Temporal Alterations in Cerebrovascular Glycocalyx and Cerebral Blood Flow after Exposure to a High-Intensity Blast in Rats.

The glycocalyx is a proteoglycan-glycoprotein structure lining the luminal surface of the vascular endothelium and is susceptible to damage due to blast overpressure (BOP) exposure. The glycocalyx is essential in maintaining the structural and functional integrity of the vasculature and regulation of cerebral blood flow (CBF). Assessment of alterations in the density of the glycocalyx; its components (heparan sulphate proteoglycan (HSPG/syndecan-2), heparan sulphate (HS), and chondroitin sulphate (CS)); CBF; and the effect of hypercapnia on CBF was conducted at 2-3 h, 1, 3, 14, and 28 days after a high-intensity (18.9 PSI/131 kPa peak pressure, 10.95 ms duration, and 70.26 PSI·ms/484.42 kPa·ms impulse) BOP exposure in rats. A significant reduction in the density of the glycocalyx was observed 2-3 h, 1-, and 3 days after the blast exposure. The glycocalyx recovered by 28 days after exposure and was associated with an increase in HS (14 and 28 days) and in HSPG/syndecan-2 and CS (28 days) in the frontal cortex. In separate experiments, we observed significant decreases in CBF and a diminished response to hypercapnia at all time points with some recovery at 3 days. Given the role of the glycocalyx in regulating physiological function of the cerebral vasculature, damage to the glycocalyx after BOP exposure may result in the onset of pathogenesis and progression of cerebrovascular dysfunction leading to neuropathology.

Metabotropic Glutamate Receptor 2 Expression Is Chronically Elevated in Male Rats With Post-Traumatic Stress Disorder Related Behavioral Traits Following Repetitive Low-Level Blast Exposure.

Many military veterans who experienced blast-related traumatic brain injuries in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems that include depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast develop cognitive and PTSD-related behavioral traits that are present for more than 1 year after exposure. We previously reported that a group II metabotropic receptor (mGluR2/3) antagonist reversed blast-induced behavioral traits. In this report, we explored mGluR2/3 expression following blast exposure in male rats. Western blotting revealed that mGluR2 protein (but not mGluR3) was increased in all brain regions studied (anterior cortex, hippocampus, and amygdala) at 43 or 52 weeks after blast exposure but not at 2 weeks or 6 weeks. mGluR2 RNA was elevated at 52 weeks while mGluR3 was not. Immunohistochemical staining revealed no changes in the principally presynaptic localization of mGluR2 by blast exposure. Administering the mGluR2/3 antagonist LY341495 after behavioral traits had emerged rapidly reversed blast-induced effects on novel object recognition and cued fear responses 10 months following blast exposure. These studies support alterations in mGluR2 receptors as a key pathophysiological event following blast exposure and provide further support for group II metabotropic receptors as therapeutic targets in the neurobehavioral effects that follow blast injury.

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7-11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups (n = 10-13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

Progressive Transcriptional Changes in the Amygdala Implicate Neuroinflammation in the Effects of Repetitive Low-Level Blast Exposure in Male Rats.

Chronic mental health problems are common among military veterans who sustained blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a delayed fashion. We examined blast-induced alterations on the transcriptome in four brain areas (anterior cortex, hippocampus, amygdala, and cerebellum) across the time frame over which the PTSD-related behavioral phenotype develops. When analyzed at 6 weeks or 12 months after blast exposure, relatively few differentially expressed genes (DEGs) were found. However, longitudinal analysis of amygdala, hippocampus, and anterior cortex between 6 weeks and 12 months revealed blast-specific DEG patterns. Six DEGs (hyaluronan and proteoglycan link protein 1 [Hapln1], glutamate metabotropic receptor 2 [Grm2], purinergic receptor P2y12 [P2ry12], C-C chemokine receptor type 5 [Ccr5], phenazine biosynthesis-like protein domain containing 1 [Pbld1], and cadherin related 23 [Cdh23]) were found altered in all three brain regions in blast-exposed animals. Pathway enrichment analysis using all DEGs or those uniquely changed revealed different transcription patterns in blast versus sham. In particular, the amygdala in blast-exposed animals had a unique set of enriched pathways related to stress responses, oxidative phosphorylation, and mitochondrial dysfunction. Upstream analysis implicated tumor necrosis factor (TNF)α signaling in blast-related effects in amygdala and anterior cortex. Eukaryotic initiating factor eIF4E (EIF4e), an upstream regulator of P2ry12 and Ccr5, was predicted to be activated in the amygdala. Quantitative polymerase chain reaction (qPCR) validated longitudinal changes in two TNFα regulated genes (cathepsin B [Ctsb], Hapln1), P2ry12, and Grm2. These studies have implications for understanding how blast injury damages the brain and implicates inflammation as a potential therapeutic target.

Medical Expulsive Therapy for Urinary Stones: Future Trends and Knowledge Gaps.

CONTEXT: Medical expulsive therapy (MET) for ureteral stones has become a controversial area due to the contradictory results of high-quality trials and meta-analyses. OBJECTIVE: We aimed to review the literature to evaluate the value of and future directions for MET for ureteral stone disease. EVIDENCE ACQUISITION: A literature search of the MEDLINE database and the Cochrane Library was conducted to collect articles about MET for ureteral calculi published up to 28 October 2018. A total of 524 articles were screened. Sixty-nine publications that met the inclusion criteria for this review were chosen. Among the primary research articles on MET with stone clearance as the primary outcome, seven responded to high-quality requirements of Cochrane Collaboration's tool for assessing the risk of bias in randomised trials. EVIDENCE SYNTHESIS: The vast majority of randomised, double-blind, placebo-controlled trials without a high or an unclear risk of bias did not find a benefit of MET for increased ureteral stone passage rates. This is in contrast to results of meta-analyses that are skewed by low-quality trials. CONCLUSIONS: The strength of evidence for the benefit of MET in ureteral stones is low, even for distal ureteral stones >5 mm. In the absence of further high-quality data, individual clinicians are required to decide for themselves whether to believe high-quality single trials or meta-analyses. PATIENT SUMMARY: We evaluated the value of and future directions for medical expulsive therapy (MET) for ureteral stone disease. We found that outcomes varied between studies. Individual clinicians are required to decide for themselves which studies to believe. Alpha-blockers as MET may retain a role in a selective group of well-counselled patients with larger stones who understand the side effects and off-label use.

Peroxide-treated metal-organic framework templated adsorbents for remediation of high level nuclear waste.

Remediation of legacy nuclear waste is one of the greatest challenges faced by the US Department of Energy, with projected cleanup efforts requiring over five decades and hundreds of billions of dollars. New materials are necessary to accelerate waste processing, achieving time and financial savings. Herein we report a peroxide treatment to a Ti metal-organic framework (MOF) and related MOF-templated adsorbents. The resulting materials displayed exceptional affinity for Am(III), achieving distribution coefficients in excess of 105 mL/g, and out-performing state-of-the-art benchmarks monosodium titanate (MST) and peroxo-treated modified MST (mMST) for removal of 85Sr(II) and 239, 240Pu(IV) from legacy nuclear waste simulant.

The Role of Medical Expulsive Therapy for Ureteral Stones: Against MET.

We no longer advocate the use of medical expulsive therapy in our patients. We also believe that the European Association of Urology guidelines group should believe the findings of the SUSPEND study and stop advocating the use of medical expulsive therapy.

Prostatic urethral lift vs transurethral resection of the prostate: 2-year results of the BPH6 prospective, multicentre, randomized study.

OBJECTIVES: To compare prostatic urethral lift (PUL) with transurethral resection of the prostate (TURP) with regard to symptoms, recovery experience, sexual function, continence, safety, quality of life, sleep and overall patient perception. PATIENTS AND METHODS: A total of 80 patients with lower urinary tract symptoms attributable to benign prostatic hyperplasia (BPH) were enrolled in a prospective, randomized, controlled, non-blinded study conducted at 10 European centres. The BPH6 responder endpoint assessed symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation and safety. Additional evaluations of patient perspective, quality of life and sleep were prospectively collected, analysed and presented for the first time. RESULTS: Significant improvements in International Prostate Symptom Score (IPSS), IPSS quality of life (QoL), BPH Impact Index (BPHII), and maximum urinary flow rate (Qmax ) were observed in both arms throughout the 2-year follow up. Change in IPSS and Qmax in the TURP arm were superior to the PUL arm. Improvements in IPSS QoL and BPHII score were not statistically different between the study arms. PUL resulted in superior quality of recovery, ejaculatory function preservation and performance on the composite BPH6 index. Ejaculatory function bother scores did not change significantly in either treatment arm. TURP significantly compromised continence function at 2 weeks and 3 months. Only PUL resulted in statistically significant improvement in sleep. CONCLUSION: PUL was compared to TURP in a randomised, controlled study which further characterized both modalities so that care providers and patients can better understand the net benefit when selecting a treatment option.

Prospective, randomized, multinational study of prostatic urethral lift versus transurethral resection of the prostate: 12-month results from the BPH6 study.

BACKGROUND: Transurethral resection of the prostate (TURP) is considered the gold standard for male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). However, TURP may lead to sexual dysfunction and incontinence, and has a long recovery period. Prostatic urethral lift (PUL) is a treatment option that may overcome these limitations. OBJECTIVE: To compare PUL to TURP with regard to LUTS improvement, recovery, worsening of erectile and ejaculatory function, continence and safety (BPH6). DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized, controlled trial at 10 European centers involving 80 men with BPH LUTS. INTERVENTION: PUL or TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The BPH6 responder endpoint assesses symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation, and safety. Noninferiority was evaluated using a one-sided lower 95% confidence limit for the difference between PUL and TURP performance. RESULTS AND LIMITATIONS: Preservation of ejaculation and quality of recovery were superior with PUL (p<0.01). Significant symptom relief was achieved in both treatment arms. The study demonstrated not only noninferiority but also superiority of PUL over TURP on the BPH6 endpoint. Study limitations were the small sample size and the inability to blind participants to enrollment arm. CONCLUSIONS: Assessment of individual BPH6 elements revealed that PUL was superior to TURP with respect to quality of recovery and preservation of ejaculatory function. PUL was superior to TURP according to the novel BPH6 responder endpoint, which needs to be validated in future studies. PATIENT SUMMARY: In this study, participants who underwent prostatic urethral lift responded significantly better than those who underwent transurethral resection of the prostate as therapy for benign prostatic hyperplasia with regard to important aspects of quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT01533038.

Methods to reduce the contraction of tissue-engineered buccal mucosa for use in substitution urethroplasty.

BACKGROUND: We previously described the production and clinical outcomes of tissue-engineered buccal mucosa (TEBM) used to treat recurrent urethral strictures. In this study, two patients developed a recurrent stricture and there was also evidence of graft contraction. OBJECTIVE: Assess possible preclinical methods to reduce contraction of TEBM. DESIGN, SETTING AND PARTICIPANTS: Using the model of TEBM in use clinically (ie, oral keratinocytes and fibroblasts cultured on de-epidermised acellular dermal scaffold), three methods of reducing TEBM contraction were investigated in vitro. INTERVENTIONS: The techniques assessed were pretreatment of de-epidermised dermis (DED) with glutaraldehyde, culture with ß-aminopropionitrile (ß-APN; a lysyl oxidase inhibitor), and physical restraint of TEBM grafts during culture. MEASUREMENTS: Contraction was assessed using serial digital image analysis. The cytotoxicity of the pharmacologic manipulations was assessed using monolayer cultures of oral mucosa cells. RESULTS AND LIMITATIONS: Control TEBM lost a mean of 45.4% of its original surface area over 28 d of culture. Treating TEBM with glutaraldehyde, ß-APN, or mechanical restraint during culture all significantly inhibited graft contraction. Glutaraldehyde treatment was most effective (only 5.5% loss of area with 0.1% glutaraldehyde), followed by mechanical restraint for at least 7 d (21.4% loss of area), and then ß-APN (28.7% loss of area). None of the treatments had any significant effect on cell viability. This in vitro study identifies solutions for graft contracture to explore in the clinic. CONCLUSIONS: Glutaraldehyde pretreatment and restraint of TEBM grafts during culture both reduce graft contraction.

A systematic review of graft augmentation urethroplasty techniques for the treatment of anterior urethral strictures.

CONTEXT: Reconstructive surgeons who perform urethroplasty have a variety of techniques in their armamentarium that may be used according to factors such as aetiology, stricture position, and length. No one technique is recommended. OBJECTIVE: Our aim was to assess the reported outcomes of the various techniques for graft augmentation urethroplasty according to site of surgery. EVIDENCE ACQUISITION: We performed an updated systematic review of the Medline literature from 1985 to date and classified the data according to the site of surgery and technique used. Data are also presented on the type of graft used and the follow-up methodology used by each centre. EVIDENCE SYNTHESIS: More than 2000 anterior urethroplasty procedures have been described in the literature. When considering the bulbar urethra there is no significant difference between the average success rates of the dorsal and the ventral onlay procedures, 88.4% and 88.8% at 42.2 and 34.4 mo in 934 and 563 patients, respectively. The lateral onlay technique has only been described in six patients and has a reported success rate of 83% at 77 mo. The Asopa and Palminteri techniques have been described in 89 and 53 patients with a success rate of 86.7% and 90.1% at 28.9 and 21.9 mo, respectively. When considering penile strictures, the success rate of the two-stage penile technique is significantly better than the one-stage penile technique, 90.5% versus 75.7% as calculated for 129 and 432 patients, respectively, although the follow-up of one-stage procedures was longer at 32.8 mo compared with 22.2 mo. CONCLUSIONS: There is no evidence in the literature of a difference between one-stage techniques for urethroplasty of the bulbar urethra. The two-stage technique has better reported outcomes than a one-stage approach for penile urethroplasty but has a shorter follow-up.

Surgical techniques in substitution urethroplasty using buccal mucosa for the treatment of anterior urethral strictures.

OBJECTIVES: Since the resurgence in the use of buccal mucosa (BM) in substitution urethroplasty in the late 1980s and early 1990s, there has been controversy as to which surgical technique is the most appropriate for its application. METHODS: The authors performed an updated literature review. Several centres have published widely on this topic, and the points considered include the use BM in dorsal onlay grafts, ventral onlay grafts, and tubularised grafts and the role of two-stage procedures. RESULTS: In experienced hands, the outcomes of both dorsal onlay grafts and ventral onlay grafts in bulbar urethroplasty are similar. The dorsal onlay technique is, however, possibly less dependent on surgical expertise and therefore more suitable for surgeons new to the practice of urethroplasty. The complications associated with ventral onlay techniques can be minimised by meticulous surgical technique, but in series with longer follow-up, complications still tend to be more prevalent. In penile urethroplasty, two-stage dorsal onlay of BM (after complete excision of the scarred urethra) still provides the best results, although in certain circumstances a one-stage dorsal onlay procedure is possible. In general, ventral onlay of BM and tube graft procedures in the management of penile strictures are associated with much higher rates of recurrence and should therefore be avoided. CONCLUSIONS: In experienced hands the results of the ventral and dorsal onlay of BM for bulbar urethroplasty are equivalent. Two-stage procedures are preferable in the penile urethra, except under certain circumstances when a one-stage dorsal onlay is feasible.

Tissue-engineered buccal mucosa urethroplasty-clinical outcomes.

INTRODUCTION: Whilst buccal mucosa is the most versatile tissue for urethral replacement, the quest continues for an ideal tissue replacement for the urethra when substantial tissue transfer is needed. Previously we described the development of autologous tissue-engineered buccal mucosa (TEBM). Here we report clinical outcomes of the first human series of its use in substitution urethroplasty. METHODOLOGY: Five patients with urethral stricture secondary to lichen sclerosus (LS) awaiting substantial substitution urethroplasty elected to undergo urethroplasty using TEBM, with full ethics committee support. Buccal mucosa biopsies (0.5 cm) were obtained from each patient. Keratinocytes and fibroblasts were isolated and cultured, seeded onto sterilised donor de-epidermised dermis, and maintained at air-liquid interface for 7-10 d to obtain full-thickness grafts. These grafts were used for urethroplasty in a one-stage (n=2) or a two-stage procedure (n=3). Follow-up was performed at 2 and 6 wk, at 3, 6, 9, and 12 mo, and every 6 mo thereafter. RESULTS: Follow-up ranged from 32 to 37 mo (mean, 33.6). The initial graft take was 100%, as assessed by visual inspection. Subsequently, one patient had complete excision of the grafted urethra and one required partial graft excision, for fibrosis and hyperproliferation of tissue, respectively. Three patients have a patent urethra with the TEBM graft in situ, although all three required some form of instrumentation. CONCLUSIONS: Whilst TEBM may in the future offer a clinically useful autologous urethral replacement tissue, in this group of patients with LS urethral strictures, it was not without complications, namely fibrosis and contraction in two of five patients.

Botulinum toxin injections for neurogenic and idiopathic detrusor overactivity: A critical analysis of results.

OBJECTIVE: In recent years there has been an increasing use of the botulinum neurotoxins for the management of conditions characterised by detrusor overactivity. Early studies showed promising results in an area where few options previously existed between pharmacotherapy and surgery. This has led to an urgent need to assess the wide range of techniques and therapies available, as well as the efficacy and tolerability of the treatment. We performed a critical analysis of the numerous clinical studies for this novel treatment option in the management of neurogenic and idiopathic detrusor overactivity, with a view to directing further research and assisting urologists in the management of these conditions. METHODS: A systematic review of the literature, as well as a search for abstracts presented to relevant peer-reviewed meetings, was performed. All articles from 1988 onwards were included, prior to which no articles describing urologic use of botulinum neurotoxins had been published, although the majority of the articles have been published since 2000. RESULTS AND CONCLUSIONS: Although many of the studies were small, overwhelming evidence supports the efficacy, safety, and tolerability of the botulinum toxins, specifically serotype A, for the management of these conditions. Before this is accepted as a widespread treatment modality, good-quality evidence from large-scale randomised controlled trials is needed. These studies should identify not only the most appropriate patients to treat but also the best dose, administration technique, and frequency for treatment.

Botulinum toxin in urinary incontinence.

PURPOSE OF REVIEW: In recent years, botulinum toxin has been investigated for treatment of lower urinary tract dysfunction. This review discusses recently published literature related to the role of botulinum toxin in treating incontinence, including the place for repeated treatment, the differing types of toxin available and the side effects of its use. RECENT FINDINGS: Botulinum toxin is safe and effective in improving both urodynamic and subjective parameters. The A serotype has a longer duration of action than the B serotype and has fewer systemic side effects; hence, it is more likely to gain favour as a suitable treatment, both in patients with neurogenic detrusor overactivity and those with idiopathic detrusor overactivity. It is especially effective in reducing incontinence associated with detrusor overactivity, and repeated treatments appear safe and efficacious. A better understanding of urothelial physiology suggests that botulinum toxin not only has efferent effects but also acts on afferent pathways. The existing data as they stand at present would also suggest it to be safe in patients of all age groups. SUMMARY: Botulinum toxin is awaiting approval for use in lower urinary tract dysfunction. Studies have been carried out in varying populations, but few have used reduction in incontinence episodes as a primary end point. The short-term and long-term efficacy and safety of botulinum toxin as a treatment modality for those with lower urinary tract dysfunction, especially for those with detrusor overactivity refractory to anticholinergics, is, however, evidenced increasingly. Further investigation is needed, specifically large randomized placebo-controlled trials, to determine the ideal conditions for the use of botulinum toxin. Some such trials are underway and we look forward to their findings with interest.