ASB strains for treatment of symptomatic urinary tract infection, and approaches to addressing translational barriers to implementing IDSA recommendations regarding diagnosis and management of ASB.

Vitamin D Repletion in Kidney Stone Formers: A Randomized Controlled Trial

Purpose: Vitamin D deficiency is often detected during metabolic evaluation in the nephrolithiasis population. Multiple vitamin D repletion protocols exist, although their differing impact on urinary stone formation risk factors is unclear. Materials and Methods: Patients with a history of calcium stones and vitamin D deficiency (less than 30 ng/ml) were randomized to receive either 1,000 IU daily or 50,000 IU weekly of vitamin D supplementation for 6 weeks. Patients completed a pretreatment and posttreatment serum vitamin D level evaluation and 24‐hour urine collections to assess the response and any changes in urine stone formation risk parameters. Results: A total of 21 patients completed the study, including 8 who received 1,000 IU daily and 13 who received 50,000 IU weekly. The 50,000 IU weekly group showed a significant increase in median serum vitamin D levels of 23 ng/ml (135%, p <0.01), while the 1,000 IU daily group showed a nonsignificant median increase of 9 ng/ml (49%, p = 0.12). Post‐repletion 24‐hour urine analysis demonstrated no significant change in urine calcium between the groups, including a median change of −11 mg (IQR −143–29) in patients receiving 1,000 IU and −16 mg (IQR −42–66) in those receiving 50,000 IU. Between the groups there was no significant difference in the supersaturation of calcium oxalate or calcium phosphate. Conclusions: High dose and low dose vitamin D repletion had no effect on urine calcium excretion or the supersaturation of calcium salts in known stone formers. The higher dosing regimen, which had superior repletion, may be the optimal protocol in patients with vitamin D deficiency.