Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay.

Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam. IL-1ß signal blockade with Anakinra has shown promising results in avoiding seizure recurrence and generalization in inflammatory refractory epilepsy. Inhibiting the IL-1ß converting enzyme (ICE)/caspase-1 is also being investigated as a possible target for managing drug-resistant epilepsies. Targeting the ATP-P2X7R signal, which activates the NLRP3 inflammasome and triggers inflammatory molecule release, is another avenue of research. Interestingly, astaxanthin has shown promise in attenuating neuroinflammation in SE by inhibiting the ATP-P2X7R signal. Furthermore, IL-6 blockade using tocilizumab has been effective in RSE and in reducing seizures in patients with febrile infection-related epilepsy syndrome (FIRES). Other potential approaches include the ketogenic diet, which may modulate pro-inflammatory cytokine production, and the use of cannabidiol (CBD), which has demonstrated antiepileptic, neuroprotective, and anti-inflammatory properties, and targeting HMGB1-TLR4 axis. Clinical experience with anti-cytokine agents such as Anakinra and Tocilizumab in SE is currently limited, although promising. Nonetheless, Etanercept and Rituximab have shown efficacy only in specific etiologies of SE, such as autoimmune encephalitis. Overall, targeting inflammatory pathways and cytokines shows potential as an innovative therapeutic option for drug-resistant epilepsies and SE, providing the chance of directly addressing its underlying mechanisms, rather than solely focusing on symptom control.

Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population.

BACKGROUND: With the increasing use of robotic surgery in the United States, the comparative effectiveness and differences in reimbursement of minimally invasive radical prostatectomy (MIRP) and open prostatectomy (ORP) in privately insured patients are unknown. Therefore, we sought to assess the differences in perioperative outcomes and hospital reimbursement in a privately insured patient population who were surgically treated for prostate cancer. METHODS: Using a large private insurance database, we identified 17,610 prostate cancer patients who underwent either MIRP or ORP from 2003 to 2010. The primary outcomes were length of stay (LOS), perioperative complications, 90-day readmissions rates and hospital reimbursement. Multivariable regression analyses were used to evaluate for differences in primary outcomes across surgical approaches. RESULTS: Overall, 8981 (51.0%) and 8629 (49.0%) surgically treated prostate cancer patients underwent MIRP and ORP, respectively. The proportion of patients undergoing MIRP markedly rose from 11.9% in 2003 to 72.5% in 2010 (P<0.001 for trend). Relative to ORP, MIRP was associated with a shorter median LOS (1.0 day vs 3.0 days; P<0.001) and lower adjusted odds ratio of perioperative complications (OR: 0.82; P<0.001). However, the 90-day readmission rates of MIRP and ORP were similar (OR: 0.99; P=0.76). MIRP provided higher adjusted mean hospital reimbursement compared with ORP (US $19,292 vs. US $17,347; P<0.001). CONCLUSIONS: Among privately insured patients diagnosed with prostate cancer, robotic surgery rapidly disseminated with over 70% of patients undergoing MIRP by 2009-2010. Although MIRP was associated with shorter LOS and modestly better perioperative outcomes, hospitals received higher reimbursement for MIRP compared with ORP.

Specialty bias in treatment recommendations and quality of life among radiation oncologists and urologists for localized prostate cancer.

BACKGROUND: Given the importance of physician attitudes about different treatments and the quality of life (QOL) in prostate cancer, we performed a national survey of specialists to assess treatment recommendations and perceptions of treatment-related survival and QOL. METHODS: We mailed a self-administered survey instrument to a random sample of 1366 specialists in the U.S. Respondents were asked for treatment recommendations and survival that varied by PSA levels and Gleason scores and estimate QOL outcomes. Pearson's chi-square and multivariable regression models were used to test for differences in each outcome. RESULTS: Response rates were similar for radiation oncologists (52.6%) and urologists (52.3%; P=0.92). Across all risk strata, urologists were more likely to recommend surgery than were radiation oncologists, for conditions ranging from PSA>20 and Gleason score 8-10 (35.2 vs. 0.2%; P<0.001) to PSA 4-10 and Gleason score 7 (87.5 vs. 20.9%; P<0.001). Radiation oncologists were also more likely to recommend radiation therapy relative to urologists (all P<0.001). From low- to high-risk prostate cancer, radiation oncologists and urologists perceived their treatment as being better for improving survival (all P<0.001). Each specialty also viewed their treatment as having less urinary incontinence (all P<0.001). CONCLUSIONS: Radiation oncologists and urologists both prefer the treatment modalities they offer, perceive them to be more effective and to lead to a better QOL. Patients may be receiving biased information, and a truly informed consent process with shared decision-making may be possible only if they are evaluated by both specialties before deciding upon a treatment course.

Strategies to enhance the efficacy of intravescical therapy for non-muscle invasive bladder cancer.

Transitional cell carcinoma (TCC) is the second most common urologic malignancy, and 70% of patients present with superficial, or non-muscle invasive disease (NMIBC). Bacillus Calmette-Guerin (BCG), currently the most effective intravesical agent at preventing disease recurrence, is the only therapy shown to inhibit disease progression. Unfortunately, approximately 20% of patients discontinue BCG due to local and systemic toxicity and more than 30% show evidence of recurrence; this has led to increased interest in alternate chemotherapeutic agents. Induction intravesical chemotherapy has shown comparable efficacy to BCG in select patients and the immediate perioperative instillation of chemotherapeutic agents has become standard of care. Clinical trial evidence demonstrating the efficacy of BCG plus interferon 2B, gemcitabine and anthracyclines (doxorubicin, epirubicin, valrubicin) in patients refractory or intolerant to BCG is accumulating. Phase I trials investigating alternative agents such as apaziquone, taxanes (docetaxel, paclitaxel), and suramin are reporting promising data. Current efforts are also being directed towards optimizing the administration of existing chemotherapeutic regimens, including the use of novel modalities including hyperthermia, photodynamic therapy, magnetically targeted carriers, and liposomes. Despite recent enthusiasm for new intravesical agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy and select patients with naive T1 tumors and aggressive features. Our aim in this report is to provide a comprehensive review of contemporary intravesical therapy options for NMIBC with an emphasis on emerging agents and novel treatment modalities.

Stem cell therapy for urethral sphincter regeneration.

In anatomical and functional studies of the human and animal urethra, the middle urethral contained rhabdosphincter is critical for maintaining continence. Transplanted stem cells may have the ability to undergo self renewal and multipotent differentiation, leading to sphincter regeneration. In addition, such cells may release, or be engineered to release, neurotrophins with subsequent paracrine recruitment of endogenous host cells to concomitantly promote a regenerative response of nerve-integrated muscle. Cell-based therapies are most often associated with the use of autologous multipotent stem cells, such as the bone marrow stromal cells. However, harvesting bone marrow stromal stem cells is difficult, painful, and may yield low numbers of stem cells upon processing. In contrast, alternative autologous adult stem cells such as muscle derived stem cells (MDSCs) and adipose-derived stem cells (ADSCs) can be easily obtained in large quantities and with minimal discomfort. This chapter aims to discuss the neurophysiology of stress urinary incontinence (highlighting the importance of the middle urethra); current injectable cell sources for endoscopic treatment; and the potential of MDSCs for the delivery of neurotrophic factors.

Validation of the Fournier's gangrene severity index in a large contemporary series.

PURPOSE: In this study we identified prognostic factors for survival and validated the accuracy of the Fournier's gangrene severity index in patients with Fournier's gangrene. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients diagnosed with Fournier's gangrene between 1996 and 2006. Fournier's gangrene severity index scores were assessed using a receiver operating characteristic curve. Using an outcome variable of inpatient mortality, univariate analyses were performed using the Mann-Whitney U, chi-square and Fisher exact tests. RESULTS: A total of 68 patients (79.4% male, mean age 55.8 +/- 15.2 years) diagnosed with Fournier's gangrene met the criteria for review. The inpatient mortality rate was 10% (7 patients). The mean Fournier's gangrene severity index score for survivors was 5.4 +/- 3.5 vs 10.9 +/- 4.7 for nonsurvivors (p = 0.006). Isolated Fournier's gangrene severity index and individual laboratory parameters associated with mortality included heart rate (p = 0.05), respiratory rate (p = 0.02), serum creatinine (p = 0.03), serum bicarbonate (p = 0.001), serum lactate (p = 0.001) and serum calcium (p = 0.03). Although mean total body surface area was only suggestive of an association (p = 0.169), abdominal wall (p = 0.004) or lower extremity (p = 0.005) involvement was associated with increased mortality. Using a Fournier's gangrene severity index score threshold of 9 (sensitivity 71.4%, specificity 90%) there was a 96% survival rate in patients with a Fournier's gangrene severity index of less than 9 and a 46% mortality rate in those with a Fournier's gangrene severity index of 9 or greater (p = 0.001, OR 22, 95% CI 3.5-139.7). CONCLUSIONS: The Fournier's gangrene severity index remains an objective and simple method to quantify the extent of metabolic aberration at presentation in patients with Fournier's gangrene. A Fournier's gangrene severity index threshold value of 9 is sensitive and specific for predicting mortality in this patient population.

Advances in pediatric urologic laparoscopy.

The spectrum of laparoscopic surgery in children has undergone a dramatic evolution. Initially used as a diagnostic modality for many pediatric urologists, complex as well as reconstructive procedures are now being performed laparoscopically. Laparoscopic orchiopexy and nephrectomy are well established and are being performed at many centers. Laparoscopic partial nephrectomy, adrenalectomy, and dismembered pyeloplasty series have reported shortened hospital stays and operative times that are comparable to that of open techniques or are decreasing with experience. The initial experiences with laparoscopic ureteral reimplantation and laparoscopic-assisted bladder reconstructive surgery have been described, reporting encouraging results with regards to feasibility, hospital stay, and cosmetic outcome. This report will provide a directed review of the literature to establish the current indications for laparoscopy in pediatric urologic surgery.

Subcutaneous reservoir placement during penile prosthesis implantation.

Currently, the prosthesis of choice for patients undergoing penile prosthesis surgery is a three piece inflatable device, as this provides optimal inflation and deflation when compared to a one or two piece prosthesis. However, prior pelvic surgery or radiation therapy can obliterate the retropubic space and make placement of the reservoir required for a three piece prosthesis difficult. We report a novel location for reservoir placement in a man who had undergone multiple pelvic surgeries after suffering a severe pelvic crush injury.

Epilepsy and erectile dysfunction: a review.

The association between epilepsy and erectile dysfunction (ED) has often been described but not clearly defined. This is a review of the literature regarding the current theories on the causes of ED in epilepsy, as well as the evaluation and treatment options available.

Female gender exacerbates respiratory depression in leptin-deficient obesity.

Obese females are less predisposed to sleep-disordered breathing and have higher serum leptin levels than males of comparable body weight. Because leptin is a powerful respiratory stimulant, especially during sleep, we hypothesized that the elevated leptin level is necessary to maintain normal ventilatory control in obese females. We examined ventilatory control during sleep and wakefulness in male and female leptin-deficient obese C57BL/6J-Lep(ob) mice, wild-type C57BL/6J mice with dietary-induced obesity and high serum leptin levels, and normal weight wild-type C57BL/6J mice. Both male and female C57BL/6J-Lep(ob) mice had depressed hypercapnic ventilatory response (HCVR) in comparison with wild-type animals. In comparison with male C57BL/6J-Lep(ob) mice, female C57BL/6J-Lep(ob) mice had reduced HCVR and respiratory drive (a ratio of tidal volume to inspiratory time) both during non-rapid eye movement (NREM) sleep and wakefulness. In contrast, the HCVR did not differ between sexes in wild-type mice during NREM sleep and wakefulness, but was lower in females during REM sleep. Thus, leptin deficiency in female obesity is even more detrimental to hypercapnic ventilatory control during wakefulness and NREM sleep than in obese, leptin-deficient males.